the jak2 protein associates with the cytoplasmic tails of various cytokine and growth factor receptors that reside on the cell surface and regulate haematopoiesis, i.e. the development and growth of blood cells. examples of such receptors include the erythropoietin receptor, thrombopoietin receptor, granulocyte colony-stimulating factor receptor, granulocyte macrophage colony-stimulating factor receptor, interleukin-3 receptor, interleukin-5 receptor, interleukin-6 receptor, and the receptor thymic stromal lymphopoietin, which is a complex composed of the crlf2 receptor combined with alpha chain of the il-7 receptor. jak2 protein's association with these receptors is responsible for a) correctly targeting and positioning these receptors at the cell surface and b) indirectly activating critical cell signaling pathways including in particular the stat family of transcription factors which are involved in promoting the growth, proliferation, differentiation, and survival of the myeloid and lymphoid precursor cells that populate the bone marrow, other blood cell forming tissues, and the blood. the pcm1 gene codes for the pcm1 protein, i.e. pericentriolar material 1. the pcm1 protein exhibits a distinct cell cycle-dependent association with the centrosome complex and microtubules; it is critical for the normal cell cycle and cell division (see pcm1). genetics acquired mutations in early hematopoietic stem cells involving the jak2 gene, located on human chromosome 8 at position p22 (i.e. 8p22), and the pcm1 gene, located at 12p13, create the pcm1-jak2 fusion gene. this fusion gene encodes the chimeric pcmi-jak2 fusion protein which has continuously active jak2-associated tyrosine kinase and therefore continuously phosphorylates tyrosine residues on the cytoplasmic tail of the cell surface receptor to which it is attached. in consequence, the receptor remains continuously active in attracting docking proteins such as sos1 and stat proteins which drive cell growth, proliferation, and survival. clinical presentation and treatment pcm1-jak2 gene positive patients present with features of myeloid neoplasms, lymphoid neoplasms, or features of both types of neoplasms. most commonly, the present with features of myeloid neoplasms with 50–70% of cases associated with eosinophilia and/or bone marrow fibrosis their disease usually progresses rapidly from a chronic phase to an acute blast cell phase resembling chronic myelogenous leukemia's conversion form chronic to acute phases. rarely, the acute phase of pcm1-jak2 gene positive disease resembles a lymoblastic leukemia. pcm1-jak2-induced hematological malignances are rare and relatively newly discovered. the disease is aggressive and therefore has been treated aggressively with chemotherapy followed by bone marrow transplantation. however, of 6 patients treated with a tyrosine kinase inhibitor, ruxolitinib, 5 experienced complete remissions and have survived for at least 30 months. one patient relapsed after 18 months ruxolitinib therapy and required hematopoietic stem cell transplantation (hsct). the efficacy of ruxolitinib therapy in this therapy requires a larger study; ultimately, the drug may find use as initial single therapy or as an adjuvant to reduce tumor load prior to combination with hcst. other clonal hypereosinophilias ongoing studies continue to find patients with eosinophilia, hypereosinophilia, or other myeloid/lymphoid neoplasms that are associated with eosinophilia and that express previously unappreciated mutations in genes coding for other tyrosine kinases in bone marrow-derived cells. these cases fit the definition of clonal hypereosinophilia. the world health organization currently includes these mutation-related diseases in the categories of 1) idiopathic hypereosinophilia when blood and bone marrow show no increase in blast cells and there is no eosinophil-related organ damage or 2) cel-nos when increased numbers of blast cells occur in blood and/or bone marrow and/or eosinophil-related tissue damage is present. further studies may allow these mutation-related diseases to be considered for inclusion in the myeloid and lymphoid neoplasms associated with eosinophilia category. genetics gene fusions of jak2 with etv6 or bcr have been discovered in rare instances of eosinophilia-associated hematological diseases. the product of the etv6 gene is a member of the ets transcription factor family; it is required for hematopoiesis and maintenance of the developing vascular network, as determined in mouse gene knockout. etv6 is located on human chromosome 12 at position p13.2; chromosome translocation between it and jak2 located on human chromosome 9 at position p24.1 form the fusion gene t(9;12)(p24;13) which encodes the etv6-jak2 fusion protein. forced expression of this fusion protein in mice causes a fatal mixed myeloid and/or t-cell lymphoproliferative disorder. bcr encodes the breakpoint cluster region protein. this protein possess serine/threonine-specific protein kinase activity and also has gpaase activating effects on rac1 and cdc42 but its normal function is unclear. bcr is located on human chromosome 22 at position q11.23. translocations between it and jak2 create the t(9;22)(p24;q11) fusion gene which codes for the bcr-jak2 fusion protein. forced expression of bcr-jak2 in mice induces a fatal myeloid neoplasm involving splenomegaly, megakaryocyte infiltration, and leukocytosis. it is assumed but not yet fully proven that the malignant transformation effects of these two fusion proteins are due to the effects of a presumptively continuously active jak2-associated tyrosine kinase. rare patients with hypereosinophilia carry a somatic point mutation in the jak2 gene which encodes for the amino acid phenylalanine (notated as f) instead of valine (notated as v) at position 617 of jak2 protein. this v617f mutation render's the protein's tyrosine kinase continuously active and results in a myeloproliferative neoplasm with eosinophilia. clinical presentation and treatment the clinical presentation of patients suffering etv6-jak2 or bcr-jak2 fusion gene-associated disease is similar to that occurring in pcm1-jak2-associated eosinophilic neoplasm. like the latter neoplasm, hematologic neoplasms cause by etv6-jak2 and bcr-jak2 are aggressive and progress rapidly. too few patients with the latter fusion proteins have been treated with tyrosine kinase inhibitors to define their efficacy. one patient with bcr-jak-related disease obtained a complete remission with ruxolitinib therapy that lasted 24 months but then required hematopoietic stem cell transplantation (hsct); a second patient wit this mutation failed treatment with dasatinib and also required hsct. patients bearing the v617f mutation exhibited features of a myleproliferative neoplasm. treated with imatinib, they exhibited some hematological improvement. genetics the abl1 gene encodes a non-receptor tyrosine kinase termed abelson murine leukemia viral oncogene homolog 1. among its numerous effects on cellular function, the abl1 kinase- regulates cell proliferation and survival pathways during development. it mediates at least in part the cell proliferating signaling stimulated by pdgf receptors as well as by antigen receptors on t cell and b cell lymphocytes. the abl1 gene is located on human chromosome 9q34.12; translocations between it and the bcr gene on human chromosome 22q11.23 create the well-known t(9;22)(q34;q11) bcr-abl1 fusion gene responsible for philadelphia chromosome positive chronic myelogenous leukemia and chronic lymphocytic leukemia. while bcr-abl1 fusion gene-induce leukemias are sometimes accompanied by eosinophilia, they are not regarded as clonal hypereosinophilias since other features of these leukemias dominate. however, translocations between abl1 and the etv6 gene, located on human chromosome 12p13.2 creates the t(9;13)(q34;p13) etv6-abl1 fusion gene. this fusion gene is regarded as continuously active in drive hematological cell proliferation leading to clonal hypereosinophilia. clinical presentation and treatment patients with etv6-abl1 fusion gene-positive disease present with various hematological disorders. children present predominantly with hematological findings similar to acute lymphocytic leukemia and less commonly with findings of acute myelogenous leukemia or chronic variants of these two leukemias. adults are more likely to present with findings similar to acute myelogenous leukemia or myeloproliferative neoplasms. in a study of 44 patients with this fusion gene, eosinophilia was found in all patients with myelogenous and myeloproliferative diseases but only 4 of 13 with acute lymphocytic leukemia presentations. the prognosis was very poor in adults with acute leukemia forms of the disease; ~80% of these patients suffered fatal disease progression or relapse. five patients with the myeloproliferative form of the disease responded to the tyrosine kinase inhibitor imatinib or sequential treatment with imatinib followed by recurrence and treatment with a second generation tyrosine kinase inhibitor nilotinib; dasatinib is also a recommended second generation tyrosine kinase inhibitor for treating the disease. follow-up of these patients is too short to determine the overall length of time to relapse and the efficacy of single or serial tyrosine kinase inhibitor treatments. patients with the blast cell phase of this disease have very poor responses to tyrosine kinase inhibitors and a median survival of ~1 year. thus, tyrosine kinase inhibitors, including second-generation inhibitors, in the treatment of etv6-abl1-positive hematological malignancies have shown varying responses; it is suggested that further investigations into the clinical efficacy of these drugs in etv6-abl1-induced clonal hypereosinophilia is warranted. genetics the flt3 gene codes for the cluster of differentiation antigen 135 (i.e. cd135) protein or flt3 protein. this protein is a member of the class iii family of receptor tyrosine kinases; pdgfra, pdgfrb, c-kit and csf1r also belong to this receptor class. flt3 protein binds and is activated by the flt3 ligand; flt3 protein activation involves its forming dimers, changing to an open conformation to allow access of the phosphate donor, atp, to its binding pocket, and autophosphorylation. the activated receptor initiates cell proliferation and survival signals in various precursor blood cells types through ras p21 protein activator 1, phospholipase cβ, stat5, and extracellular signal-regulated kinases. the flt3 gene is located on human chromosome 13q12.2. chromosome translocations between it and etv6 (chromosome 12p13.2), sptbn1 (2p16.2), golgb1 (3q13.33), or trip11 (14q32.12) genes create fusion genes which, it is hypothesized, encode for fusion proteins that have continuously active flt3 protein-related tyrosine kinase activity and thereby force the uncontrolled proliferation and survival of hematological cells. clinical presentation and treatment patients with hematological disease related to the cited flt3 fusion genes present with either a myeloid or lymphoid neoplasm plus eosinophilia. four of 6 patients with etv6-flt3-related disease, a patient with golgb1-flt3-related disease, and a patient with trip11-flt3-related disease presented with findings similar to t-cell lymphoma while a patient with sptbn1-flt3-related disease had findings of chronic myelogenous leukemia. two patients with etv6-flt3-related disease experienced complete hematologic remissions when treated with a multi-kinase inhibitor, sunitinib, that has inhibitory activity against flt3 protein. however, these remissions were short-lived. a third patient with etv6-flt3-related disease was treated with a similarly active kinase inhibitor, sorafenib. this patient achieved a complete hematological response and was then given a hematopoietic stem cell transplantation. the latter treatment regimen, flt3 inhibitor followed by hematopoietic stem cell transplantation, may be the best approach currently available for treating flt3-related hematological disease. genetics the etv6 gene (also known as translocation-ets-leukemia) is a member of the ets transcription factor family. the gene codes for a transcription factor protein, etv6, which acts to inhibit the expression of various genes which in mice appear to be required for normal hematopoiesis and the development and maintenance of the vascular network. the gene is located on human chromosome 12 at position p13.2 and is well-known to be involved in a large number of chromosomal rearrangements associated with leukemia and congenital fibrosarcoma. heterozygous etv6 germline mutations have been identified in several families with inherited thrombocytopenia, variable red blood cell macrocytosis, and hematologic malignancies, primarily b-cell acute lymphoblastic leukemia. the acsl6 gene encodes a protein, csl6 acyl-coa synthetase long-chain family member 6 (or acsl6 protein). this protein is a long-chain-fatty-acid—coa ligase that plays a major role in fatty acid metabolism (particularly in the brain) by charging fatty acids with coenzyme a to form acyl-coa. this function can not only alter fatty acid metabolism but also modulate the function of protein kinase cs and nuclear thyroid hormone receptor. the gene is located on human chromosome 5 at position q31.1. chromosome translocations between etv6 and acsl6 at different chromosome break points create various t(5:12)(q31;p13) etv6-acsl6 fusion genes encoding etv6-acsl6 fusion proteins. the functionality of etv6-acsl6 fusion proteins and the mechanism by which they promote clonal hypereosinophil may, based on indirect evidence in 5 case studies, relate to a loss or gain in function of the etv6 portion of the fusion protein. however, these issues have not been fully investigated or defined. two cases involving etv6-acsl6 fusion genes were associated with the ectopic and uncontrolled expression of interleukin 3. the gene for interleukin 3 is close to the acsl6 gene at position 5q31 and could also be mutated during at least some etv6-acsl6 translocation events. interleukin 3 stimulates the activation, growth, and survival of eosinophils and therefore its mutation could be involved in the clonal hypereosinophilia occurring in etv6-acsl6-related disease. clinical presentation and treatment most patients with etv6-acsl6-related disease present with findings similar to eosinophilia, hypereosinophilia, or chronic eosinophilic leukemia; at least 4 cases presented with eosinophilia plus findings of the red blood cell neoplasm, polycythemia vera; three