Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia

Abstract

Recent studies of the spectrum of somatic genetic alterations in acute myeloid leukemia (AML) have identified frequent somatic mutations in genes that encode proteins important in the epigenetic regulation of gene transcription. This includes proteins involved in the modification of DNA cytosine residues and enzymes which catalyze posttranslational modifications of histones. Here we describe the clinical, biological, and therapeutic relevance of mutations in epigenetic regulators in AML. In particular, we focus on the role of loss-of-function mutations in TET2, gainof-function mutations in IDH1 and IDH2, and loss-of-function mutations in ASXL1 and mutations of unclear impact in DNMT3A in AML pathogenesis and therapy. Multiple studies have consistently identified that mutations in these genes have prognostic relevance, particularly in intermediate-risk AML patients, arguing for inclusion of mutational testing of these genetic abnormalities in routine clinical practice. Moreover, biochemical, biological, and epigenomic analyses of the effects of these mutations have informed the development of novel therapies which target pathways deregulated by these mutations. Our understanding of the effects of these mutations on hematopoiesis and potential for therapeutic targeting of specific AML subsets is also reviewed here. (Blood. 2013;121(18):3563-3572)

Aspects moléculaires des lymphomes T périphériques (1)

“…En effet, les marqueurs de TFH, CXCL13, PD1 ou ICOS, sont validés en tant que nouveaux biomarqueurs des LAIT et permettent en particulier de distinguer ce lymphome d'autres entités de LTP [17,18] (Figure 1). De façon intéressante, les mutations de TET2, DNMT3A, IDH2 sont également observées dans les hémopathies myéloïdes (non lymphoïdes) [33]. Or, certains patients porteurs de mutations de TET2 et/ou DNMT3A pré-sentent, séquentiellement ou de façon concomitante, un lymphome T et un syndrome myélodysplasique [27].…”

Erratum: Highly effective combination of LSD1 (KDM1A) antagonist and pan-histone deacetylase inhibitor against human AML cells

“…In the pathogenesis of AML, multiple mechanisms involving genetic alterations and epigenetic deregulations collaborate to cause aberrant maturation arrest, growth and survival of early myeloid progenitor cells (3,4). Among the deregulated epigenetic mechanisms, in addition to DNA methylation and histone (H) de-acetylation, alterations in histone H3 lysine (K)-specific methylation are involved in promoting the aberrant gene expression or 'transcriptome' in AML cells, which includes the deregulated expression of oncogenes and tumor suppressor genes (5,6). While the levels H3K27 trimethylation (3Me) and H3K9Me3 are among the repressive chromatin marks, H3K4Me3 is a permissive histone modification that promotes gene transcription (3,6).…”

Insights into cell ontogeny, age, and acute myeloid leukemia

“…TET2 mutations in adult AML commonly co-occur with other somatic mutations including NPM1, RARα, KIT, FLT3, RAS, MLL and C/EBPα [92][93][94][95][96]. ASXL1 mutations occur in adult AML (5-30%) more often in patients over 60 years (16%) than in patients 60 years and younger (3.2%).…”