Genetics of Myelodysplastic Syndromes: New Insights

Abstract

Myelodysplastic syndromes (MDS) are a heterogenous group of hematologic malignancies characterized by clonal expansion of BM myeloid cells with impaired differentiation. The identification of recurrent mutations in MDS samples has led to new insights into the pathophysiology of these disorders. Of particular interest is the recent recognition that genes involved in the regulation of histone function (EZH2, ASXL1, and UTX) and DNA methylation (DNMT3A, IDH1/IDH2, and TET2) are recurrently mutated in MDS, providing an important link between genetic and epigenetic alterations in this disease. The mechanism by which these mutated genes contribute to disease pathogenesis is an active area of research, with a current focus on which downstream target genes may be affected. Recent advances from sequencing studies suggest that multiple mutations are required for MDS initiation and progression to acute myeloid leukemia (AML). The past several years have yielded many new insights, but the complete genetic landscape of MDS is not yet known. Moreover, few (if any) of the findings are sufficiently robust to be incorporated into routine clinical practice at this time. Additional studies will be required to understand the prognostic implications of these mutations for treatment response, progression to AML, and survival.

Age-related epigenetic drift in the pathogenesis of MDS and AML

“…TET2 is the most frequent gene abnormality in MDS (Kosmider et al 2009;Langemeijer et al 2009), and DNMT3A mutation is a very early genetic event in MDS . These mutations in epigenetic modifiers indicate that epigenetic changes contribute to MDS pathogenesis (Graubert and Walter 2011;Nikoloski et al 2012).…”

Genotyping of 25 Leukemia-Associated Genes in a Single Work Flow by Next-Generation Sequencing Technology with Low Amounts of Input Template DNA

“…related tyrosine kinase 3), JAK2 (Janus kinase 2), MPL (myeloproliferative leukemia virus oncogene), and CBL (Cbl proto-oncogene, E3 ubiquitin protein ligase); genes encoding transcription and other nuclear factors, such as RUNX1 (runt-related transcription factor 1), TP53 (tumor protein p53), and NPM1 [nucleophosmin (nucleolar phosphoprotein B23, numatrin)]; and genes involved in epigenetic regulation, such as TET2 (tet methylcytosine dioxygenase 2), ASXL1 [additional sex combs like 1 (Drosophila)], EZH2 [enhancer of zeste homolog 2 (Drosophila)], DNMT3A [DNA (cytosine-5-)-methyltransferase 3 alpha], IDH1 [isocitrate dehydrogenase 1 (NADPϩ), soluble], and IDH2 [isocitrate dehydrogenase 2 (NADPϩ), mitochondrial]. None of these aberrations, however, are specific to any particular AML, MDS, MPN, or MDS/ MPN subtype (1)(2)(3)(4). In addition, mutations in genes involved in the RNA-splicing machinery, such as SF3B1 (splicing factor 3b, subunit 1, 155kDa), SRSF2 (serine/arginine-rich splicing factor 2), U2AF1 [U2 small nuclear RNA auxiliary factor 1 (also known as U2AF35)], and ZRSR2 [zinc finger (CCCH type), RNA-binding motif and serine/arginine rich], have recently been identified in MDS and in chronic myelomonocytic leukemia (CMML), as well as in AML and MPN at lower frequencies (5)(6)(7).…”

Epigenetic alterations and microRNAs

“…Of note, isocitrate dehydrogenase 1 (IDH1) converts isocitrate to aKG which is necessary for TET2 function. 22 As a result, proper function of DNMTs, TET proteins and IDH1 protein are necessary for normal DNA methylation.…”