AML and Drug Resistance Challenges

Introduction

Acute myeloid leukemia (AML) is a type of cancer of hematopoietic system. Accumulation of aberrant immature white blood cells called granulocytes (or monocytes) in the bone marrow, are responsible for the initiation of this type of leukemia. Current treatment of AML is not effective enough due to drug resistance. In consequence, researchers are trying to investigate and identify new molecules that can be assessed as therapeutic targets for more efficacious therapy of AML. The better understanding of AML biology, the closer the researchers come to the optimal therapy of this disease. The discovery and development of new drugs are extremely promising to achieve a therapeutic strategy. This project is focused on the investigation of the efficacy of two combined drugs to reduce or eliminate the number of cancerous cells of interest.

The term epigenetics indicates gene expression’s alternations inherited after the division of cell with no changes in the sequence of DNA (Egger et al., 2004). Adding to DNA methylation, histones’ epigenetic modification of increasing number, which includes ubiquitination, methylation and acetylation; have been subject to identification and deregulated frequently in AML (Wouters and Delwel, 2016). This has resulted in tumour suppressor genes’ repression and/or oncogenic pathways’ activation (Baylin and Jones, 2011). The histone acetylation and aberrant DNA methylation leads to silencing of gene and having prevalence in cancers such as leukaemia and has been the cancer therapy’s target since the approval of FDA of decitabine, azacytidine and DNMTi (DNA methyltransferase inhibitors) for treating certain AML and myelodysplastic syndrome (Navada et al., 2014). AML patients having age of over 65 years, although, having been under treatment with DNMTi cease to show longer OS (overall survival) significantly in comparison to the decitabine, azacytidine and conventional care regimen, decitabine and azacytidine, displaying better clinical efficacy and safety in patients with unfavorable myelodysplasia or cytogenetics related changes which indicates the reasons for them to preferred therapies for the AML population who are difficult to treat (Huls, 2015). Added to DNMTi, there have been several pan-histone deacetylase inhibitors that induce tumour suppressor genes’ re-expression and chromatin remodeling and being utilized and designed in AML treatment (Quintas-Cardama et al., 2011). While there has been the report of a single agent therapy having only clinical activity of modest measure, conjunction of DNMTi with histone deacetylase inhibitors (complete remission, decitabine: 31 percent) or with Ara-c (OS: 82 weeks, complete remission, cytarabine: 78 percent) in clinical trials appearing to have profound improvement in responses and being synergistic (Kirschbaum et al., 2014). Although, heterogeneous myeloid malignancies’ early endeavors have had the demonstration of safety and the potentiality of therapeutic values to target in clinical settings with epigenetic machinery, it also provides urgency with respect to the need for epigenetic regulation’s better understanding and exploration of novel critical targets to have more effectiveness in treatment of AML. In overcoming the problems having association with genetic heterogeneity, which can be, in part, responsible for histone deacetylase inhibitors or DNMTi’s poor efficacy in clinics, the studies conducted in recent times that focuses on leukaemia’s systematic analyses which carries specific mutations or transcription factors that affects histone methylation-modifying enzymes with the provision of novel tractable targets and important insights for epigenetic therapies in AML.

Discussion

MLL gene rearrangement can be termed as acute leukemias’ genetically distinct subset with poor prognosis. The options of treatment available currently are limitedly effective. Therefore, for the new therapies there is a pressing need in relation to the disease (Hess, 2004). The small molecular and genetic inhibitor studies have shown that there is requirement for histone methyltransferase DOT1L to develop and maintain MLL-rearranged leukemia. The characteristics of EPZ-5676, a selective and potent activity related to the DOT1L histone methyltransferase has been the aminonucleoside inhibitor. There is an inhibition constant value of the compound which is 80 pM, and its demonstration of selectivity to the tune of 37 000-fold over all other tested methyltransferases. The inhibition of EPZ-5676, in cellular studies, has been H3K79 methylation and the target gene expression of MLL-fusion and the killing of the potent cell been demonstrated have selectiveness for acute leukemia lines that bears the MLL translocations (Muntean and Hess, 2012). The continual EPZ-5676 IV infusion in the model of rat xenograft of the rearranged leukemia of MLL have the causation of complete regressions of tumor sustainable beyond the period of compound infusion having no significance in the toxicity signs or weight loss. Therefore, the EPZ-5676 has the potentiality to treat rearranged leukemia of MLL and is subject to clinical investigation.

The protein methyltransferases’ selective inhibition has a promise of fresh approach to the discovery of drug. Towards this goal, an attractive strategy is the developing of the compounds that do inhibition of binding selectively of the methyltransferases specific protein, within which, the binding of S-adenosylmethionine and the cofactor takes place. Protein methyltransferase’s three-dimensional structure is reported that are bound to EPZ004777 (Chi et al., 2010). The protein methyltransferase’s competitive inhibitor of S-adenosylmethionine has an efficacy in vivo. The four new analogues and the structure mentioned above have shown the catalytic site’s remodeling. A brominated analogue and EPZ004777, SGC0946, does inhibition of DOT1L in vitro and kill selectively the leukaemia cells of mixed lineage (Copeland et al., 2009). Here, the DOT1L is localized aberrantly via interacting with fusion protein of oncogenic MLL. The provision of significant new insight by these data has been to methyltransferase inhibitors of S-adenosylmethioninecompetitive protein that are cell active and the establishment of foundation to develop further the DOT1L inhibitors which are drug like for cancer therapy.

The studies conducted recently have the clarification, in part, with which transcriptional activity is modulated by the DOT1L and does contribution in deregulating the gene expression observable in MLL-rearranged leukemias. The DOT1L capacity in interacting with other proteins in forming the multiprotein complexes has been primary for transcriptional regulator’s physiological function and for the relevance in the contribution to the MLL-rearranged leukemias’ pathogenesis. The finding of the DOT1L is for the involvement to form the complexes with an AF10 family protein and ENL family protein, such as AF9 and AF10. The DOT1L’s association with these proteins augments the activity of methyltransferase of DOT1L in producing highly methylated 3 markers/ H3K79 me2 (Chen et al., 2015).

There is interaction between DOT1L and AF9 which forms with its C-terminus a stable complex. The interaction between H3K9ac and AF9 that takes place in active genes transcriptionally has been enriched. The enrichment takes place of most AF9-bound genes for both H3K79 me3 and H3K9 ac. The higher state of H3K79 methylation has been determined by AF10. Therefore, this augments the activity of methyltransferase in relation to DOT1L. The interaction of AF10 with H3K27 that has been unmodified, although cease to be methylated H3K27, which explains the reason of H3K27 methylation not co-occurring often with H3K79 methylation on the regions of genetics (Deshpande et al., 2014).

Future work

A key role is played by the transcriptional deregulation in acute leukaemogenesis and possibly on the responses of the treatment. The functions that have been emerging related to a range of histone methylome’s epigenetic modifying enzymes in AML pathogenesis have the provisions of unique opportunities in targeting this dismal disease group. Here the treatment regime of it for decades has not changed much. Adding to the histone mark erasers and writers, there is also the possibility of targeting readers that have the essentiality of recognizing the specific marks of histone like these for the aberrant transformation and the gene expression. There has been proposition that WDR5, one of the MLL complexes’ primary components for the activity of MLL histone methyltransferase, that have the recognition of H3K4me and the presentation thereof with the K4 side chain for the MLL causing methylation (Ruthenburg et al., 2006).

To block the interaction between the WDR5 and MLL1 with the help of MM-401, a small molecule inhibitor with diminished levels specifically at HOXA loci of H3K4me, inducing the myeloid differentiation and MLL-AF9 leukaemic cells of apoptosis of mouse being triggred (Cao et al., 2014). Adding to the WRD5 family, the considerable progress is being achieved in targeting bromodomain with its recognition of acetyl-lysine marks. The examples that can be the best here is the potentiality to target the MLL leukaemia’s BRD family. The pharmacological or the genetic inhibition of BRD3/4 by JQ1 or the GSK1210151A (I-BET151) led to the suppressing of the CDK6, Myc and BCL-2in leukaemic cells and displaying of the exceptional efficacy against human and mouse leukaemia cells that MLL fusions drives in vivo and in vitro (Zuber et al., 2011). Despite the fact that rapid development is taking place in preclinical models of drug resistance that has been due, in part, for the activation of the b-catenin or the canonical Wnt that signals for posing a threat for the effectiveness of the treatment by the inhibitors of BRD, the studies like these extends a key proof-of-principle data indicating the targeting protein–protein interaction feasibility which involves the epigenetic regulation for the treatment of leukaemia. The principles of similar nature will have the likelihood of applicability to the other readers having the involvement in histone methylome such as PHD domain and the chromodomain. The future studies to dissect the regulation of molecules of critical writers involved in histone methylome, the erasers and the readers shall open a capable venue to develop the effective AML treatments of next generation.

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