期刊
EXPERIMENTAL HEMATOLOGY
卷 92, 期 -, 页码 19-31出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.exphem.2020.09.189
关键词
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资金
- Council for Scientific & Industrial Research (CSIR) [NWP/HCP-0008]
- Department of Biotechnology (DBT) [BT/RLF/RE-ENTRY/06/2010]
- DBT [BT/PR13023/MED/31/311/2015]
- SERB-Department of Science & Technology (DST), Government of India [SB/SO/HS-053/2013]
- Indian Council of Medical Research-Department of Health Research (ICMR-DHR) International Fellowship for Indian Biomedical Scientists [INDO/FRC/452/S-11/2019-20-lHD]
- CSIR
- Shyama Prasad Mukherjee Fellowship
Acute myeloid leukemia (AML) is an aggressive, disseminated hematological malignancy associated with clonal selection of aberrant self-renewing hematopoietic stem cells and progenitors and poorly differentiated myeloid blasts. The most prevalent form of leukemia in adults, AML is predominantly an age-related disorder and accounts for more than 10,000 deaths per year in the United States alone. In comparison to solid tumors, AML has an overall low mutational burden, albeit more than 70% of AML patients harbor somatic mutations in genes encoding epigenetic modifiers and chromatin regulators. In the past decade, discoveries highlighting the role of DNA and histone modifications in determining cellular plasticity and lineage commitment have attested to the importance of epigenetic contributions to tumor cell de-differentiation and heterogeneity, tumor initiation, maintenance, and relapse. Orchestration in histone methylation levels regulates pluripotency and multicellular development. The increasing number of reversible methylation regulators being identified, including histone methylation writer, reader, and eraser enzymes, and their implications in AML pathogenesis have widened the scope of epigenetic reprogramming, with multiple drugs currently in various stages of preclinical and clinical trials. AML methylome also determines response to conventional chemotherapy, as well as AML cell interaction within a tumor-immune microenvironment ecosystem. Here we summarize the latest developments focusing on molecular derangements in histone methyltransferases (HMTs) and histone demethylases (HDMs) in AML pathogenesis. AML-associated HMTs and HDMs, through intricate crosstalk mechanisms, maintain an altered histone methylation code conducive to disease progression. We further discuss their importance in governing response to therapy, which can be used as a biomarker for treatment efficacy. Finally we deliberate on the therapeutic potential of targeting aberrant histone methylome in AML, examine available small molecule inhibitors in combination with immunomodulating therapeutic approaches and caveats, and discuss how future studies can enable posited epigenome-based targeted therapy to become a mainstay for AML treatment. (C) 2020 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
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