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Insight into the molecular pathophysiology of myelodysplastic syndromes: targets for novel therapy
Author(s) -
Zahid Mohammad Faizan,
Patnaik Mrinal M.,
Gangat Naseema,
Hashmi Shahrukh K.,
Rizzieri David A.
Publication year - 2016
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.12771
Subject(s) - biology , epigenetics , cancer research , stromal cell , progenitor cell , myelodysplastic syndromes , chromatin remodeling , stem cell , tumor microenvironment , chromatin , bone marrow , immune system , immunology , microbiology and biotechnology , genetics , gene
Myelodysplastic syndromes ( MDS ) are clonal hematopoietic stem cell disorders characterized by abnormal cellular differentiation and maturation with variable progression to acute leukemia. Over the last decade, scientific discoveries have unraveled specific pathways involved in the complex pathophysiology of MDS . Prominent examples include aberrations in cytokines and their signaling pathways (such as tumor necrosis factor‐alpha, interferon‐gamma, SMAD proteins), mutations in genes encoding the RNA splicing machinery ( SF 3B1 , SRSF 2 , ZRSR 2 , and U2 AF 1 genes), mutations in genes disrupting the epigenetic machinery ( TET 2 , DNMT 3A , DNMT 3B , EZH 2 , ASXL 1 ). In addition, abnormalities in regulatory T‐cell dynamics and atypical interactions between the bone marrow microenvironment, stroma and progenitor cells, and abnormal maintenance of telomeres are also notable contributors to the complex pathogenesis of MDS . These pathways represent potential targets for novel therapies. Specific therapies include drugs targeting aberrant DNA methylation and chromatin remodeling, modulating/activating the immune system to enhance tumor‐specific cellular immune responses and reduce anomalous cytokine signaling, and blocking abnormal interaction between hematopoietic progenitors and stromal cells.