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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,
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.
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
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