and other acute lymphoblastic leukemia and AML. A number of JAK2 fusion proteins, such as TEL-JAK2, PCM1-JAK2, and BCR-JAK2, lead to activation of JAK kinase activity and have also been associated with myeloid and lymphoid leukemia or atypical CML [60, 72].

Along with other driver mutations connected with clonal expansion of hematopoietic cells, *JAK2* V617F mutation might also represent a feature of the aging hematopoietic system in individuals without a malignant disease [149, 150]. There is increasing evidence that *JAK2* V617F is relatively frequent in the aging healthy population and is presently estimated to be 0.5% [120]. These individuals usually present higher erythrocyte, platelet, and leucocyte counts and are more likely to develop a hematological cancer. Aging is generally associated with a deregulation of hematopoietic stem cells, which lose their function and become myeloid-biased and less quiescent as a consequence of intrinsic and environmental changes, with *JAK2* V617F hematopoietic stem cells having higher competitive properties in this context [120, 150].

#### *3.3.1 Prognosis and predictive factors*

*Tyrosine Kinases as Druggable Targets in Cancer*

of elevated hematocrit [119].

East Asians [139, 142].

separate clones [70, 140].

[102]. Mitotic recombination is more likely to occur in PV patients with mutation in exon 14 of the *JAK2* gene than in those with exon 12 mutations [133] and is an early genetic event in the development of PV, but not ET [102]. Although *JAK2* V617F homozygous subclones can be identified both in PV and ET patients, expression of a dominant homozygous subclone is almost exclusive in PV patients (~80% in PV and 50% in ET) [78, 119], originated by additional genetic or epigenetic events or, e.g., low levels of circulating erythropoietin in consequence

Although in the heterozygous state *JAK2* V617F-bearing receptors are still responsive to growth factors, in JAK2 V617F homozygosity, these receptors become

Almost all patients diagnosed with PV negative for *JAK2* V617F mutation are exon 12 positive (95% vs. 2–4%, respectively) [53, 103, 134–141]. Some studies have reported that Chinese PV patients have a relatively lower *JAK2* V617F mutation frequency (82%), in line with a Portuguese study [23], while the mutations in *JAK2* exon 12 are much more pervasive (13%), when compared to Westerns and other

Unlike *JAK2* V617F, which can be detected in any of the PN-MPNs, *JAK2* exon 12 mutations are almost exclusive of *JAK2* V617F-negative PV patients [24, 103]. PV patients who present *JAK2* exon 12 mutations, unlike those who are V617F positive, are not commonly homozygous [70, 103, 124, 138]. PV patients with the *JAK2* exon 12 mutations are usually younger than those with the *JAK2* V617F mutation and have a phenotype usually more benign than that of JAK2V617F, usually without panmyelosis [53], with normal leukocyte and platelet counts [61, 70]. Although *JAK2* V617F and exon 12 mutations express through the same C-terminal tyrosine kinase of JAK2, they originate very different phenotypic outcomes. These patients appear to be associated with a distinct syndrome, with higher hemoglobin concentrations, without concomitant leukocytosis or thrombocytosis (or minimal thrombocytosis), and isolated bone marrow erythroid hyperplasia [124], independently of the mutational variant [24, 124, 140]. The reasons for these various abnormal phenotypic readouts also remain unclear and are likely to be complex [124, 140]. The fact that exon 12 mutations are more frequently associated with erythrocytosis is consistent with their absence in ET but possible existence in PMF or AML secondary to PV [138]. However, there are exceptions as evidenced in some clinical reports [24]. Despite the phenotypical diversity, the clinical course and outcome seem overlapping between *JAK2* V617F and *JAK2* exon 12-positive patients, with convergent incidences of thrombosis, myelofibrosis, leukemia, and death [140]. There are also reports of the coexistence of *JAK2* V617F and *JAK2* exon 12 mutations as two

As published by Rumi and Cazzola [78], patients with the wild-type genotype for *JAK2* are extremely rare. However, a recent study [23] demonstrated a prevalence of 12.8% of patients with that genotype. This finding is consistent with the fact that the *JAK2* mutation expression alone may not be sufficient to induce the PV

Some reports have also suggested *JAK2* V617F clonal involvement of B [143, 144],

phenotype. However, larger studies are required to confirm this hypothesis.

T [143], and NK lymphocytes [83], also confirming the stem cell nature of *JAK2* V617F MPNs [102]. Lower frequencies of V617F mutation occur in PN-CML, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, and rare cases of AML (megakaryocytic and in combination with other well-defined genetic abnormalities, such as BCR-ABL1) [145]. There is also evidence of association with certain solid tumors (generally non-hematological types) [51, 114, 117, 146–148]. Other mutations in the JAK2 pseudokinase domain (including point mutations involving R683) have been detected in about 20% of Down syndrome-associated

autonomous with respect to growth factor [70], as referred earlier.

**28**

Besides mutations and other molecular defects, various factors, such as gene burden and individual genetic background, may be responsible for predisposition for developing an MPN, as well as influence their heterogeneity [78, 97].

Several published data have shown the contribution and influence of *JAK2* V617F mutation allelic burden in the definition of phenotype and prognostic impact in PN-MPNs [151, 152]. *JAK2* V617F allelic burden corresponds to the ratio between mutant and wild-type *JAK2* in hematopoietic cells and is on the basis of a stronger activation of intracellular signaling pathways [153]. Between MPN patients there is a variability in the number of cells carrying the *JAK2* V617F mutation, and there is a variability in the alleles that carry the mutation.

It is recognized that the allele burden tends to be higher in PV (due to the higher number of homozygous cases) and PMF, associated with the presence of acquired UPD, with defined hematological and clinical markers indicative of a more aggressive phenotype [153]. Indeed, a lower allele burden is generally observed in ET patients [97, 119, 152, 154, 155], but when it increases, some of them transform over time to PV or PMF. Importantly, ET patients positive for the *JAK2* V617F mutation have a "PV-like" phenotype compared to ET patients without this genetic abnormality. However, patients carrying *JAK2* V617F mutation do not have a higher risk of evolution to post-PV and post-ET myelofibrosis than patients without the mutation [61].

Another possible explanation concerns the concept of a "pre-JAK2" phase in which additional somatic mutations or inherited predisposing alleles present before the mutation are responsible for the clonal hematopoiesis, determine the phenotype, influence the risk of progression to AML, and might even be responsible for generating the mutation or act synergistically [55, 61]. In fact, although *JAK2* V617F mutation is crucial to the pathogenesis of PV, ET, and PMF, the existence of the same allele in three clinically distinct entities suggests that there might be additional inherited or acquired genetic predisposition. Indeed, a familial tendency has been identified in 72 families, which is consistent with an inherited genetic predisposition to MPNs [156].

On the other hand, the role of the *JAK2* V617F mutation in the pathogenicity of the various MPNs may differ among different MPNs, involving the *JAK2* V617F mutation more often than others (e.g., ET vs. PV), which would indicate other oncogenic mutations or factors that may be determinant for certain cases other than *JAK2* V617F [97, 119, 157, 158].

Moreover, mutations in epigenetic regulators, transcription factors, and signaling components modify the course of the disease and can contribute to disease initiation and/ or progression [55]. Some studies performed in mice and humans led to the "host genetic factor" concept, acting as modifiers in combination with the mutation, for instance, single nucleotide polymorphisms (SNPs) [90, 110, 111, 159, 160]. Even gender could be an independent modifier, with women having a lower allele burden than men [61].

Also, the coexistence of autonomous *JAK2* mutant and *JAK2* wild-type clonal populations in the same patient can be an explanation. It is observed that *JAK2* positive AML patients are preceded by evolution to myelofibrosis during their disease course, in contrast to *JAK2* wild-type AML, which is preceded by chronicphase ET and PV patients [61].

On the other hand, the role of the JAK/STAT signaling pathway in the pathogenesis of MPNs and other cancers is questionable when taking into account the example of rare families hosting germline mutations leading to weak JAK expression. The mutations induce a hereditary thrombocytosis, but hematopoiesis is polyclonal, and there is no generation of hematological malignancies or solid tumors, indicating that JAK/STAT activation alone does not drive malignant disease [147].

In PV and ET, risk factors influencing survival include older age, leukocytosis, and thrombosis. In ET, the *JAK2* V617F mutation is associated with increased risk of thrombosis, leading to inclusion into the International Prognostic Score of Thrombosis for ET-thrombosis score [90, 94, 161]. Expansion of *JAK2*-mutated allele promotes the transformation of PV and ET to secondary myelofibrosis [153]. Furthermore, the presence of two or more mutations is associated with a worse survival and predicts shortened leukemia-free survival [162].

*JAK2* V617F has not been correlated to an increased risk of transformation to AML [90]; nevertheless, *JAK2* V617F-positive patients with MPN diagnosis can transform to *JAK2* V617F-negative AML [163].

The pathogenesis of thrombosis in PN-MPN patients is complex, involving clinical factors such as age, previous history of thrombotic events, obesity, hypertension, and hyperlipemia, as well increased blood cell counts (i.e., leukocytosis, erythrocytosis, and thrombocytosis), high hematocrit, and *JAK2* mutation [164]. The most important risk factor for future arterial and venous thrombosis in MPNs is the previous history of arterial and venous thrombosis, respectively [9]. The influence of the *JAK2* V617F mutational status and allele burden on the thrombotic risk has been evaluated and established in several studies among PN-MPNs [90]; however, regarding the presence of *MPL* mutation, the published results are discrepant [164]. Older (age > 60 years) patients are no longer considered "high risk," unless they have a history of thrombosis or are *JAK2*-mutated [9, 164].

In patients with ET, the frequency of thromboembolic events in different studies ranges from 10 to 30% at diagnosis and between 8 and 31% during follow-up [165], and the rate of fatal and nonfatal thrombotic events ranged from 2 to 4% patientyears, with a predominance of arterial events [164], whose risk is higher in patients with *JAK2* and *MPL* mutations [90, 166].

Risk factors for fibrotic transformation in PV include *JAK2* V617F allele burden of >50%; in ET they include advanced age and anemia, with the presence of *JAK2* V617F being associated with a lower risk of fibrotic transformation and *CALR* with a higher risk [9]. *JAK2* V617F mutational status may have prognostic significance in PV, ET, and PMF [102]. In PV, despite the phenotypic differences, the clinical course seems similar between *JAK2* V617F and *JAK2* exon 12-positive patients, with similar incidences of thrombosis, myelofibrosis, leukemia, and death [24, 140]. *JAK2/CALR* mutational status did not affect survival in ET [9]. In PMF and ET, triple-negative patients appear to have a less favorable prognosis than patients with

**31**

*Non-receptor Tyrosine Kinases Role and Significance in Hematological Malignancies*

tend to have a better prognosis than patients with *JAK2* or *MPL* mutations.

a driver mutation (*JAK2*, *CALR*, or *MPL*), whereas patients with *CALR* mutations

Another important concern refers to the increased risk of generation of new non-hematological and nonmyeloid neoplasms in MPNs, with an incidence ratio of 1.2–1.4 and 3.4, respectively, compared to the general population [90, 167]. There is evidence that this risk is higher when *JAK2* V617F mutation is identified and other

The discovery of the *JAK2* mutations and their relation with the subsequent activation of the JAK-STAT pathway was crucial to the understanding of the pathogenesis of PV, ET, and PMF. This knowledge has led to the development of small-molecular *JAK* inhibitors to target autoimmune disease/immunosuppression (anti-*JAK1*, *JAK3*) and MPNs and leukemia/lymphoma (anti-*JAK2*, *JAK1*), which have been tested in several clinical trials, suggesting an overall reduction in JAK-STAT signaling and pro-inflammatory cytokines [141, 168, 169]. About 10 compounds were studied for MPNs, rheumatoid arthritis, psoriasis, and inflammatory bowel disease, all of them targeting the ATP-binding site of JAKs, but none is absolutely specific for any JAK [88]. Nevertheless, ruxolitinib (a *JAK1*, *JAK2* inhibitor, trade name Jakavi®) has been approved by the Food and Drug Administration (FDA) in November 2011, for use in myelofibrosis, and tofacitinib (a *JAK1*, J*AK3* inhibitor) has been approved for use in rheumatoid arthritis. The first two randomized controlled trials (Comfort I and II) on the effect of the JAK2 inhibitor ruxolitinib versus placebo and versus the best available therapy in intermediate-2 and high-risk PMF showed a decrease in spleen size and symptom burden in the experimental arm of both studies. In Comfort I, a survival benefit was also observed in the ruxolitinib arm compared to patients on placebo [170, 171]. Although ruxolitinib was recently approved for use in hydroxyurea-resistant PV, its role in routine clini-

The treatment options of PMF patients are currently limited, with stem cell transplant being the current treatment of choice for genetically or clinically high-risk disease. PMF patients may benefit from *JAK2* inhibition with immediate clinical value in the management of symptoms, through directly modulating the pro-growth signals of the JAK-STAT pathway, suppression of hematopoietic progenitor cell proliferation, and from downregulating specific pro-inflammatory

Ruxolitinib treatment substantially alleviates symptomatic splenomegaly and constitutional symptoms and improves quality of life in a significant proportion of patients with primary or post-PV/ET myelofibrosis [88]. Surprisingly, treatment with ruxolitinib is also effective in patients without mutated *JAK2*, suggesting that other, still unknown, underlying mechanisms are responsible for the increased JAK/ STAT pathway activity in PN-MPN patients. On the other hand, there is no convincing evidence of reduction in mutated allele burden, disease modification, nor

The identification of *JAK2* represented a milestone for the following studies and for today's knowledge, but the ongoing discovery of other mutations in MPNs will make possible the establishment of new drug targets and prognostic biomarkers that will for certain improve clinical practice and patients' outcome. All in all, it remains to be fully clarified whether *JAK2* mutations may be considered as "driver mutations" for MPNs or if they can act as "passenger mutations" which may alter-

*DOI: http://dx.doi.org/10.5772/intechopen.84873*

patient-related factors may be also present.

cal practice remains controversial [9, 52, 95, 172, 173].

cytokines produced by the affected clone [70, 113].

nate place with the former and have "driver" functions [129].

progression to AML [9, 174].

*3.3.2 Therapy management*

#### *Non-receptor Tyrosine Kinases Role and Significance in Hematological Malignancies DOI: http://dx.doi.org/10.5772/intechopen.84873*

a driver mutation (*JAK2*, *CALR*, or *MPL*), whereas patients with *CALR* mutations tend to have a better prognosis than patients with *JAK2* or *MPL* mutations.

Another important concern refers to the increased risk of generation of new non-hematological and nonmyeloid neoplasms in MPNs, with an incidence ratio of 1.2–1.4 and 3.4, respectively, compared to the general population [90, 167]. There is evidence that this risk is higher when *JAK2* V617F mutation is identified and other patient-related factors may be also present.

#### *3.3.2 Therapy management*

*Tyrosine Kinases as Druggable Targets in Cancer*

phase ET and PV patients [61].

Moreover, mutations in epigenetic regulators, transcription factors, and signaling components modify the course of the disease and can contribute to disease initiation and/ or progression [55]. Some studies performed in mice and humans led to the "host genetic factor" concept, acting as modifiers in combination with the mutation, for instance, single nucleotide polymorphisms (SNPs) [90, 110, 111, 159, 160]. Even gender could be an independent modifier, with women having a lower allele burden than men [61]. Also, the coexistence of autonomous *JAK2* mutant and *JAK2* wild-type clonal populations in the same patient can be an explanation. It is observed that *JAK2* positive AML patients are preceded by evolution to myelofibrosis during their disease course, in contrast to *JAK2* wild-type AML, which is preceded by chronic-

On the other hand, the role of the JAK/STAT signaling pathway in the pathogenesis of MPNs and other cancers is questionable when taking into account the example of rare families hosting germline mutations leading to weak JAK expression. The mutations induce a hereditary thrombocytosis, but hematopoiesis is polyclonal, and there is no generation of hematological malignancies or solid tumors, indicating

In PV and ET, risk factors influencing survival include older age, leukocytosis, and thrombosis. In ET, the *JAK2* V617F mutation is associated with increased risk of thrombosis, leading to inclusion into the International Prognostic Score of Thrombosis for ET-thrombosis score [90, 94, 161]. Expansion of *JAK2*-mutated allele promotes the transformation of PV and ET to secondary myelofibrosis [153]. Furthermore, the presence of two or more mutations is associated with a worse

*JAK2* V617F has not been correlated to an increased risk of transformation to AML [90]; nevertheless, *JAK2* V617F-positive patients with MPN diagnosis can

The pathogenesis of thrombosis in PN-MPN patients is complex, involving clinical factors such as age, previous history of thrombotic events, obesity, hypertension, and hyperlipemia, as well increased blood cell counts (i.e., leukocytosis, erythrocytosis, and thrombocytosis), high hematocrit, and *JAK2* mutation [164]. The most important risk factor for future arterial and venous thrombosis in MPNs is the previous history of arterial and venous thrombosis, respectively [9]. The influence of the *JAK2* V617F mutational status and allele burden on the thrombotic risk has been evaluated and established in several studies among PN-MPNs [90]; however, regarding the presence of *MPL* mutation, the published results are discrepant [164]. Older (age > 60 years) patients are no longer considered "high risk,"

In patients with ET, the frequency of thromboembolic events in different studies ranges from 10 to 30% at diagnosis and between 8 and 31% during follow-up [165], and the rate of fatal and nonfatal thrombotic events ranged from 2 to 4% patientyears, with a predominance of arterial events [164], whose risk is higher in patients

Risk factors for fibrotic transformation in PV include *JAK2* V617F allele burden of >50%; in ET they include advanced age and anemia, with the presence of *JAK2* V617F being associated with a lower risk of fibrotic transformation and *CALR* with a higher risk [9]. *JAK2* V617F mutational status may have prognostic significance in PV, ET, and PMF [102]. In PV, despite the phenotypic differences, the clinical course seems similar between *JAK2* V617F and *JAK2* exon 12-positive patients, with similar incidences of thrombosis, myelofibrosis, leukemia, and death [24, 140]. *JAK2/CALR* mutational status did not affect survival in ET [9]. In PMF and ET, triple-negative patients appear to have a less favorable prognosis than patients with

unless they have a history of thrombosis or are *JAK2*-mutated [9, 164].

that JAK/STAT activation alone does not drive malignant disease [147].

survival and predicts shortened leukemia-free survival [162].

transform to *JAK2* V617F-negative AML [163].

with *JAK2* and *MPL* mutations [90, 166].

**30**

The discovery of the *JAK2* mutations and their relation with the subsequent activation of the JAK-STAT pathway was crucial to the understanding of the pathogenesis of PV, ET, and PMF. This knowledge has led to the development of small-molecular *JAK* inhibitors to target autoimmune disease/immunosuppression (anti-*JAK1*, *JAK3*) and MPNs and leukemia/lymphoma (anti-*JAK2*, *JAK1*), which have been tested in several clinical trials, suggesting an overall reduction in JAK-STAT signaling and pro-inflammatory cytokines [141, 168, 169]. About 10 compounds were studied for MPNs, rheumatoid arthritis, psoriasis, and inflammatory bowel disease, all of them targeting the ATP-binding site of JAKs, but none is absolutely specific for any JAK [88]. Nevertheless, ruxolitinib (a *JAK1*, *JAK2* inhibitor, trade name Jakavi®) has been approved by the Food and Drug Administration (FDA) in November 2011, for use in myelofibrosis, and tofacitinib (a *JAK1*, J*AK3* inhibitor) has been approved for use in rheumatoid arthritis. The first two randomized controlled trials (Comfort I and II) on the effect of the JAK2 inhibitor ruxolitinib versus placebo and versus the best available therapy in intermediate-2 and high-risk PMF showed a decrease in spleen size and symptom burden in the experimental arm of both studies. In Comfort I, a survival benefit was also observed in the ruxolitinib arm compared to patients on placebo [170, 171]. Although ruxolitinib was recently approved for use in hydroxyurea-resistant PV, its role in routine clinical practice remains controversial [9, 52, 95, 172, 173].

The treatment options of PMF patients are currently limited, with stem cell transplant being the current treatment of choice for genetically or clinically high-risk disease. PMF patients may benefit from *JAK2* inhibition with immediate clinical value in the management of symptoms, through directly modulating the pro-growth signals of the JAK-STAT pathway, suppression of hematopoietic progenitor cell proliferation, and from downregulating specific pro-inflammatory cytokines produced by the affected clone [70, 113].

Ruxolitinib treatment substantially alleviates symptomatic splenomegaly and constitutional symptoms and improves quality of life in a significant proportion of patients with primary or post-PV/ET myelofibrosis [88]. Surprisingly, treatment with ruxolitinib is also effective in patients without mutated *JAK2*, suggesting that other, still unknown, underlying mechanisms are responsible for the increased JAK/ STAT pathway activity in PN-MPN patients. On the other hand, there is no convincing evidence of reduction in mutated allele burden, disease modification, nor progression to AML [9, 174].

The identification of *JAK2* represented a milestone for the following studies and for today's knowledge, but the ongoing discovery of other mutations in MPNs will make possible the establishment of new drug targets and prognostic biomarkers that will for certain improve clinical practice and patients' outcome. All in all, it remains to be fully clarified whether *JAK2* mutations may be considered as "driver mutations" for MPNs or if they can act as "passenger mutations" which may alternate place with the former and have "driver" functions [129].

#### **4. Conclusions and future perspectives**

Non-receptor tyrosine kinases play an important role in the development of human malignancies, including hematological and others, and of inflammatory, and autoimmune diseases, through their profound involvement in the regulation of several vital cellular mechanisms, including cell proliferation, differentiation, maturation, apoptosis, and survival.

Targeting dysregulated NRTKs may prevent the process of tumorigenesis. The screening and clinical use of tyrosine kinase inhibitors, in combination with conventional treatments, have allowed the potential of targeted-based cancer therapy using specific cancer cell molecules, which are less toxic than traditional cytotoxic chemotherapy. The establishment of effective strategies in cancer research and patient care is mandatory.

#### **Acknowledgements**

This revision included data obtained from patients and controls who generously participate to whom authors gratefully acknowledge. Appreciation and thankfulness are extended to Luísa Manso Oliveira and Inês Sousa for their expert technical assistance.

The mentioned work was supported by funding through project UID/ BIM/00009/2016 (Centre for Toxicogenomics and Human Health (ToxOmics), from Fundação para a Ciência e Tecnologia (FCT), Portugal.

#### **Conflict of interest**

The authors claim no competing financial or intellectual conflicts of interest in the preparation and submission of this chapter.

#### **Author details**

Ana Azevedo1,2\*, Susana Silva1 and José Rueff<sup>1</sup>

1 Faculty of Medical Sciences, NOVA Medical School, Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, NOVA University of Lisbon, Lisbon, Portugal

2 Department of Clinical Pathology, Hospital of São Francisco Xavier, West Lisbon Hospital Centre, Lisbon, Portugal

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**33**

*Non-receptor Tyrosine Kinases Role and Significance in Hematological Malignancies*

Clinical Medicine Insights: Oncology.

[11] Lamontanara AJ, Georgeon S, Tria G, Svergun DI, Hantschel O. The SH2 domain of ABL kinases regulates kinase autophosphorylation by controlling activation loop accessibility. Nature Communications. 2014;**5**:5470

[12] Gromicho M, Rueff J, Rodrigues AS. Dynamics of expression of drug transporters: Methods for appraisal. Methods in Molecular Biology.

[13] Gromicho M, Magalhães M, Torres F, Dinis J, Fernandes AR, Rendeiro P, et al. Instability of mRNA expression signatures of drug transporters in chronic myeloid leukemia patients resistant to imatinib. Oncology Reports.

[14] Gromicho M, Dinis J, Magalhães M, Fernandes AR, Tavares P, Laires A, et al. Development of imatinib and dasatinib resistance: Dynamics of expression of drug transporters ABCB1, ABCC1, ABCG2, MVP, and SLC22A1. Leukemia & Lymphoma.

[15] Voisset E, Lopez S, Dubreuil P, De Sepulveda P. The tyrosine kinase FES is an essential effector of KITD816V proliferation signal. Blood.

[16] Hellwig S, Miduturu CV, Kanda S, Zhang J, Filippakopoulos P, Salah E, et al. Small-molecule inhibitors of the c-FES protein-tyrosine kinase. Chemistry & Biology. 2012;**19**:529-540

[17] Condorelli F, Stec-Martyna E, Zaborowska J, Felli L, Gnemmi I, Ponassi M, et al. Role of the nonreceptor tyrosine kinase FES in cancer. Current Medicinal Chemistry.

2017;**11**:1179554917702870

2016;**1395**:75-85

2013;**29**:741-750

2011;**52**:1980-1990

2007;**110**:2593-2599

2011;**18**:2913-2920

*DOI: http://dx.doi.org/10.5772/intechopen.84873*

[1] Lahiry P, Torkamani A, Schork NJ, Hegele RA. Kinase mutations in human disease: Interpreting genotypephenotype relationships. Nature Reviews. Genetics. 2010;**11**:60-74

**References**

[2] Paul MK, Mukhopadhyay AK. Tyrosine kinase—Role and significance in cancer. International Journal of Medical Sciences. 2004;**1**:101-115

[3] Siveen KS, Prabhu KS, Achkar IW, Kuttikrishnan S, Shyam S, Khan AQ, et al. Role of non receptor tyrosine kinases in hematological malignances and its targeting by natural products.

Molecular Cancer. 2018;**17**:31

2011;**65**:819-828

[4] Kosior K, Lewandowska-Grygiel M, Giannopoulos K. Tyrosine kinase inhibitors in hematological malignancies. Postȩpy Higieny i Medycyny Doświadczalnej (Online).

[5] Du Z, Lovly CM. Mechanisms of receptor tyrosine kinase activation in cancer. Molecular Cancer. 2018;**17**:58

of inhibitors for protein tyrosine kinases. Oncogene. 2000;**19**:5690-5701

[7] Wang J, Pendergast AM. The emerging role of ABL kinases in solid tumors. Trends Cancer. 2015;**1**:110-123

[8] Sirvent A, Benistant C, Roche S. Cytoplasmic signalling by the c-ABL tyrosine kinase in normal and cancer cells. Biology of the Cell.

[9] Tefferi A. Myeloproliferative

of Hematology. 2016;**91**:50-58

neoplasms: A decade of discoveries and treatment advances. American Journal

[10] Azevedo AP, Reichert A, Afonso C, Alberca MD, Tavares P, Lima F. V280G mutation, potential role in imatinib resistance: First case report.

2008;**100**:617-631

[6] Al-Obeidi FA, Lam KS. Development

*Non-receptor Tyrosine Kinases Role and Significance in Hematological Malignancies DOI: http://dx.doi.org/10.5772/intechopen.84873*

#### **References**

*Tyrosine Kinases as Druggable Targets in Cancer*

maturation, apoptosis, and survival.

patient care is mandatory.

**Acknowledgements**

**Conflict of interest**

**Author details**

Ana Azevedo1,2\*, Susana Silva1

of Lisbon, Lisbon, Portugal

Hospital Centre, Lisbon, Portugal

assistance.

**4. Conclusions and future perspectives**

Non-receptor tyrosine kinases play an important role in the development of human malignancies, including hematological and others, and of inflammatory, and autoimmune diseases, through their profound involvement in the regulation of several vital cellular mechanisms, including cell proliferation, differentiation,

Targeting dysregulated NRTKs may prevent the process of tumorigenesis. The screening and clinical use of tyrosine kinase inhibitors, in combination with conventional treatments, have allowed the potential of targeted-based cancer therapy using specific cancer cell molecules, which are less toxic than traditional cytotoxic chemotherapy. The establishment of effective strategies in cancer research and

This revision included data obtained from patients and controls who generously participate to whom authors gratefully acknowledge. Appreciation and thankfulness are extended to Luísa Manso Oliveira and Inês Sousa for their expert technical

The authors claim no competing financial or intellectual conflicts of interest in

The mentioned work was supported by funding through project UID/ BIM/00009/2016 (Centre for Toxicogenomics and Human Health (ToxOmics),

and José Rueff<sup>1</sup>

1 Faculty of Medical Sciences, NOVA Medical School, Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, NOVA University

2 Department of Clinical Pathology, Hospital of São Francisco Xavier, West Lisbon

from Fundação para a Ciência e Tecnologia (FCT), Portugal.

the preparation and submission of this chapter.

**32**

provided the original work is properly cited.

\*Address all correspondence to<EMAIL_ADDRESS>
© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Lahiry P, Torkamani A, Schork NJ, Hegele RA. Kinase mutations in human disease: Interpreting genotypephenotype relationships. Nature Reviews. Genetics. 2010;**11**:60-74

[2] Paul MK, Mukhopadhyay AK. Tyrosine kinase—Role and significance in cancer. International Journal of Medical Sciences. 2004;**1**:101-115

[3] Siveen KS, Prabhu KS, Achkar IW, Kuttikrishnan S, Shyam S, Khan AQ, et al. Role of non receptor tyrosine kinases in hematological malignances and its targeting by natural products. Molecular Cancer. 2018;**17**:31

[4] Kosior K, Lewandowska-Grygiel M, Giannopoulos K. Tyrosine kinase inhibitors in hematological malignancies. Postȩpy Higieny i Medycyny Doświadczalnej (Online). 2011;**65**:819-828

[5] Du Z, Lovly CM. Mechanisms of receptor tyrosine kinase activation in cancer. Molecular Cancer. 2018;**17**:58

[6] Al-Obeidi FA, Lam KS. Development of inhibitors for protein tyrosine kinases. Oncogene. 2000;**19**:5690-5701

[7] Wang J, Pendergast AM. The emerging role of ABL kinases in solid tumors. Trends Cancer. 2015;**1**:110-123

[8] Sirvent A, Benistant C, Roche S. Cytoplasmic signalling by the c-ABL tyrosine kinase in normal and cancer cells. Biology of the Cell. 2008;**100**:617-631

[9] Tefferi A. Myeloproliferative neoplasms: A decade of discoveries and treatment advances. American Journal of Hematology. 2016;**91**:50-58

[10] Azevedo AP, Reichert A, Afonso C, Alberca MD, Tavares P, Lima F. V280G mutation, potential role in imatinib resistance: First case report. Clinical Medicine Insights: Oncology. 2017;**11**:1179554917702870

[11] Lamontanara AJ, Georgeon S, Tria G, Svergun DI, Hantschel O. The SH2 domain of ABL kinases regulates kinase autophosphorylation by controlling activation loop accessibility. Nature Communications. 2014;**5**:5470

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[40] Boggon TJ, Eck MJ. Structure and regulation of SRC family kinases.

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[43] Salmond RJ, Filby A, Qureshi I, Caserta S, Zamoyska R. T-cell receptor proximal signaling via the SRC-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance. Immunological Reviews.

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2009;**276**:6714-6724

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*Tyrosine Kinases as Druggable Targets in Cancer*

[26] Mahajan K, Mahajan NP. ACK1/ TNK2 tyrosine kinase: Molecular signaling and evolving role in cancers.

[27] Mócsai A, Ruland J, Tybulewicz VL. The SYK tyrosine kinase: A crucial player in diverse biological functions. Nature Reviews. Immunology.

[28] Liu D, Mamorska-Dyga A. SYK inhibitors in clinical development for hematological malignancies. Journal of Hematology & Oncology.

[29] Krisenko MO, Geahlen RL. Calling in SYK: SYK's dual role as a tumor promoter and tumor suppressor in cancer. Biochimica et Biophysica Acta.

[30] Qiu L, Wang F, Liu S, Chen XL. Current understanding of tyrosine kinase BMX in inflammation and its inhibitors. Burns & Trauma.

[31] Mohamed AJ, Yu L, Bäckesjö CM, Vargas L, Faryal R, Aints A, et al. Bruton's tyrosine kinase (Btk): Function, regulation, and transformation with special emphasis on the PH domain. Immunological

[32] Mohammad DK, Nore BF, Hussain A, Gustafsson MO, Mohamed AJ, Smith CI. Dual phosphorylation of Btk by Akt/protein kinase b provides docking for 14-3-3ζ, regulates shuttling, and attenuates both tonic and induced signaling in B cells. Molecular and Cellular Biology.

[33] Tojo A. Kinase inhibitors against hematological malignancies. Nihon

[34] Yu L, Simonson OE, Mohamed AJ, Smith CI. NF-kappaB regulates

Reviews. 2009;**228**:58-73

2013;**33**:3214-3226

Rinsho. 2014;**72**:1118-1124

Oncogene. 2015;**34**:4162-4167

2010;**10**:387-402

2017;**10**:145

2015;**1853**:254-263

2014;**2**:121-124

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[19] McLornan D, Percy M, McMullin MF. JAK2 V617F: A single mutation in the myeloproliferative group of disorders. The Ulster Medical Journal.

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[21] Wilks AF. The JAK kinases: Not just another kinase drug discovery target. Seminars in Cell & Developmental

Biomarker Research. 2013;**1**:5

Biology. 2008;**19**:319-328

[22] Constantinescu SN, Girardot M, Pecquet C. Mining for JAK-STAT mutations in cancer. Trends in

Biochemical Sciences. 2008;**33**:122-131

[23] Azevedo AP, Silva SN, Reichert A, Lima F, Júnior E, Rueff J. Prevalence

[24] Pita ASA, Azevedo APDS, Reichert A, Silva CJPD, Henriques V, Mendes DS, et al. Atypical haematological presentation in a case of polycythaemia vera with a new variant mutation detected in exon 12: c.1605G>T (p.Met535Ile). Journal of Clinical Pathology. 2018;**71**:180-184

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2011;**2011**:742372

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[18] Becerra-Díaz M, Valderrama-Carvajal H, Terrazas LI. Signal transducers and activators of

2011;**7**:1371-1381

2006;**75**:112-119

**34**

[35] Lietha D, Cai X, Ceccarelli DF, Li Y, Schaller MD, Eck MJ. Structural basis for the autoinhibition of focal adhesion kinase. Cell. 2007;**129**:1177-1187

[36] Yin B. Focal adhesion kinase as a target in the treatment of hematological malignancies. Leukemia Research. 2011;**35**:1416-1418

[37] Carter BZ, Mak PY, Wang X, Yang H, Garcia-Manero G, Mak DH, et al. Focal adhesion kinase as a potential target in AML and MDS. Molecular Cancer Therapeutics. 2017;**16**:1133-1144

[38] Sen B, Johnson FM. Regulation of SRC family kinases in human cancers. Journal of Signal Transduction. 2011;**2011**:865819

[39] Parsons SJ, Parsons JT. SRC family kinases, key regulators of signal transduction. Oncogene. 2004;**23**:7906-7909

[40] Boggon TJ, Eck MJ. Structure and regulation of SRC family kinases. Oncogene. 2004;**23**:7918-7927

[41] Ku M, Wall M, MacKinnon RN, Walkley CR, Purton LE, Tam C, et al. SRC family kinases and their role in hematological malignancies. Leukemia & Lymphoma. 2015;**56**:577-586

[42] Palacios EH, Weiss A. Function of the SRC-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene. 2004;**23**:7990-8000

[43] Salmond RJ, Filby A, Qureshi I, Caserta S, Zamoyska R. T-cell receptor proximal signaling via the SRC-family kinases, Lck and Fyn, influences T-cell activation, differentiation, and tolerance. Immunological Reviews. 2009;**228**:9-22

[44] Elias D, Ditzel HJ. Fyn is an important molecule in cancer pathogenesis and drug resistance. Pharmacological Research. 2015;**100**:250-254

[45] Kim MS, Kim GM, Choi YJ, Kim HJ, Kim YJ, Jin W. c-SRC activation through a TrkA and c-SRC interaction is essential for cell proliferation and hematological malignancies. Biochemical and Biophysical Research Communications. 2013;**441**:431-437

[46] Warmuth M, Damoiseaux R, Liu Y, Fabbro D, Gray N. SRC family kinases: Potential targets for the treatment of human cancer and leukemia. Current Pharmaceutical Design. 2003;**9**:2043-2059

[47] Pene-Dumitrescu T, Smithgall TE. Expression of a SRC family kinase in chronic myelogenous leukemia cells induces resistance to imatinib in a kinase-dependent manner. The Journal of Biological Chemistry. 2010;**285**:21446-21457

[48] Zhang S, Yu D. Targeting SRC family kinases in anti-cancer therapies: Turning promise into triumph. Trends in Pharmacological Sciences. 2012;**33**:122-128

[49] Okada M. Regulation of the SRC family kinases by CSK. International Journal of Biological Sciences. 2012;**8**:1385-1397

[50] Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;**100**:2292-2302

[51] Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO Classification of Tumours of Haematopioetic and Lymphoid Tissues. Lyon: World Health Organization; 2008

[52] Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, riskstratification, and management. American Journal of Hematology. 2017;**92**:94-108

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**37**

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2005;**92**:845-857

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Hematology. 2013;**4**:237-253

DA. The JAK/STAT signaling pathway. Journal of Cell Science.

Medicine. 2017;**376**:2168-2181

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*Tyrosine Kinases as Druggable Targets in Cancer*

[52] Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, riskstratification, and management. American Journal of Hematology.

[61] Koopmans SM, Schouten HC, van Marion AM. BCR-ABL negative myeloproliferative neoplasia: A review of involved molecular mechanisms. Histology and Histopathology.

[62] Numata A, Shimoda K, Kamezaki K, Haro T, Kakumitsu H, Shide K, et al. Signal transducers and activators of transcription 3 augments the transcriptional activity of CCAAT/ enhancer-binding protein alpha in granulocyte colony-stimulating factor signaling pathway. The Journal of Biological Chemistry.

[63] Kieslinger M, Woldman I, Moriggl R, Hofmann J, Marine JC, Ihle JN, et al. Antiapoptotic activity of Stat5 required during terminal stages of myeloid differentiation. Genes & Development.

2015;**30**:151-161

2005;**280**:12621-12629

2000;**14**:232-244

1957;**179**:633-634

1999;**283**:990-993

1993;**74**:227-236

[64] Jacobson LO, Goldwasser E, Fried W, Plzak L. Role of the kidney in erythropoiesis. Nature.

[65] Maxwell AP, Lappin TR, Johnston CF, Bridges JM, McGeown MG. Erythropoietin production in kidney tubular cells. British Journal of

Haematology. 1990;**74**:535-539

[67] Witthuhn BA, Quelle FW, Silvennoinen O, Yi T, Tang B, Miura O, et al. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell.

[68] Kralovics R, Buser AS, Teo SS, Coers J, Tichelli A, van der Maas AP,

[66] Remy I, Wilson IA, Michnick SW. Erythropoietin receptor activation by a ligand-induced conformation change. Science.

[53] Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.

[54] DAMESHEK W. Some speculations on the myeloproliferative syndromes.

[55] Skoda RC, Duek A, Grisouard J. Pathogenesis of myeloproliferative neoplasms. Experimental Hematology.

[56] NOWELL PC, HUNGERFORD DA. Chromosome studies on normal and leukemic human leukocytes. Journal of the National Cancer Institute.

[57] Adamson JW, Fialkow PJ, Murphy S, Prchal JF, Steinmann L. Polycythemia vera: Stem-cell and probable clonal origin of the disease. The New England Journal of Medicine.

[58] Fialkow PJ. Glucose-6-phosphate dehydrogenase (G-6-PD) markers in Burkitt lymphoma and other malignancies. Haematology and Blood

[59] Fialkow PJ, Faguet GB, Jacobson RJ, Vaidya K, Murphy S. Evidence that essential thrombocythemia is a clonal disorder with origin in a multipotent stem cell. Blood. 1981;**58**:916-919

Transfusion. 1977;**20**:297-305

[60] Babon JJ, Lucet IS, Murphy JM, Nicola NA, Varghese LN. The molecular regulation of Janus kinase (JAK) activation. Biochemical Journal.

Blood. 2016;**127**:2391-2405

Blood. 1951;**6**:372-375

2015;**43**:599-608

1960;**25**:85-109

1976;**295**:913-916

2017;**92**:94-108

**36**

2014;**462**:1-13

[69] Li Y, Hetet G, Maurer AM, Chait Y, Dhermy D, Briere J. Spontaneous megakaryocyte colony formation in myeloproliferative disorders is not neutralizable by antibodies against IL3, IL6 and GM-CSF. British Journal of Haematology. 1994;**87**:471-476

[70] Spivak JL. Myeloproliferative Neoplasms. The New England Journal of Medicine. 2017;**376**:2168-2181

[71] Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nature Reviews. Cancer. 2007;**7**:673-683

[72] Meyer SC, Levine RL. Molecular pathways: Molecular basis for sensitivity and resistance to JAK kinase inhibitors. Clinical Cancer Research. 2014;**20**:2051-2059

[73] Rawlings JS, Rosler KM, Harrison DA. The JAK/STAT signaling pathway. Journal of Cell Science. 2004;**117**:1281-1283

[74] Espert L, Dusanter-Fourt I, Chelbi-Alix MK. Negative regulation of the JAK/STAT: Pathway implication in tumorigenesis. Bulletin du Cancer. 2005;**92**:845-857

[75] Valentino L, Pierre J. JAK/STAT signal transduction: Regulators and implication in hematological malignancies. Biochemical Pharmacology. 2006;**71**:713-721

[76] Jones AV, Cross NC. Inherited predisposition to myeloproliferative neoplasms. Therapeutic Advances in Hematology. 2013;**4**:237-253

[77] Passamonti F, Mora B, Maffioli M. New molecular genetics in

the diagnosis and treatment of myeloproliferative neoplasms. Current Opinion in Hematology. 2016;**23**:137-143

[78] Rumi E, Cazzola M. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood. 2017;**129**:680-692

[79] Titmarsh GJ, Duncombe AS, McMullin MF, O'Rorke M, Mesa R, De Vocht F, et al. How common are myeloproliferative neoplasms? A systematic review and meta-analysis. American Journal of Hematology. 2014;**89**:581-587

[80] Moulard O, Mehta J, Fryzek J, Olivares R, Iqbal U, Mesa RA. Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. European Journal of Haematology. 2014;**92**:289-297

[81] Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leukemia & Lymphoma. 2014;**55**:595-600

[82] Srour SA, Devesa SS, Morton LM, Check DP, Curtis RE, Linet MS, et al. Incidence and patient survival of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms in the United States, 2001-12. British Journal of Haematology. 2016;**174**:382-396

[83] Bellanné-Chantelot C, Chaumarel I, Labopin M, Bellanger F, Barbu V, De Toma C, et al. Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders. Blood. 2006;**108**:346-352

[84] Passamonti F, Rumi E, Arcaini L, Boveri E, Elena C, Pietra D, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: A study of 605 patients. Haematologica. 2008;**93**:1645-1651

[85] Bai J, Xue Y, Ye L, Yao J, Zhou C, Shao Z, et al. Risk factors of long-term incidences of thrombosis, myelofibrosis and evolution into malignance in polycythemia vera: A single center experience from China. International Journal of Hematology. 2008;**88**:530-535

[86] Hultcrantz M, Kristinsson SY, Andersson TM, Landgren O, Eloranta S, Derolf AR, et al. Patterns of survival among patients with myeloproliferative neoplasms diagnosed in Sweden from 1973 to 2008: A population-based study. Journal of Clinical Oncology. 2012;**30**:2995-3001

[87] Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L, et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014;**124**:2507-2513 (quiz 2615)

[88] Tefferi A. Essential thrombocythemia, polycythemia vera, and myelofibrosis: Current management and the prospect of targeted therapy. American Journal of Hematology. 2008;**83**:491-497

[89] Hultcrantz M, Wilkes SR, Kristinsson SY, Andersson TM, Derolf Å, Eloranta S, et al. Risk and cause of death in patients diagnosed with myeloproliferative neoplasms in sweden between 1973 and 2005: A populationbased study. Journal of Clinical Oncology. 2015;**33**:2288-2295

[90] Azevedo AP, Silva SN, Reichert A, Lima F, Júnior E, Rueff J. Effects of polymorphic DNA genes involved in BER and caspase pathways on the clinical outcome of myeloproliferative neoplasms under treatment with hydroxyurea. Molecular Medicine Reports. 2018;**18**:5243-5255

[91] James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;**434**:1144-1148

[92] Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. The New England Journal of Medicine. 2005;**352**:1779-1790

[93] Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;**7**:387-397

[94] Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;**365**:1054-1061

[95] Tefferi A, Pardanani A. Myeloproliferative neoplasms: A contemporary review. JAMA Osncology. 2015;**1**:97-105

[96] Levine RL. Mechanisms of mutations in myeloproliferative neoplasms. Best Practice & Research. Clinical Haematology. 2009;**22**:489-494

[97] Hinds DA, Barnholt KE, Mesa RA, Kiefer AK, Do CB, Eriksson N, et al. Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood. 2016;**128**:1121-1128

[98] Cazzola M, Kralovics R. From Janus kinase 2 to calreticulin: The clinically relevant genomic landscape of myeloproliferative neoplasms. Blood. 2014;**123**:3714-3719

**39**

2010;**91**:165-173

*Non-receptor Tyrosine Kinases Role and Significance in Hematological Malignancies*

[108] Mambet C, Matei L, Necula LG, Diaconu CC. A link between the driver mutations and dysregulated apoptosis in BCR-ABL1 negative myeloproliferative neoplasms. Journal of Immunoassay & Immunochemistry.

[109] Kang MG, Choi HW, Lee JH, Choi YJ, Choi HJ, Shin JH, et al. Coexistence of JAK2 and CALR mutations and their clinical implications in patients with essential thrombocythemia. Oncotarget.

[110] Azevedo AP, Silva SN, De Lima JP, Reichert A, Lima F, Júnior E, et al. DNA repair genes polymorphisms and genetic susceptibility to Philadelphianegative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms. Oncology Letters.

[111] Azevedo AP, Silva S, Reichert A, Lima F, Júnior E, Rueff J. The role of caspase genes polymorphisms in genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population. Pathology & Oncology Research. 2018; 1-9. DOI:

[112] Reuther GW. Myeloproliferative neoplasms: Molecular drivers and therapeutics. Progress in Molecular Biology and Translational Science.

[113] Tefferi A, Pardanani A. JAK inhibitors in myeloproliferative neoplasms: Rationale, current data and perspective. Blood Reviews.

patients. International Journal of Clinical and Experimental Pathology.

[114] Ebid GT, Ghareeb M, Salaheldin O, Kamel MM. Prevalence of the frequency of JAK2 (V617F) mutation in different myeloproliferative disorders in Egyptian

2016;**37**:331-345

2016;**7**:57036-57049

2017;**13**:4641-4650

10.1007/s12253-018-0411-y

2016;**144**:437-484

2011;**25**:229-237

2015;**8**:11555-11559

*DOI: http://dx.doi.org/10.5772/intechopen.84873*

[99] Oh ST, Gotlib J. JAK2 V617F and beyond: Role of genetics and aberrant signaling in the pathogenesis of myeloproliferative neoplasms. Expert Review of Hematology. 2010;**3**:323-337

[100] Bench AJ, Baxter EJ, Green AR. Methods for detecting mutations in the human JAK2 gene. Methods in Molecular Biology. 2013;**967**:115-131

[101] Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Medicine. 2006;**3**:e270

[102] Tefferi A. JAK and MPL mutations in myeloid malignancies. Leukemia &

Lymphoma. 2008;**49**:388-397

2007;**356**:459-468

[103] Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. The New England Journal of Medicine.

[104] Nangalia J, Green TR. The evolving genomic landscape of myeloproliferative neoplasms. Hematology. American Society of Hematology. Education Program. 2014;**2014**:287-296

[105] Langabeer SE, Andrikovics H, Asp J, Bellosillo B, Carillo S, Haslam K, et al. MPN&MPNr-EuroNet, molecular diagnostics of myeloproliferative neoplasms. European Journal of Haematology. 2015;**95**:270-279

[106] Klampfl T, Gisslinger H,

Medicine. 2013;**369**:2379-2390

[107] Delhommeau F, Jeziorowska D, Marzac C, Casadevall N. Molecular aspects of myeloproliferative neoplasms. International Journal of Hematology.

Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. The New England Journal of *Non-receptor Tyrosine Kinases Role and Significance in Hematological Malignancies DOI: http://dx.doi.org/10.5772/intechopen.84873*

[99] Oh ST, Gotlib J. JAK2 V617F and beyond: Role of genetics and aberrant signaling in the pathogenesis of myeloproliferative neoplasms. Expert Review of Hematology. 2010;**3**:323-337

*Tyrosine Kinases as Druggable Targets in Cancer*

[91] James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature.

[92] Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. The New England Journal of Medicine.

[93] Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell.

[94] Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet.

2005;**434**:1144-1148

2005;**352**:1779-1790

2005;**7**:387-397

2005;**365**:1054-1061

2015;**1**:97-105

2009;**22**:489-494

2016;**128**:1121-1128

2014;**123**:3714-3719

[95] Tefferi A, Pardanani A. Myeloproliferative neoplasms: A

[96] Levine RL. Mechanisms of mutations in myeloproliferative neoplasms. Best Practice & Research. Clinical Haematology.

contemporary review. JAMA Osncology.

[97] Hinds DA, Barnholt KE, Mesa RA, Kiefer AK, Do CB, Eriksson N, et al. Germ line variants predispose to both JAK2 V617F clonal hematopoiesis and myeloproliferative neoplasms. Blood.

[98] Cazzola M, Kralovics R. From Janus kinase 2 to calreticulin: The clinically relevant genomic landscape of myeloproliferative neoplasms. Blood.

of 605 patients. Haematologica.

[85] Bai J, Xue Y, Ye L, Yao J, Zhou C, Shao Z, et al. Risk factors of long-term incidences of thrombosis, myelofibrosis and evolution into malignance in polycythemia vera: A single center experience from China. International Journal of Hematology.

[86] Hultcrantz M, Kristinsson SY, Andersson TM, Landgren O, Eloranta S, Derolf AR, et al. Patterns of survival among patients with myeloproliferative neoplasms diagnosed in Sweden from 1973 to 2008: A population-based study. Journal of Clinical Oncology.

[87] Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L, et al. Long-term survival and blast transformation in molecularly

annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014;**124**:2507-2513 (quiz 2615)

thrombocythemia, polycythemia vera, and myelofibrosis: Current management and the prospect of targeted therapy. American Journal of Hematology.

Kristinsson SY, Andersson TM, Derolf Å, Eloranta S, et al. Risk and cause of death in patients diagnosed with myeloproliferative neoplasms in sweden between 1973 and 2005: A populationbased study. Journal of Clinical Oncology. 2015;**33**:2288-2295

[90] Azevedo AP, Silva SN, Reichert A, Lima F, Júnior E, Rueff J. Effects of polymorphic DNA genes involved in BER and caspase pathways on the clinical outcome of myeloproliferative neoplasms under treatment with hydroxyurea. Molecular Medicine Reports. 2018;**18**:5243-5255

2008;**93**:1645-1651

2008;**88**:530-535

2012;**30**:2995-3001

[88] Tefferi A. Essential

[89] Hultcrantz M, Wilkes SR,

2008;**83**:491-497

**38**

[100] Bench AJ, Baxter EJ, Green AR. Methods for detecting mutations in the human JAK2 gene. Methods in Molecular Biology. 2013;**967**:115-131

[101] Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Medicine. 2006;**3**:e270

[102] Tefferi A. JAK and MPL mutations in myeloid malignancies. Leukemia & Lymphoma. 2008;**49**:388-397

[103] Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. The New England Journal of Medicine. 2007;**356**:459-468

[104] Nangalia J, Green TR. The evolving genomic landscape of myeloproliferative neoplasms. Hematology. American Society of Hematology. Education Program. 2014;**2014**:287-296

[105] Langabeer SE, Andrikovics H, Asp J, Bellosillo B, Carillo S, Haslam K, et al. MPN&MPNr-EuroNet, molecular diagnostics of myeloproliferative neoplasms. European Journal of Haematology. 2015;**95**:270-279

[106] Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. The New England Journal of Medicine. 2013;**369**:2379-2390

[107] Delhommeau F, Jeziorowska D, Marzac C, Casadevall N. Molecular aspects of myeloproliferative neoplasms. International Journal of Hematology. 2010;**91**:165-173

[108] Mambet C, Matei L, Necula LG, Diaconu CC. A link between the driver mutations and dysregulated apoptosis in BCR-ABL1 negative myeloproliferative neoplasms. Journal of Immunoassay & Immunochemistry. 2016;**37**:331-345

[109] Kang MG, Choi HW, Lee JH, Choi YJ, Choi HJ, Shin JH, et al. Coexistence of JAK2 and CALR mutations and their clinical implications in patients with essential thrombocythemia. Oncotarget. 2016;**7**:57036-57049

[110] Azevedo AP, Silva SN, De Lima JP, Reichert A, Lima F, Júnior E, et al. DNA repair genes polymorphisms and genetic susceptibility to Philadelphianegative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms. Oncology Letters. 2017;**13**:4641-4650

[111] Azevedo AP, Silva S, Reichert A, Lima F, Júnior E, Rueff J. The role of caspase genes polymorphisms in genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population. Pathology & Oncology Research. 2018; 1-9. DOI: 10.1007/s12253-018-0411-y

[112] Reuther GW. Myeloproliferative neoplasms: Molecular drivers and therapeutics. Progress in Molecular Biology and Translational Science. 2016;**144**:437-484

[113] Tefferi A, Pardanani A. JAK inhibitors in myeloproliferative neoplasms: Rationale, current data and perspective. Blood Reviews. 2011;**25**:229-237

[114] Ebid GT, Ghareeb M, Salaheldin O, Kamel MM. Prevalence of the frequency of JAK2 (V617F) mutation in different myeloproliferative disorders in Egyptian patients. International Journal of Clinical and Experimental Pathology. 2015;**8**:11555-11559

[115] Jatiani SS, Baker SJ, Silverman LR, Reddy EP. JAK/STAT pathways in cytokine signaling and myeloproliferative disorders: Approaches for targeted therapies. Genes & Cancer. 2010;**1**:979-993

[116] Anand S, Stedham F, Beer P, Gudgin E, Ortmann CA, Bench A, et al. Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms. Blood. 2011;**118**:177-181

[117] Steensma DP, McClure RF, Karp JE, Tefferi A, Lasho TL, Powell HL, et al. JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. Leukemia. 2006;**20**:971-978

[118] Green DR, Llambi F. Cell death signaling. Cold Spring Harb Perspect Biol. Dec 2015;**7**(12):a006080. DOI: 10.1101/cshperspect.a006080

[119] Chen E, Mullally A. How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms? Hematology. American Society of Hematology. Education Program. 2014;**2014**:268-276

[120] Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood. 2017;**129**:667-679

[121] Michiels JJ. Clinical, pathological and molecular features of the chronic myeloproliferative disorders: MPD 2005 and beyond. Hematology. 2005;**10**(Suppl 1):215-223

[122] Yao H, Ma Y, Hong Z, Zhao L, Monaghan SA, Hu MC, et al. Activating JAK2 mutants reveal cytokine receptor coupling differences that impact outcomes in myeloproliferative neoplasm. Leukemia. 2017

[123] Vorechovsky I, Jones AV, Cross NC. Why do we see JAK2 exon 12 mutations in myeloproliferative neoplasms? Leukemia. 2013;**27**:1930-1932

[124] Godfrey AL, Chen E, Massie CE, Silber Y, Pagano F, Bellosillo B, et al. STAT1 activation in association with JAK2 exon 12 mutations. Haematologica. 2016;**101**:e15-e19

[125] Bolufer P, Barragan E, Collado M, Cervera J, López JA, Sanz MA. Influence of genetic polymorphisms on the risk of developing leukemia and on disease progression. Leukemia Research. 2006;**30**:1471-1491

[126] Beer PA, Delhommeau F, LeCouédic JP, Dawson MA, Chen E, Bareford D, et al. Two routes to leukemic transformation after a JAK2 mutation-positive myeloproliferative neoplasm. Blood. 2010;**115**:2891-2900

[127] Kilpivaara O, Levine RL. JAK2 and MPL mutations in myeloproliferative neoplasms: Discovery and science. Leukemia. 2008;**22**:1813-1817

[128] Björkholm M, Hultcrantz M, Derolf Å. Leukemic transformation in myeloproliferative neoplasms: Therapy-related or unrelated? Best Practice & Research. Clinical Haematology. 2014;**27**:141-153

[129] Rueff J, Rodrigues AS. Cancer drug resistance: A brief overview from a genetic viewpoint. Methods in Molecular Biology. 2016;**1395**:1-18

[130] Rice KL, Lin X, Wolniak K, Ebert BL, Berkofsky-Fessler W, Buzzai M, et al. Analysis of genomic aberrations and gene expression profiling identifies novel lesions and pathways in myeloproliferative neoplasms. Blood Cancer Journal. 2011;**1**:e40

**41**

*Non-receptor Tyrosine Kinases Role and Significance in Hematological Malignancies*

[138] Scott LM. The JAK2 exon 12 mutations: A comprehensive review. American Journal of Hematology.

[139] Park CH, Lee KO, Jang JH, Jung CW, Kim JW, Kim SH, et al. High frequency of JAK2 exon 12 mutations in Korean patients with polycythaemia vera: Novel mutations and clinical significance. Journal of Clinical Pathology. 2016;**69**:737-741

[140] Passamonti F, Elena C, Schnittger S, Skoda RC, Green AR, Girodon F, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood.

[141] Pardanani A, Lasho TL, Finke C, Hanson CA, Tefferi A. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617Fnegative polycythemia vera. Leukemia.

[142] Wu Z, Zhang X, Xu X, Chen Y, Hu T, Kang Z, et al. The mutation profile of JAK2 and CALR in Chinese Han patients

negative myeloproliferative neoplasms. Journal of Hematology & Oncology.

with Philadelphia chromosome-

[143] Ishii T, Bruno E, Hoffman R, Xu M. Involvement of various hematopoietic-cell lineages by the JAK2V617F mutation in polycythemia vera. Blood. 2006;**108**:3128-3134

[144] Mousinho F, Santos PSE, Azevedo AP, Pereira JM, Lemos R, Matos S, et al. Concomitant

lymphoproliferative neoplasms, distinct progenitors: A case report and review of the literature. Molecular and Clinical Oncology. 2018;**9**:347-349

[145] Mousinho F, Azevedo AP, Mendes T, Santos PSE, Cerqueira R, Matos S,et al. Concomitant

myeloproliferative and

2011;**86**:668-676

2011;**117**:2813-2816

2007;**21**:1960-1963

2014;**7**:48

*DOI: http://dx.doi.org/10.5772/intechopen.84873*

[131] Campregher PV, Santos FP, Perini GF, Hamerschlak N. Molecular biology of Philadelphia-negative myeloproliferative neoplasms. Revista Brasileira de Hematologia e Hemoterapia. 2012;**34**:150-155

[132] Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, Marchioli R, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood.

[133] Pietra D, Li S, Brisci A, Passamonti F, Rumi E, Theocharides A, et al. Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood.

[134] Passamonti F, Rumi E, Pietra D, Elena C, Boveri E, Arcaini L, et al. A prospective study of 338 patients with polycythemia vera: The impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia.

[135] Butcher CM, Hahn U, To LB, Gecz J, Wilkins EJ, Scott HS, et al. Two

in JAK2V617F-negative polycythaemia

novel JAK2 exon 12 mutations

[136] Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, Milosevic JD, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood.

[137] Scott LM, Beer PA, Bench AJ, Erber WN, Green AR. Prevalence of JAK2 V617F and exon 12 mutations in polycythaemia vera. British Journal of Haematology. 2007;**139**:511-512

vera patients. Leukemia.

2008;**22**:870-873

2014;**123**:1544-1551

2007;**110**:840-846

2008;**111**:1686-1689

2010;**24**:1574-1579

*Non-receptor Tyrosine Kinases Role and Significance in Hematological Malignancies DOI: http://dx.doi.org/10.5772/intechopen.84873*

[131] Campregher PV, Santos FP, Perini GF, Hamerschlak N. Molecular biology of Philadelphia-negative myeloproliferative neoplasms. Revista Brasileira de Hematologia e Hemoterapia. 2012;**34**:150-155

*Tyrosine Kinases as Druggable Targets in Cancer*

[123] Vorechovsky I, Jones AV, Cross NC. Why do we see JAK2 exon 12 mutations in myeloproliferative

[124] Godfrey AL, Chen E, Massie CE, Silber Y, Pagano F, Bellosillo B, et al. STAT1 activation in association with JAK2 exon 12 mutations. Haematologica. 2016;**101**:e15-e19

[125] Bolufer P, Barragan E, Collado M, Cervera J, López JA, Sanz MA. Influence of genetic polymorphisms on the risk of developing leukemia and on disease progression. Leukemia Research.

[126] Beer PA, Delhommeau F, LeCouédic JP, Dawson MA, Chen E, Bareford D, et al. Two routes to leukemic transformation after a

myeloproliferative neoplasm. Blood.

[127] Kilpivaara O, Levine RL. JAK2 and MPL mutations in myeloproliferative neoplasms: Discovery and science. Leukemia. 2008;**22**:1813-1817

[128] Björkholm M, Hultcrantz M, Derolf Å. Leukemic transformation in

[129] Rueff J, Rodrigues AS. Cancer drug resistance: A brief overview from a genetic viewpoint. Methods in Molecular Biology. 2016;**1395**:1-18

[130] Rice KL, Lin X, Wolniak K, Ebert BL, Berkofsky-Fessler W, Buzzai M, et al. Analysis of genomic aberrations

and gene expression profiling identifies novel lesions and pathways in myeloproliferative neoplasms. Blood

Cancer Journal. 2011;**1**:e40

myeloproliferative neoplasms: Therapy-related or unrelated? Best Practice & Research. Clinical Haematology. 2014;**27**:141-153

JAK2 mutation-positive

2010;**115**:2891-2900

2006;**30**:1471-1491

neoplasms? Leukemia. 2013;**27**:1930-1932

[115] Jatiani SS, Baker SJ, Silverman

[116] Anand S, Stedham F, Beer P, Gudgin E, Ortmann CA, Bench A, et al. Effects of the JAK2 mutation on the hematopoietic stem and progenitor compartment in human myeloproliferative neoplasms. Blood.

[117] Steensma DP, McClure RF, Karp JE, Tefferi A, Lasho TL, Powell HL, et al. JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. Leukemia.

[118] Green DR, Llambi F. Cell death signaling. Cold Spring Harb Perspect Biol. Dec 2015;**7**(12):a006080. DOI: 10.1101/cshperspect.a006080

[119] Chen E, Mullally A. How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms? Hematology. American Society of Hematology. Education Program. 2014;**2014**:268-276

[120] Vainchenker W, Kralovics R. Genetic basis and molecular pathophysiology of classical

2017;**129**:667-679

myeloproliferative neoplasms. Blood.

[121] Michiels JJ. Clinical, pathological and molecular features of the chronic myeloproliferative disorders: MPD 2005 and beyond. Hematology. 2005;**10**(Suppl 1):215-223

[122] Yao H, Ma Y, Hong Z, Zhao L, Monaghan SA, Hu MC, et al. Activating JAK2 mutants reveal cytokine receptor coupling differences that impact outcomes in myeloproliferative neoplasm. Leukemia. 2017

LR, Reddy EP. JAK/STAT pathways in cytokine signaling and myeloproliferative disorders: Approaches for targeted therapies. Genes & Cancer. 2010;**1**:979-993

2011;**118**:177-181

2006;**20**:971-978

**40**

[132] Vannucchi AM, Antonioli E, Guglielmelli P, Rambaldi A, Barosi G, Marchioli R, et al. Clinical profile of homozygous JAK2 617V>F mutation in patients with polycythemia vera or essential thrombocythemia. Blood. 2007;**110**:840-846

[133] Pietra D, Li S, Brisci A, Passamonti F, Rumi E, Theocharides A, et al. Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood. 2008;**111**:1686-1689

[134] Passamonti F, Rumi E, Pietra D, Elena C, Boveri E, Arcaini L, et al. A prospective study of 338 patients with polycythemia vera: The impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia. 2010;**24**:1574-1579

[135] Butcher CM, Hahn U, To LB, Gecz J, Wilkins EJ, Scott HS, et al. Two novel JAK2 exon 12 mutations in JAK2V617F-negative polycythaemia vera patients. Leukemia. 2008;**22**:870-873

[136] Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, Milosevic JD, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2014;**123**:1544-1551

[137] Scott LM, Beer PA, Bench AJ, Erber WN, Green AR. Prevalence of JAK2 V617F and exon 12 mutations in polycythaemia vera. British Journal of Haematology. 2007;**139**:511-512

[138] Scott LM. The JAK2 exon 12 mutations: A comprehensive review. American Journal of Hematology. 2011;**86**:668-676

[139] Park CH, Lee KO, Jang JH, Jung CW, Kim JW, Kim SH, et al. High frequency of JAK2 exon 12 mutations in Korean patients with polycythaemia vera: Novel mutations and clinical significance. Journal of Clinical Pathology. 2016;**69**:737-741

[140] Passamonti F, Elena C, Schnittger S, Skoda RC, Green AR, Girodon F, et al. Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood. 2011;**117**:2813-2816

[141] Pardanani A, Lasho TL, Finke C, Hanson CA, Tefferi A. Prevalence and clinicopathologic correlates of JAK2 exon 12 mutations in JAK2V617Fnegative polycythemia vera. Leukemia. 2007;**21**:1960-1963

[142] Wu Z, Zhang X, Xu X, Chen Y, Hu T, Kang Z, et al. The mutation profile of JAK2 and CALR in Chinese Han patients with Philadelphia chromosomenegative myeloproliferative neoplasms. Journal of Hematology & Oncology. 2014;**7**:48

[143] Ishii T, Bruno E, Hoffman R, Xu M. Involvement of various hematopoietic-cell lineages by the JAK2V617F mutation in polycythemia vera. Blood. 2006;**108**:3128-3134

[144] Mousinho F, Santos PSE, Azevedo AP, Pereira JM, Lemos R, Matos S, et al. Concomitant myeloproliferative and lymphoproliferative neoplasms, distinct progenitors: A case report and review of the literature. Molecular and Clinical Oncology. 2018;**9**:347-349

[145] Mousinho F, Azevedo AP, Mendes T, Santos PSE, Cerqueira R, Matos S,et al. Concomitant

presence of JAK2V617F mutation and BCR-ABL translocation in two patients: A new entity or a variant of myeloproliferative neoplasms (Case report). Molecular Medicine Reports. 2018;**18**:1001-1006

[146] Vainchenker W, Constantinescu SN. JAK/STAT signaling in hematological malignancies. Oncogene. 2013;**32**:2601-2613

[147] Thomas SJ, Snowden JA, Zeidler MP, Danson SJ. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. British Journal of Cancer. 2015;**113**:365-371

[148] Nielsen C, Birgens HS, Nordestgaard BG, Kjaer L, Bojesen SE. The JAK2 V617F somatic mutation, mortality and cancer risk in the general population. Haematologica. 2011;**96**:450-453

[149] Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. The New England Journal of Medicine. 2014;**371**:2488-2498

[150] Nielsen C, Birgens HS, Nordestgaard BG, Bojesen SE. Diagnostic value of JAK2 V617F somatic mutation for myeloproliferative cancer in 49 488 individuals from the general population. British Journal of Haematology. 2013;**160**:70-79

[151] Nielsen C, Bojesen SE, Nordestgaard BG, Kofoed KF, Birgens HS. JAK2V617F somatic mutation in the general population: Myeloproliferative neoplasm development and progression rate. Haematologica. 2014;**99**:1448-1455

[152] Larsen TS, Pallisgaard N, Møller MB, Hasselbalch HC. The JAK2 V617F allele burden in essential thrombocythemia, polycythemia vera and primary myelofibrosis--impact on disease phenotype. European Journal of Haematology. 2007;**79**:508-515

[153] Vannucchi AM, Pieri L, Guglielmelli P. JAK2 allele burden in the myeloproliferative neoplasms: Effects on phenotype, prognosis and change with treatment. Therapeutic Advances in Hematology. 2011;**2**:21-32

[154] Duletić AN, Dekanić A, Hadzisejdić I, Kusen I, Matusan-Ilijas K, Grohovac D, et al. JAK2-v617F mutation is associated with clinical and laboratory features of myeloproliferative neoplasms. Collegium Antropologicum. 2012;**36**:859-865

[155] Ha JS, Kim YK, Jung SI, Jung HR, Chung IS. Correlations between Janus kinase 2 V617F allele burdens and clinicohematologic parameters in myeloproliferative neoplasms. Annals of Laboratory Medicine. 2012;**32**:385-391

[156] Pardanani A, Lasho T, McClure R, Lacy M, Tefferi A. Discordant distribution of JAK2V617F mutation in siblings with familial myeloproliferative disorders. Blood. 2006;**107**:4572-4573

[157] Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood. 2005;**106**:2162-2168

[158] Lundberg P, Takizawa H, Kubovcakova L, Guo G, Hao-Shen H, Dirnhofer S, et al. Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F. The Journal of Experimental Medicine. 2014;**211**:2213-2230

[159] Bastos HN, Antão MR, Silva SN, Azevedo AP, Manita I, Teixeira V, et al. Association of polymorphisms in genes of the homologous recombination DNA repair pathway and thyroid cancer risk. Thyroid. 2009;**19**:1067-1075

**43**

*Non-receptor Tyrosine Kinases Role and Significance in Hematological Malignancies*

transformation and new nonmyeloid

thrombocythemia and polycythemia vera. Blood. 2012;**119**:5221-5228

[168] Pardanani A, Fridley BL, Lasho TL, Gilliland DG, Tefferi A. Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders.

malignancies in essential

Blood. 2008;**111**:2785-2789

2008;**22**:1790-1792

2012;**366**:787-798

2012;**366**:799-807

2017;**129**:693-703

2017;**10**:459-477

[169] Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A. TG101348, a JAK2 selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia.

[170] Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. The New England Journal of Medicine.

[171] Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. The New England Journal of Medicine.

[172] Hobbs GS, Rozelle S, Mullally A. The development and use of Janus kinase 2 inhibitors for the treatment of myeloproliferative neoplasms. Hematology/Oncology Clinics of North

[173] Vannucchi AM, Harrison CN. Emerging treatments for classical myeloproliferative neoplasms. Blood.

[174] Stahl M, Zeidan AM. Management of myelofibrosis: JAK inhibition and beyond. Expert Review of Hematology.

America. 2017;**31**:613-626

*DOI: http://dx.doi.org/10.5772/intechopen.84873*

[160] Conde J, Silva SN, Azevedo AP, Teixeira V, Pina JE, Rueff J, et al. Association of common variants in mismatch repair genes and breast cancer susceptibility: A multigene study. BMC

Cancer. 2009;**9**:344

[161] Barbui T, Vannucchi AM,

Buxhofer-Ausch V, De Stefano V, Betti S, Rambaldi A, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer Journal. 2015;**5**:e369

[162] Guglielmelli P, Lasho TL, Rotunno G, Score J, Mannarelli C, Pancrazzi A, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: An international

study of 797 patients. Leukemia.

[163] Theocharides A, Boissinot M, Girodon F, Garand R, Teo SS, Lippert E, et al. Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood.

[164] Barbui T, Finazzi G, Falanga A. Myeloproliferative neoplasms and thrombosis. Blood. 2013;**122**:2176-2184

[165] Carobbio A, Finazzi G, Guerini V, Spinelli O, Delaini F, Marchioli R, et al.

thrombosis in essential thrombocythemia: Interaction with treatment, standard risk factors, and JAK2 mutation status. Blood.

[166] Tefferi A, Vannucchi AM. Genetic risk assessment in myeloproliferative neoplasms. Mayo Clinic Proceedings.

Leukocytosis is a risk factor for

2014;**28**:1804-1810

2007;**110**:375-379

2007;**109**:2310-2313

2017;**92**:1283-1290

[167] Hernández-Boluda JC, Pereira A, Cervantes F, Alvarez-Larrán A, Collado M, Such E, et al. A polymorphism in the XPD gene predisposes to leukemic

*Non-receptor Tyrosine Kinases Role and Significance in Hematological Malignancies DOI: http://dx.doi.org/10.5772/intechopen.84873*

[160] Conde J, Silva SN, Azevedo AP, Teixeira V, Pina JE, Rueff J, et al. Association of common variants in mismatch repair genes and breast cancer susceptibility: A multigene study. BMC Cancer. 2009;**9**:344

*Tyrosine Kinases as Druggable Targets in Cancer*

disease phenotype. European Journal of

Guglielmelli P. JAK2 allele burden in the myeloproliferative neoplasms: Effects on phenotype, prognosis and change with treatment. Therapeutic Advances

Haematology. 2007;**79**:508-515

[153] Vannucchi AM, Pieri L,

in Hematology. 2011;**2**:21-32

[154] Duletić AN, Dekanić A,

2012;**36**:859-865

2012;**32**:385-391

Hadzisejdić I, Kusen I, Matusan-Ilijas K, Grohovac D, et al. JAK2-v617F mutation is associated with clinical and laboratory features of myeloproliferative neoplasms. Collegium Antropologicum.

[155] Ha JS, Kim YK, Jung SI, Jung HR, Chung IS. Correlations between Janus kinase 2 V617F allele burdens and clinicohematologic parameters in myeloproliferative neoplasms. Annals of Laboratory Medicine.

[156] Pardanani A, Lasho T, McClure R, Lacy M, Tefferi A. Discordant distribution of JAK2V617F mutation in siblings with familial myeloproliferative disorders. Blood. 2006;**107**:4572-4573

[157] Jones AV, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L, et al. Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.

Blood. 2005;**106**:2162-2168

2014;**211**:2213-2230

[158] Lundberg P, Takizawa H, Kubovcakova L, Guo G, Hao-Shen H, Dirnhofer S, et al. Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F. The Journal of Experimental Medicine.

[159] Bastos HN, Antão MR, Silva SN, Azevedo AP, Manita I, Teixeira V, et al. Association of polymorphisms in genes of the homologous recombination DNA repair pathway and thyroid cancer risk.

Thyroid. 2009;**19**:1067-1075

presence of JAK2V617F mutation and BCR-ABL translocation in two patients: A new entity or a variant of myeloproliferative neoplasms (Case report). Molecular Medicine Reports.

[146] Vainchenker W, Constantinescu

[147] Thomas SJ, Snowden JA, Zeidler MP, Danson SJ. The role of JAK/STAT signalling in the pathogenesis, prognosis and treatment of solid tumours. British Journal of Cancer. 2015;**113**:365-371

Nordestgaard BG, Kjaer L, Bojesen SE. The JAK2 V617F somatic mutation, mortality and cancer risk in the general population. Haematologica.

[149] Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG, et al. Age-related clonal hematopoiesis associated with adverse outcomes. The New England Journal of Medicine.

Diagnostic value of JAK2 V617F somatic

Nordestgaard BG, Kofoed KF, Birgens HS. JAK2V617F somatic mutation in the general population: Myeloproliferative

[152] Larsen TS, Pallisgaard N, Møller MB, Hasselbalch HC. The JAK2 V617F allele burden in essential thrombocythemia, polycythemia vera and primary myelofibrosis--impact on

hematological malignancies. Oncogene.

2018;**18**:1001-1006

2013;**32**:2601-2613

2011;**96**:450-453

2014;**371**:2488-2498

[150] Nielsen C, Birgens HS, Nordestgaard BG, Bojesen SE.

mutation for myeloproliferative cancer in 49 488 individuals from the general population. British Journal of

Haematology. 2013;**160**:70-79

[151] Nielsen C, Bojesen SE,

neoplasm development and progression rate. Haematologica.

2014;**99**:1448-1455

SN. JAK/STAT signaling in

[148] Nielsen C, Birgens HS,

**42**

[161] Barbui T, Vannucchi AM, Buxhofer-Ausch V, De Stefano V, Betti S, Rambaldi A, et al. Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia. Blood Cancer Journal. 2015;**5**:e369

[162] Guglielmelli P, Lasho TL, Rotunno G, Score J, Mannarelli C, Pancrazzi A, et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: An international study of 797 patients. Leukemia. 2014;**28**:1804-1810

[163] Theocharides A, Boissinot M, Girodon F, Garand R, Teo SS, Lippert E, et al. Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood. 2007;**110**:375-379

[164] Barbui T, Finazzi G, Falanga A. Myeloproliferative neoplasms and thrombosis. Blood. 2013;**122**:2176-2184

[165] Carobbio A, Finazzi G, Guerini V, Spinelli O, Delaini F, Marchioli R, et al. Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: Interaction with treatment, standard risk factors, and JAK2 mutation status. Blood. 2007;**109**:2310-2313

[166] Tefferi A, Vannucchi AM. Genetic risk assessment in myeloproliferative neoplasms. Mayo Clinic Proceedings. 2017;**92**:1283-1290

[167] Hernández-Boluda JC, Pereira A, Cervantes F, Alvarez-Larrán A, Collado M, Such E, et al. A polymorphism in the XPD gene predisposes to leukemic

transformation and new nonmyeloid malignancies in essential thrombocythemia and polycythemia vera. Blood. 2012;**119**:5221-5228

[168] Pardanani A, Fridley BL, Lasho TL, Gilliland DG, Tefferi A. Host genetic variation contributes to phenotypic diversity in myeloproliferative disorders. Blood. 2008;**111**:2785-2789

[169] Lasho TL, Tefferi A, Hood JD, Verstovsek S, Gilliland DG, Pardanani A. TG101348, a JAK2 selective antagonist, inhibits primary hematopoietic cells derived from myeloproliferative disorder patients with JAK2V617F, MPLW515K or JAK2 exon 12 mutations as well as mutation negative patients. Leukemia. 2008;**22**:1790-1792

[170] Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. The New England Journal of Medicine. 2012;**366**:787-798

[171] Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. The New England Journal of Medicine. 2012;**366**:799-807

[172] Hobbs GS, Rozelle S, Mullally A. The development and use of Janus kinase 2 inhibitors for the treatment of myeloproliferative neoplasms. Hematology/Oncology Clinics of North America. 2017;**31**:613-626

[173] Vannucchi AM, Harrison CN. Emerging treatments for classical myeloproliferative neoplasms. Blood. 2017;**129**:693-703

[174] Stahl M, Zeidan AM. Management of myelofibrosis: JAK inhibition and beyond. Expert Review of Hematology. 2017;**10**:459-477

**45**

**Chapter 3**

**Abstract**

JAK, an Oncokinase in

Hematological Cancer

*Borja Guerra and Leandro Fernández-Pérez*

*Mercedes de Mirecki-Garrido, Patricia Martín-Rodríguez,*

Janus kinases (JAKs) play an essential role in the regulation of cytokine signaling. They control cell survival, proliferation, differentiation, immune response, and hematopoiesis. Deregulation of JAK signaling has been associated to the pathogenesis of numerous immune-inflammatory diseases, hematological malignancies, and solid tumors. Thus, JAK proteins have emerged as attractive therapeutic targets in the last decade. The discovery of the gain-of-function JAK2 mutation (JAK2 V617F) as the main cause of polycythemia vera—a chronic myeloproliferative syndrome led to the development of the JAK inhibitor ruxolitinib. This key finding opened the door to the search for new therapeutic agents able to suppress the constitutive activation of JAK signaling in hematological cancers and other tumors. However, given the conserved nature of the kinase domain among JAK family members, and the interrelated roles of JAK kinases in many physiological processes, including hematopoiesis and immunity, the broad usage of JAK inhibitors in hematology is challenged by their narrow therapeutic window. Novel therapies are, therefore, needed. This chapter focuses on the understanding of the complex signaling of JAK proteins in cancerous cells, the various JAK aberrations implicated in myeloproliferative neoplasms, leukemia, and lymphoma, and the clinically available JAK

**Keywords:** blood cancer, hematological tumor, JAK, STAT, mutation, JAK2 V617F

The Janus kinase (JAK) signal transducer and activators of transcription (STAT) intracellular pathway connects the signaling from extracellular cytokines, hormones, and growth factors, with the nuclear transcriptional machinery [1]. It is expressed in animals from flies to humans, being highly evolutionarily conserved [2]. The cascade consists of the tyrosine kinase JAK, the transcription factor STAT, and different regulatory proteins. In mammals, four JAKs and seven STATs have been identified [3]. JAK/STAT signaling controls numerous essential cellular responses, including cell proliferation, differentiation, migration, immune response, apoptosis, and cell survival, according to the signal, cell context, and tissue [4, 5]. These cellular events are crucial to a wide range of biological functions

*Carlota Recio, Haidée Aranda-Tavío,*

*Miguel Guerra-Rodríguez,*

inhibitors in cancer therapy.

**1. Introduction**

#### **Chapter 3**

## JAK, an Oncokinase in Hematological Cancer

*Carlota Recio, Haidée Aranda-Tavío, Miguel Guerra-Rodríguez, Mercedes de Mirecki-Garrido, Patricia Martín-Rodríguez, Borja Guerra and Leandro Fernández-Pérez*

#### **Abstract**

Janus kinases (JAKs) play an essential role in the regulation of cytokine signaling. They control cell survival, proliferation, differentiation, immune response, and hematopoiesis. Deregulation of JAK signaling has been associated to the pathogenesis of numerous immune-inflammatory diseases, hematological malignancies, and solid tumors. Thus, JAK proteins have emerged as attractive therapeutic targets in the last decade. The discovery of the gain-of-function JAK2 mutation (JAK2 V617F) as the main cause of polycythemia vera—a chronic myeloproliferative syndrome led to the development of the JAK inhibitor ruxolitinib. This key finding opened the door to the search for new therapeutic agents able to suppress the constitutive activation of JAK signaling in hematological cancers and other tumors. However, given the conserved nature of the kinase domain among JAK family members, and the interrelated roles of JAK kinases in many physiological processes, including hematopoiesis and immunity, the broad usage of JAK inhibitors in hematology is challenged by their narrow therapeutic window. Novel therapies are, therefore, needed. This chapter focuses on the understanding of the complex signaling of JAK proteins in cancerous cells, the various JAK aberrations implicated in myeloproliferative neoplasms, leukemia, and lymphoma, and the clinically available JAK inhibitors in cancer therapy.

**Keywords:** blood cancer, hematological tumor, JAK, STAT, mutation, JAK2 V617F

#### **1. Introduction**

The Janus kinase (JAK) signal transducer and activators of transcription (STAT) intracellular pathway connects the signaling from extracellular cytokines, hormones, and growth factors, with the nuclear transcriptional machinery [1]. It is expressed in animals from flies to humans, being highly evolutionarily conserved [2]. The cascade consists of the tyrosine kinase JAK, the transcription factor STAT, and different regulatory proteins. In mammals, four JAKs and seven STATs have been identified [3]. JAK/STAT signaling controls numerous essential cellular responses, including cell proliferation, differentiation, migration, immune response, apoptosis, and cell survival, according to the signal, cell context, and tissue [4, 5]. These cellular events are crucial to a wide range of biological functions like hematopoiesis, immune development, inflammatory response, adipogenesis, and angiogenesis, among others [6]. Under normal physiological conditions, JAK/ STAT pathway signaling is strictly regulated. However, in different pathological conditions such as cancer, atherosclerosis, rheumatoid arthritis, or diabetes, an "aberrant" regulation of JAK/STAT signaling has been described [6]. Mutations on JAK proteins have been reported in certain cancers, highlighting hematological cancers (HCs). Generally, these are JAK gain-of-function mutations that promote constitutive STAT activation, which triggers tumorigenesis, high-grade inflammation, or hypergrowing, among other pathological consequences [7]. As consequence, JAK inhibitors are gaining prominence in clinical use, mainly in the treatment of HCs driven by JAK mutations, or in those tumors in which JAK/STAT pathway is determinant for the pathogenesis [8, 9]. Interestingly, not only in HCs therapy, but also in the treatment of advanced solid tumors such as pancreatic cancer and triplenegative breast cancer, and certain autoimmune and inflammatory diseases such as rheumatoid arthritis, JAK inhibitors are under clinical trial [10, 11].

### **2. The JAK/STAT pathway**

#### **2.1 JAKs**

JAK proteins are nonreceptor tyrosine kinases that are essential for the activation of signaling mediated by receptors for cytokines, hormones, or several growth factors. The family includes four 120–130 kDa proteins, named JAK1, JAK2, JAK3, and TYK2, with seven defined regions of homology, called JAK homology (JH) domains (JH1–JH7) [5] (**Figure 1**). The C-terminal region includes the kinase (JH1) and the pseudokinase (JH2) domains. JH1 domain contains tyrosine residues in the activation loop, essential for JAK activation. The pseudokinase domain JH2 is structurally analogous to JH1 and participates on its activity regulation but lacks characteristic residues of tyrosine kinases, which makes it catalytically inactive [12]. Next, the SH2-related domain is constituted by JH3 and part of JH4; this region mediates JAK docking to phosphorylated tyrosine residues [13]. The other half of JH4 to JH7 domains compose the N-terminal region, called FERM (four-point-one, ezrin, radixin, and moesin), which are involved in the association between JAK and cytokine receptors [12].

#### **2.2 STATs**

The STAT family consists of seven members, named STAT1 to STAT4, STAT5A, STAT5B, and STAT6, of 80–100 kDa, which share highly conserved homology

**47**

**2.4 Regulation of JAK/STAT pathway**

*JAK, an Oncokinase in Hematological Cancer DOI: http://dx.doi.org/10.5772/intechopen.84177*

**2.3 Pathway signaling**

regions. These include (a) an N-terminal domain, (b) a spiral domain, (c) a DNA-binding domain, (d) a SH2 domain, and (e) a transactivation domain at the C-terminal end [7] (**Figure 1**). The N-terminal region is the less conserved one among the STATs, and it is implicated in some STAT dimer-dimer and other protein interactions. The spiral coiled-coil domain is responsible for many other proteinprotein interactions [6]. The STAT binding to DNA is mediated by the DNA-binding domain, which defines that STAT dimers recognize an 8- to 10-base pair inverted repeat DNA element with a consensus sequence of 5′-TTCN2–4GAA-3′. Differential binding affinity of an activated STAT dimer for a single target DNA sequence is determined by the number of nucleotides between TTC and GAA [14]. The SH2 domain is responsible to target STATs to specific tyrosine-phosphorylated peptide sequences within their binding molecules, thus controlling a broad range of intracellular signaling functions [7]. The transactivation domain holds two aminoacidic residues (tyrosine and serine) essential for STAT activity; so that JAK-promoted tyrosine phosphorylation leads to STAT dimerization, whereas STAT serine phosphorylation mediated by mitogen-activated protein kinases (MAPKs) enhances its transcriptional activity [7, 15]. All these domains are essential for STAT biological functions in response to extracellular stimuli such as cytokines or growth factors.

External stimuli (i.e., cytokines, growth factors) bind their receptors in the cellular membrane activating receptor-associated JAK autophosphorylation and subsequent activation. This event triggers a conformational change in JAK structure, which gets it ready for binding substrate and exerting its kinase activity. JAK binding sites are then exposed to the cytoplasm, where STAT monomers are found themselves in latency. STATs are recruited to the recognition areas at JAK-binding sites being phosphorylated by JAKs, which triggers their dimerization in homodimers (STAT1, STAT3, STAT4, STAT5A, and STAT5B) or heterodimers (STAT1-STAT2 and STAT1- STAT3). Consequently, active STAT dimers translocate into the nucleus where they bind to DNA, activating or repressing the transcription of their target genes [3, 6] (**Figure 2**). According to the cellular context, the external stimuli implicated, and the receptors engaged, different JAKs and STATs can be activated [16, 17] (**Table 1**). Interestingly, through a noncanonical signaling, other tyrosine kinases different from JAKs can activate STAT factors, including membrane-bound growth factor receptor tyrosine kinases (e.g., epidermal growth factor receptor—EGFR, platelet-derived growth factor receptor—PDGFR) and nonreceptor tyrosine kinases (e.g., the proto-oncogene tyrosine kinases Src and Bcr-Abl) [2, 18]. Furthermore, STAT has been shown to be able to form dimers and exert biological activity in absence of canonical JAK tyrosine phosphorylation [19]. In fact, activated JAK2 has been reported that it can enter the nucleus where it mediates epigenetic modifications of histones [20]. Furthermore, a fraction of inactive STAT5 has been found to be localized in the nucleus (instead of in the cytoplasm as the canonical signaling describes), where it is not susceptible of being phosphorylated by tyrosine kinases, mediating chromatin stabilization [21, 22].

Owing to the implication of JAK/STAT pathway in many relevant biological processes, its endogenous regulation is tight and precise. Besides, since deregulated JAKs and STATs have been associated with several pathological disorders, most of JAK/STAT modulators have been largely assessed as interesting therapeutic approaches. One of the conventional JAK/STAT modulators is protein tyrosine

**Figure 1.** *JAKs and STATs structural domains.*

#### *JAK, an Oncokinase in Hematological Cancer DOI: http://dx.doi.org/10.5772/intechopen.84177*

*Tyrosine Kinases as Druggable Targets in Cancer*

**2. The JAK/STAT pathway**

cytokine receptors [12].

**2.2 STATs**

**2.1 JAKs**

like hematopoiesis, immune development, inflammatory response, adipogenesis, and angiogenesis, among others [6]. Under normal physiological conditions, JAK/ STAT pathway signaling is strictly regulated. However, in different pathological conditions such as cancer, atherosclerosis, rheumatoid arthritis, or diabetes, an "aberrant" regulation of JAK/STAT signaling has been described [6]. Mutations on JAK proteins have been reported in certain cancers, highlighting hematological cancers (HCs). Generally, these are JAK gain-of-function mutations that promote constitutive STAT activation, which triggers tumorigenesis, high-grade inflammation, or hypergrowing, among other pathological consequences [7]. As consequence, JAK inhibitors are gaining prominence in clinical use, mainly in the treatment of HCs driven by JAK mutations, or in those tumors in which JAK/STAT pathway is determinant for the pathogenesis [8, 9]. Interestingly, not only in HCs therapy, but also in the treatment of advanced solid tumors such as pancreatic cancer and triplenegative breast cancer, and certain autoimmune and inflammatory diseases such as

rheumatoid arthritis, JAK inhibitors are under clinical trial [10, 11].

JAK proteins are nonreceptor tyrosine kinases that are essential for the activation of signaling mediated by receptors for cytokines, hormones, or several growth factors. The family includes four 120–130 kDa proteins, named JAK1, JAK2, JAK3, and TYK2, with seven defined regions of homology, called JAK homology (JH) domains (JH1–JH7) [5] (**Figure 1**). The C-terminal region includes the kinase (JH1) and the pseudokinase (JH2) domains. JH1 domain contains tyrosine residues in the activation loop, essential for JAK activation. The pseudokinase domain JH2 is structurally analogous to JH1 and participates on its activity regulation but lacks characteristic residues of tyrosine kinases, which makes it catalytically inactive [12]. Next, the SH2-related domain is constituted by JH3 and part of JH4; this region mediates JAK docking to phosphorylated tyrosine residues [13]. The other half of JH4 to JH7 domains compose the N-terminal region, called FERM (four-point-one, ezrin, radixin, and moesin), which are involved in the association between JAK and

The STAT family consists of seven members, named STAT1 to STAT4, STAT5A,

STAT5B, and STAT6, of 80–100 kDa, which share highly conserved homology

**46**

**Figure 1.**

*JAKs and STATs structural domains.*

regions. These include (a) an N-terminal domain, (b) a spiral domain, (c) a DNA-binding domain, (d) a SH2 domain, and (e) a transactivation domain at the C-terminal end [7] (**Figure 1**). The N-terminal region is the less conserved one among the STATs, and it is implicated in some STAT dimer-dimer and other protein interactions. The spiral coiled-coil domain is responsible for many other proteinprotein interactions [6]. The STAT binding to DNA is mediated by the DNA-binding domain, which defines that STAT dimers recognize an 8- to 10-base pair inverted repeat DNA element with a consensus sequence of 5′-TTCN2–4GAA-3′. Differential binding affinity of an activated STAT dimer for a single target DNA sequence is determined by the number of nucleotides between TTC and GAA [14]. The SH2 domain is responsible to target STATs to specific tyrosine-phosphorylated peptide sequences within their binding molecules, thus controlling a broad range of intracellular signaling functions [7]. The transactivation domain holds two aminoacidic residues (tyrosine and serine) essential for STAT activity; so that JAK-promoted tyrosine phosphorylation leads to STAT dimerization, whereas STAT serine phosphorylation mediated by mitogen-activated protein kinases (MAPKs) enhances its transcriptional activity [7, 15]. All these domains are essential for STAT biological functions in response to extracellular stimuli such as cytokines or growth factors.

#### **2.3 Pathway signaling**

External stimuli (i.e., cytokines, growth factors) bind their receptors in the cellular membrane activating receptor-associated JAK autophosphorylation and subsequent activation. This event triggers a conformational change in JAK structure, which gets it ready for binding substrate and exerting its kinase activity. JAK binding sites are then exposed to the cytoplasm, where STAT monomers are found themselves in latency. STATs are recruited to the recognition areas at JAK-binding sites being phosphorylated by JAKs, which triggers their dimerization in homodimers (STAT1, STAT3, STAT4, STAT5A, and STAT5B) or heterodimers (STAT1-STAT2 and STAT1- STAT3). Consequently, active STAT dimers translocate into the nucleus where they bind to DNA, activating or repressing the transcription of their target genes [3, 6] (**Figure 2**). According to the cellular context, the external stimuli implicated, and the receptors engaged, different JAKs and STATs can be activated [16, 17] (**Table 1**).

Interestingly, through a noncanonical signaling, other tyrosine kinases different from JAKs can activate STAT factors, including membrane-bound growth factor receptor tyrosine kinases (e.g., epidermal growth factor receptor—EGFR, platelet-derived growth factor receptor—PDGFR) and nonreceptor tyrosine kinases (e.g., the proto-oncogene tyrosine kinases Src and Bcr-Abl) [2, 18]. Furthermore, STAT has been shown to be able to form dimers and exert biological activity in absence of canonical JAK tyrosine phosphorylation [19]. In fact, activated JAK2 has been reported that it can enter the nucleus where it mediates epigenetic modifications of histones [20]. Furthermore, a fraction of inactive STAT5 has been found to be localized in the nucleus (instead of in the cytoplasm as the canonical signaling describes), where it is not susceptible of being phosphorylated by tyrosine kinases, mediating chromatin stabilization [21, 22].

#### **2.4 Regulation of JAK/STAT pathway**

Owing to the implication of JAK/STAT pathway in many relevant biological processes, its endogenous regulation is tight and precise. Besides, since deregulated JAKs and STATs have been associated with several pathological disorders, most of JAK/STAT modulators have been largely assessed as interesting therapeutic approaches. One of the conventional JAK/STAT modulators is protein tyrosine

**Figure 2.** *JAK/STAT signaling pathway.*

#### **Table 1.**

*Differential activation of JAK/STAT pathway upon ligand binding.*

phosphatases (PTPs), which negatively regulate the signaling of the pathway by dephosphorylating the JAK-associated receptor and/or JAK itself. Furthermore, the protein inhibitors of activated STATs (PIAS) constitute another classical group of JAK/STAT negative regulators. This family of proteins can inhibit STAT signaling

**49**

*JAK, an Oncokinase in Hematological Cancer DOI: http://dx.doi.org/10.5772/intechopen.84177*

and (3) proteasomal degradation [23].

B cell numbers and aberrant myelopoiesis [27].

**4. Aberrant JAK signaling and hematological cancer development**

The multifactorial process of tumorigenesis is characterized by cellular fail in sensing and repairing DNA damage, loss of regulation of cell cycle progression and

**3. JAK in hematopoiesis**

and function by directly preventing STAT from binding DNA or indirectly inhibiting STAT dimerization [23, 24]. But doubtlessly, the most broadly studied group of negative modulators of JAK/STAT signaling is the family of Suppressor of Cytokine Signaling (SOCS) proteins [25]. The family comprises eight members (SOCS1–7 and CIS) of 20–30 kDa, which show different structural domains including a N-terminal domain of variable length, little conserved; a central Src homology region that contains an extended SH2 sequence that leads to SOCS binding to tyrosine-phosphorylated residues either on the associated receptor or at JAK protein; and a highly conserved C-terminal domain, called SOCS box [25, 26]. Furthermore, SOCS1 and SOCS3 share a small kinase inhibitory region (KIR) located at their N-terminal region, which is implicated in the inhibition of JAK-catalytic activity. SOCS proteins exert a negative feedback loop mechanism, so that activated STATs induce the expression of SOCS, which then control STAT transduction signaling (**Figure 2**). The mechanisms by which SOCS proteins suppress JAK/STAT signaling include (1) binding to JAK catalytic site and subsequent inhibition of its kinase activity; (2) competition with STAT for the binding sites on the associated receptor;

Hematopoiesis is a multistep process by which blood cells, which have a limited life span, are continuously renewed. It is initiated in the bone marrow with the proliferation and differentiation of pluripotent hematopoietic stem cells, which undergo asymmetric divisions and differentiate into lineage-committed progenitors that eventually give rise to specialized blood cells [9]. Deregulation in hematopoiesis leads to the accumulation of intermediate progenitors or mature cells in the bone marrow, blood, or lymphoid tissues driving hematological malignancies [9]. Hematopoietic cytokines including erythropoietin (EPO), thrombopoietin (TPO), granulocyte colony-stimulating factor (GM-CSF), among others, tightly regulate hematopoiesis. They maintain regular levels of blood cells or induce their production according to physiological needs. These cytokines bind to their cognate receptors at the cell membrane, which generally (except some tyrosine kinases such as c-KIT, FLT-3, or GM-CSF receptor) lack intrinsic enzymatic activity at their intracellular part. Nevertheless, these receptor chains are constitutively associated with a JAK kinase, which mediates cytokine-induced signaling [9]. During myelopoiesis, JAK2 has been found to respond upon EPO, TPO, G-CSF, GM-CSF, IL-3, and IL-5 binding, mediating myeloid cell proliferation and differentiation [9], whereas in lymphopoiesis are mainly JAK1 and JAK3, which cooperate by binding to specific cytokine receptors (IL-2R, IL-4R, IL-7R and IL-15R). It has been suggested that JAK1 functions as the primary signaling effector since JAK3 is a JAK1 scaffold [9]. Gene disruption studies have confirmed the essential role of JAK proteins in hematopoiesis. JAK1-deficient mice showed perinatal lethality and defective lymphoid development [27]. Lack of JAK2 expression resulted in an embryonic lethality due to a block in erythropoiesis but with intact lymphoid development [27]. JAK3 deficiency revealed severe combined immunodeficiency with low functional T and

#### *JAK, an Oncokinase in Hematological Cancer DOI: http://dx.doi.org/10.5772/intechopen.84177*

*Tyrosine Kinases as Druggable Targets in Cancer*

**48**

**Table 1.**

**Figure 2.**

**factor**

*JAK/STAT signaling pathway.*

**Cytokine/growth**

IL-12, G-CSF, EPO, TPO, PRL, GH

CSF-1/M-CSF, EGF, PDGF, insulin

IFN (α,β,γ) JAK1, JAK2,

IL-4, IL-13 JAK1, JAK2,

IL-6, IL-11, leptin, CT-1 JAK2, JAK1,

**Activated JAK**

IL-10 JAK1, TYK2 STAT1, STAT3 Immune regulation

IL-2, IL-7, IL-9, IL-15 JAK1, JAK3 STAT5, STAT3 Immune regulation, asthma

IL-3, IL-5, GM-CSF JAK2 STAT5 Myeloid reconstitution, asthma

JAK1 STAT1, STAT3, STAT5

STAT5, STAT3, STAT4, STAT1

STAT1, STAT3, STAT5

TYK2

JAK3

TYK2

*Differential activation of JAK/STAT pathway upon ligand binding.*

JAK2, JAK1, TYK2

**Activated STAT Therapeutic area**

STAT6 Allergy, asthma

STAT1, STAT2 Immune regulation, cancer

Immune regulation, myeloid reconstitution, anemia, platelet production, growth, aging

Inflammation, platelet production, obesity, cardiovascular disease

Cancer, diabetes

phosphatases (PTPs), which negatively regulate the signaling of the pathway by dephosphorylating the JAK-associated receptor and/or JAK itself. Furthermore, the protein inhibitors of activated STATs (PIAS) constitute another classical group of JAK/STAT negative regulators. This family of proteins can inhibit STAT signaling

and function by directly preventing STAT from binding DNA or indirectly inhibiting STAT dimerization [23, 24]. But doubtlessly, the most broadly studied group of negative modulators of JAK/STAT signaling is the family of Suppressor of Cytokine Signaling (SOCS) proteins [25]. The family comprises eight members (SOCS1–7 and CIS) of 20–30 kDa, which show different structural domains including a N-terminal domain of variable length, little conserved; a central Src homology region that contains an extended SH2 sequence that leads to SOCS binding to tyrosine-phosphorylated residues either on the associated receptor or at JAK protein; and a highly conserved C-terminal domain, called SOCS box [25, 26]. Furthermore, SOCS1 and SOCS3 share a small kinase inhibitory region (KIR) located at their N-terminal region, which is implicated in the inhibition of JAK-catalytic activity. SOCS proteins exert a negative feedback loop mechanism, so that activated STATs induce the expression of SOCS, which then control STAT transduction signaling (**Figure 2**). The mechanisms by which SOCS proteins suppress JAK/STAT signaling include (1) binding to JAK catalytic site and subsequent inhibition of its kinase activity; (2) competition with STAT for the binding sites on the associated receptor; and (3) proteasomal degradation [23].

#### **3. JAK in hematopoiesis**

Hematopoiesis is a multistep process by which blood cells, which have a limited life span, are continuously renewed. It is initiated in the bone marrow with the proliferation and differentiation of pluripotent hematopoietic stem cells, which undergo asymmetric divisions and differentiate into lineage-committed progenitors that eventually give rise to specialized blood cells [9]. Deregulation in hematopoiesis leads to the accumulation of intermediate progenitors or mature cells in the bone marrow, blood, or lymphoid tissues driving hematological malignancies [9]. Hematopoietic cytokines including erythropoietin (EPO), thrombopoietin (TPO), granulocyte colony-stimulating factor (GM-CSF), among others, tightly regulate hematopoiesis. They maintain regular levels of blood cells or induce their production according to physiological needs. These cytokines bind to their cognate receptors at the cell membrane, which generally (except some tyrosine kinases such as c-KIT, FLT-3, or GM-CSF receptor) lack intrinsic enzymatic activity at their intracellular part. Nevertheless, these receptor chains are constitutively associated with a JAK kinase, which mediates cytokine-induced signaling [9]. During myelopoiesis, JAK2 has been found to respond upon EPO, TPO, G-CSF, GM-CSF, IL-3, and IL-5 binding, mediating myeloid cell proliferation and differentiation [9], whereas in lymphopoiesis are mainly JAK1 and JAK3, which cooperate by binding to specific cytokine receptors (IL-2R, IL-4R, IL-7R and IL-15R). It has been suggested that JAK1 functions as the primary signaling effector since JAK3 is a JAK1 scaffold [9]. Gene disruption studies have confirmed the essential role of JAK proteins in hematopoiesis. JAK1-deficient mice showed perinatal lethality and defective lymphoid development [27]. Lack of JAK2 expression resulted in an embryonic lethality due to a block in erythropoiesis but with intact lymphoid development [27]. JAK3 deficiency revealed severe combined immunodeficiency with low functional T and B cell numbers and aberrant myelopoiesis [27].

#### **4. Aberrant JAK signaling and hematological cancer development**

The multifactorial process of tumorigenesis is characterized by cellular fail in sensing and repairing DNA damage, loss of regulation of cell cycle progression and apoptosis, and expression of aberrant patterns of growth signaling and angiogenesis [28, 29]. Numerous studies have provided strong evidence for the key role that JAK kinases play in hematologic cancer genesis and progression. This is not surprising considering the close relation between JAKs and cytokine and growth factor signaling, hematopoiesis, proliferation, apoptosis, and immune response, processes that, when deregulated, contribute to tumor development [29, 30]. Either gain-offunction mutations in JAKs, cognate JAK tyrosine kinases, or JAK associate receptors, the generation of fusion proteins, or the loss of negative feedback regulation of JAK signaling can contribute to constitutive and aberrant STAT signaling and therefore to oncogenesis [18]. The first evidence of the strong implication of JAK kinases in HCs was the identification of oncogenic fusion proteins involving JAK kinase domain (e.g., TEL/ETV6-JAK2) [31]. Subsequently, other JAK2 fusion proteins and JAK2 gene amplifications have been identified. However, although they were more recently discovered, JAK point somatic mutations are the most common JAK deregulations found in hematological tumors, being the mutation JAK2 V617F found in more than half of all classical myeloproliferative disorders (MPDs) [32]. Besides, other JAK mutations are associated to hematological malignancies, such as JAK1 mutations, found in 10–20% of T-ALL, and other JAK2 mutations associated to ∼20% of Down syndrome (DS)-associated B-ALL [32] (**Table 2**). Interestingly, the discovery of all these mutations has highlighted JAK proteins as potent drug targets and biomarkers for HCs.

#### **4.1 JAK2 mutations**

#### *4.1.1 JAK2V617F mutation in myeloproliferative disorders*