Genetic mutations in epigenetic modifiers as therapeutic targets in acute myeloid leukemia

Abstract

Current clinical and preclinical studies are underscoring the importance of targeting epigenetic modifiers as new biomarkers for a better prognostic risk stratification and therapeutic evaluation of intermediate-risk patients. Combining data from traditional and modern methodologies will allow a definition of the complex networks of epigenetic changes and molecular interactions between candidate epitargets and key regulators of hematopoiesis. It will thus be possible to achieve an overview of potential aberrant mechanisms driving leukemogenesis in different classes of AML patients. Such an improved approach could pave the way towards 'personalized' therapies.

Molecular and Cellular Mechanisms of Myelodysplastic Syndrome: Implications on Targeted Therapy

“…DNMT3A mutations occur in 30%–35% of AML with normal karyotype, and about 10% of MDS and 20% of T-lineage acute lymphoblastic leukemia [ 27 , 28 , 29 ]. DNMT3A mutations result in loss of function, and are present in pre-leukemic hematopoietic stem cells, remaining stable through disease evolution to MDS and AML [ 30 , 31 ].…”

“…Azacitidine and decitabine incorporate into DNA, resulting in proteosomal degradation of DNMTs. Guadecitibine (SGI-110) is a second generation HMA and a dinucleotide of decitabine and deoxyguanosine [ 28 ], with its use leading to extended decitabine exposure via resistance to deamination. Apart from DNA methylation, histone deacetylation is the other post-translational modification involved in the silencing of genes.…”

“…Phase II trials of HDAC inhibitors in combination with HMAs are ongoing. Examples of HDAC inhibitors that have shown activity in combination with HMAs include pracinostat, vorinostat, and valproic acid [ 28 ].…”

“…Isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) are a family of NADP-dependent enzymes critically involved in the conversion of isocitrate to α-ketoglutarate (α-KG) [ 27 , 28 ]. IDH1/2 mutations are heterozygous and occur mostly at residues R132 in IDH1 , and R140 or R172 in IDH2 .…”

“…As a result, abnormal intracellular accumulation of 2-HG inhibits the dioxygenase enzymes JumonjiC (JmjC) and TET2, prolyl/lysyl hydroxylases, and cytochrome C oxidase (COX). These enzyme inhibitions lead to epigenetic dysregulations [ 27 , 28 ] postulated to be involved in oncogenesis, so that 2-HG is considered an oncometabolite. IDH1/2 mutations are seen in patients with cytogenetically normal AML, MDS, MPN, angioimmunoblastic T-cell lymphoma, glioma, cholangiocarcinoma, and chondrosarcoma [ 27 , 35 ].…”