This subtype is characterized by a translocation of a part of chromosome 8 to chromosome 21, written as t(8;21). On both sides of the splice the DNA coded for different proteins, RUNX1 and ETO, These two sequences are then transcribed and translated into a single large protein, "M2 AML" which allows the cell to divide unchecked, leading to cancer. Genetics Acute myeloid leukemia is a very heterogeneous disease, composed of a variety of translocations and mutations. However, one tenth of all acute myeloid leukemia cases diagnosed have the AML1-ETO fusion oncoprotein due to the t(8;21) translocation. AML1 or RUNX1 is a DNA-binding transcription factor located at the 21q22. ETO is a protein with transcriptional repressing abilities located at the 8q22. Less than 1% of acute myeloid leukemia patients have the t(6;9) mutation. The rare translocation causes the formation of fusion oncoprotein DEK-NUP214 (Huret, 2005). DEK functions as a transcriptional repressor by interfering with histone acetyl transferases, regulator for a number of stem cells, and activates gene expression in myeloid cells (Koleva et al., 2012). The NUP214 protein is involved in mRNA export as well as nuclear membrane localization and nuclear pore complex (Koser et al., 2011). Molecular mechanism Figure 1. Overview of major interaction with tumor suppressor p14ARF and downstream effects of fusion protein AML1-ETO in M2 acute myeloid leukemia. Elimination of the tumor suppressor ARF gene is often seen in cancer cells. In adult M2<unk> , ARF expression is suppressed via chromosome translocations that fuse AML1 or Runx1 to an ETO gene. The AML1 or Runx1 gene is in charge of activating transcription of the ARF gene while the ETO protein is involved in transcriptional repression. The AML1-ETO fusion protein ultimately causes transcriptional repression of the p14ARF gene, which deregulates the expression levels of Mdm2 and p53. The down regulation of ARF, increases Mdm2 levels due to the lack of regulation by the ARF gene. Unregulated, overexpressed Mdm2 will suppress p53 levels. The suppression of p53 levels is an anti-apoptotic mechanism for cancer cells to survive (Elagib, 2006, Weinberg, 2014).The fusion oncoprotein involves the gene AML1 (now known as RUNX1) and ETO (now known as RUNX1T1). AML1, located at the 21q22, normally has the ability to activate transcription of the ARF gene and ETO, located at the 8q22, normally has the ability to repress transcription. The fusion protein AML1-ETO is commonly found in acute myeloid leukemia patients. p14ARF is a well known tumor suppressor that serves as the safety net when p53 tumor suppressor's functions are inhibited. Many cancers recognize the potential of the p14ARF tumor suppressor to block cell growth so it is commonly mutated or inhibited in cancer cells. The AML1-ETO is incapable of p14ARF transcription as the fusion protein took on AML1's involvement with ARF gene expression and ETO's transcription repression. The Akt/PKB signaling is a pathway that is pro-survival and growth. By activating Mdm2, the signal transduction pathway will trigger the anti-apoptotic downstream effects of Mdm2. With no p14ARF to regulate and inhibit Mdm2, there will be an increased level of suppression of p53. Mdm2 is a proto-oncogene that directly antagonizes p53 to ubiquitination (Figure 1). The p53 protein is known as the “guardian of the genome” due to its ability to induce DNA repair enzymes and regulate cell cycle advancements. The down regulation of p53 by Mdm2 would lead to unchecked proliferative growth. The direct consequence of having the fusion protein, AML1-ETO, is the lack of p53 regulation in pre-leukemic cells. Therefore, there are an increased number of immature cells that are unable to carry out normal function, which is essentially cancer (Faderi et al., 2000, Song et al. 2005, Weinberg, 2014). Autophagy in M2 AML Autophagy is an innate pathway used for degradation of cellular components (Kobayashi, 2015). In recent studies, scientists recognize the significance of autophagy both as a potential anti-apoptotic response to cancer treatments as well as a potential mechanism for getting rid of undesirable fusion proteins such as AML1-ETO. In a 2013 study, scientists demonstrated that the degradation of fusion oncoprotein AML1-ETO is not mediated by autophagy through a set of drug dosage trials testing the levels of AML1-ETO protein expression. The acute myeloid leukemia Kasumi-1 cell line was selected for the experiment due to its AML1-ETO positive characteristics. These cells were treated with increasing concentrations of each histone deacetylase inhibitors – valproic acid (VPA) (epileptic and bipolar drug) or vorinostat (cutaneous T cell lymphoma drug), which are known to induce autophagy associated with loss of the fusion protein. The two inhibitors were added to the cell line in doses of 0, 0.38 uM, 0.74 uM, and 1.5 uM. The cell lysates were then treated with autophagy inhibitors Baf or CQ, or control. Through immunoblotting, there is no reduction of AML1-ETO observed across the different concentrations of VPA or vorinostat. The results indicate that AML1-ETO degradation is not mediated by autophagy, but there is an observed pro-survival autophagy in the leukemic cells (Torgersen et al., 2013). Thus, an inhibition of autophagy would be a viable treatment method for subtype M2 acute myeloid leukemia.
Acute myeloblastic leukemia with maturation
Acute myeloblastic leukemia without maturation
B-cell prolymphocytic leukemia
Minimally differentiated acute myeloblastic leukemia
Acute megakaryoblastic leukemia
Precursor B-cell lymphoblastic leukemia
Prolymphocytic leukemia
T-cell prolymphocytic leukemia