Acute myeloblastic leukemia with maturation

Many of the immature blast cells in acute myeloid leukemia have a higher loss of function and thus, a higher inability to carry out normal functions than those more developed immature myeloblast cells in chronic myeloid leukemia (O’Donnell et al. 2012).

This rare translocation has a poor prognosis compared to the t(8;21) because 70% of t(6;9) acute myeloid leukemia patients have the FLT3-ITD mutation (Schwartz et al., 1983, Kottaridis, 2001).

M2 acute myeloblastic leukemia with maturation, as classified by the FAB system, constitutes 25% of adult AML.

However, one tenth of all acute myeloid leukemia cases diagnosed have the AML1-ETO fusion oncoprotein due to the t(8;21) translocation.

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.

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).

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.

Cytogenetic assays, such as fluorescence in situ hybridization (FISH) would help evaluate the structure and function of the cell's chromosomes.

Therefore, in terms of M2 subtype acute myeloid leukemia, the most prominent target is the abnormal AML1-ETO fusion protein.

The developed tyrosine kinase inhibitor, imatinib mesylate, has had a tremendous effect on stopping cancer progression in the majority of chronic myeloid leukemia patients.

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.

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.

Figure 1. Overview of major interaction with tumor suppressor p14 ARF 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 acute myeloblastic leukemia with maturation, 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 p14 ARF 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).