Cause
This subtype is characterized by a translocation of a part ofGenetics
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
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.Diagnosis
The first red flag that indicates M2 acute myeloblastic leukemia with maturation is the skewed ratio of white blood cells to red blood cells. Leukemia is initially diagnosed by a peripheral blood smear, a procedure used to check for cell count and cell shapes. Then a bone marrow aspiration and biopsy would be conducted to collect and view the bone, bone marrow, and blood under a microscope. Cytogenetic assays, such as fluorescence in situ hybridization (FISH) would help evaluate the structure and function of the cell's chromosomes. The criteria for an acute myeloid leukemia case to fall under the M2 subtype is the following: 20%+ nonerythroid cells in peripheral blood or bone marrow are myeloblasts; monocytic precursors are < 20% in bone marrow and granulocytes are 10%+ of cells (Mihova, 2013).Treatments
Generally, acute myeloid leukemia is treated using chemotherapy consisting of an induction phase and consolidation phase (Dohner et al., 2009). Patients may also consider hematopoietic stem cell transplantation as a second mode of tackling the cancer. The most novel research is being done in tyrosine kinase inhibitors; however M2 acute myeloid leukemia treatment research involves molecules that inhibit the fusion oncoprotein AML1-ETO. Therefore, in terms of M2 subtype acute myeloid leukemia, the most prominent target is the abnormal AML1-ETO fusion protein. Similarly, chronic myeloid leukemia (CML) is comparable to acute myeloid leukemia M2 because it also forms a fusion oncoprotein – BCR-Abl. The developed tyrosine kinase inhibitor, imatinib mesylate, has had a tremendous effect on stopping cancer progression in the majority of chronic myeloid leukemia patients. BCR-Abl is constitutively active due chromosome translocation; therefore it over-phosphorylates the tyrosine kinase. Imatinib mesylate works to block BCR-Abl's activity by blocking the active kinase domain (Fava et al., 2011). Celastrol is a compound extracted from Tripterygium wilfordii that has anti-cancer properties. It was found to inhibit cell proliferation through the down regulation of AML1-ETO fusion oncoprotein. Celastrol inhibits the fusion oncoprotein by inducing mitochondrial instability and initiating caspase activity. The decrease of AML1-ETO also results in lower levels of C-KIT kinases, Akt/PKB, STAT3, and Erk1/2 – all of which are involved in cell signaling and gene transcription. Histone deacetylase inhibitors such as valproic acid (VPA), vorinostat, and all-trans retinoic acid (ATRA) are effective in targeting acute myeloid leukemia with the AML1-ETO fusion protein. The HDAC inhibitors are known to induce apoptosis through accumulation of DNA damage, inhibition of DNA repair, and activation of caspases. These inhibitors are extra sensitive to the fusion proteins. Vorinostat has been proven to cause a greater accumulation of DNA damage in fusion protein expressing cells and is directly correlated with the reduction of DNA repair enzymes (Garcia et al., 2008). Romidepsin, a drug in phase two clinical trials, has demonstrated higher efficacy in patients with AML1-ETO fusion protein leukemia (Odenike et al., 2008). Although many clinical evaluations have proven HDAC inhibitors have a promising effect on M2 subtype acute myeloid leukemia, it has not been approved as an official treatment. In t(6;9) acute myeloid leukemia, FLT3-ITD and the DEK-NUP214 protein are potential targets for treatment. Sorafenib is a kinase inhibitor used as a treatment for kidney and liver cancer. The kinase inhibitor blocks serine-threonine kinase RAF-1 as well as FLT-ITD (Kindler, 2010). The drug has been proven to be effective in reducing FLT3-ITD overexpression (Metzelder et al., 2009). In patients with DEK-NUP214, it was found that the fusion oncoprotein caused an upregulation of mTORC1 (Sanden et al., 2013). Thus, a mTORC inhibitor could be a potential treatment.References
* American Cancer Society (ACS) (2016). Cancer Facts and Figures. * * Bennett, J.H. (1852). Leucocythemia or White Cell Blood, pp 7–82. Edinburgh. * * * * * * * * * * * * Huret, J. t(6;9)(p23;q34). (2005). ''Atlas Genet Cytogenet Oncol Haematol.'' * * * * * * * * Mihova, D. (2013). Leukemia - Acute - Acute myeloid leukemia with maturation (FAB AML M2). Pathologyoutlines.com. Retrieved 5 May 2016, from http://www.pathologyoutlines.com/topic/leukemiaM2.html * * * * * * * * * * * Weinberg, R. (2014). The Biology of Cancer (2nd ed.). New York: Garland Science. *External links
{{Chromosomal abnormalities Acute myeloid leukemia