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European Oncology & Haematology Highlights Haematological Malignancies Myelodysplastic Syndromes – The Epigenetic Model for Drug Development? Guillermo Montalban-Bravo and Guillermo Garcia-Manero Department of Leukemia, The University of Texas MD Anderson Cancer Centre, Houston, Texas, US A pplication of sequencing technology has advanced our understanding of the molecular landscape of myelodysplastic syndromes (MDS). Recurrent driver mutations in genes implicated in epigenetic regulation, and functional modelling of the disease has proven the importance of epigenetic dysregulation in MDS pathogenesis. Although available therapies such as azacitidine and decitabine are thought to exert their effect by epigenetic modulation, deep understanding of disease biology and development of specific epigenetically targeted therapies is still an area under active research. In this editorial we will focus on the molecular basis of MDS with particular focus on epigenetic dysregulation and new agents under development targeting this group of biological processes. Keywords Myelodysplastic syndromes, MDS, epigenetics, targeted therapies Disclosure: Guillermo Montalban-Bravo and Guillermo Garcia-Manero have nothing to disclose in relation to this article. This article is a short opinion piece and has not been submitted to external peer reviewers. No funding has been received for the publication of this article. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: 7 April 2016 Accepted: 24 May 2016 Citation: European Oncology & Haematology, 2016;12(1):13–4 Corresponding Author: Guillermo Garcia-Manero MD, Department of Leukemia, University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77015, US. E: ggarciam@mdanderson.org Epigenetic dysregulation in myelodysplastic syndromes – how important is it? Our understanding of the biology and pathogenesis of myelodysplastic syndromes (MDS) has evolved dramatically in the last two decades. Evidence of an epigenetic background of the disease identified by a hypermethylation of specific genes and promoter-associated CpG islands was reported in the late 1990s 1 and first decade of this century. 2 Multiple sequencing efforts have shed light in the molecular annotation of the disease 3–6 and have allowed to better group and dissect the different entities within this heterogeneous group of diseases. 7,8 Dysregulation of epigenetic processes such as DNA methylation, histone modifications, miRNA and splicing machinery are essential in MDS pathogenesis and, in fact, multiple mutations and epimutations in well characterised epigenetically related genes such as DNTM3A, TET2, ASXL1, EZH2, IDH1/2 and splicing factors such as U2AF1, SF3B1, ZRSR2 and SRSF2 have been consistently described. 9–12 Functional assays in cellular and murine models exploring the leukemogenic potential of such mutations have also confirmed these findings 13–18 As a result of this, despite the complexity and heterogeneity of MDS pathogenesis, MDS can be considered, at least partially, an epigenetic disease. Interestingly, recent studies by several groups including Jaiwal et al., 19 Xie et al. 20 and Genovese et al. 21 have confirmed that many of such mutations, particularly DNTM3A, TET2 and ASXL1 mutations, can be identified with increased frequency in elderly individuals with no evidence of haematological malignancy as part of what has been named clonal haematopoiesis of indeterminate potential (CHIP). This is particularly relevant considering haematopoietic stem-cell aging is likely one of the mechanisms implicated in MDS clonal initiation and progression 19,22–24 and that these same mutations are known to participate in this aging process. In fact, there is evidence supporting that individuals with CHIP, as those with idiopathic cytopenias of unknown significance (ICUS), characterised by cytopenias with no significant dysplasia and presence of CHIP-like mutations in up to 28% of cases, are at an increased risk of ultimately developing MDS. 25,26 These findings suggest epigenetic dysregulation is at the base of the progressive biological process driving clonal evolution leading to MDS. Targeting the epigenome in myelodysplastic syndromes – state of the art and future perspectives While the above mentioned findings have clearly advanced the knowledge-base of MDS pathophysiology, clear therapeutic and prognostic impact of this data still remains elusive and, despite a few exceptions, has not yet allowed modifying disease treatment. One of such exceptions was the development and subsequent approval by the FDA of azacitidine and decitabine, two cytidine analogues with a potent inhibitory effect of DNA methylation by induction of DNA methyl transferase (DNMT) depletion. Although approval of these agents led to a revolution of the treatment of these patients, reducing and delaying the risk of transformation to acute leukaemia and prolonging 102 TOUCH ME D ICA L ME D IA