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Haematologica. 2019 Apr 11. pii: haematol.2018.208835. doi: 10.3324/haematol.2018.208835. [Epub ahead of print]

Homoharringtonine exhibits potent anti-tumor effect and modulates DNA epigenome in acute myeloid leukemia by targeting SP1/TET1/5hmC.

Author information

1
Dept of Hematology, First Affiliated Hospital of Zhejiang Univ College of Medicine, Hangzhou, China.
2
Dept of Systems Biology & the Gehr Family Center for Leukemia Research, City of Hope, USA.
3
Ludwig Institute for Cancer Research & Target Discovery Institute, University of Oxford, UK.
4
Division of Gynecologic Oncology, Feinberg School of Medicine, Northwestern University.
5
Depart of Gynecologic Oncology,Chongqing University Cancer Hospital & Chongqing Cancer Institute.
6
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
7
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA.
8
Dept of Hematology, First Affiliated Hospital of Zhejiang Univ College of Medicine, Hangzhou, China; jiej0503@zju.edu.cn.

Abstract

Homoharringtonine, a plant alkaloid, has been reported to suppress protein synthesis and approved by U.S. Food and Drug Administration for chronic myeloid leukemia treatment. Here we show that homoharringtonine also potently inhibits cell growth/viability and induces cell cycle arrest and apoptosis in acute myeloid leukemia, and significantly inhibits acute myeloid leukemia progression in vivo and substantially prolongs survival of mice bearing murine or human acute myeloid leukemia. Strikingly, homoharringtonine treatment dramatically decreases global DNA 5-hydroxymethylcytosine abundance through targeting the SP1/TET1 axis, and TET1 depletion mimics homoharringtonine's therapeutic effects in acute myeloid leukemia. Our further 5hmC-seq and RNA-seq analyses, followed by a series of validation and functional studies, suggest that FLT3 is a critical down-stream target of the homoharringtonine/SP1/TET1/5hmC signaling, and suppression of FLT3 and its downstream targets (e.g., MYC) contributes to the high sensitivity of FLT3-mutated acute myeloid leukemia cells to homoharringtonine. Collectively, our studies uncover a previously unappreciated, DNA epigenome-related mechanism underlying the potent antileukemic effect of homoharringtonine, which involves suppression of the SP1/TET1/5hmC/FLT3/MYC signaling pathways in acute myeloid leukemia. Our work also highlights the particular promise of clinical application of homoharringtonine to treat human acute myeloid leukemia with FLT3 mutations, which accounts for more than 30% of total acute myeloid leukemia cases.

KEYWORDS:

Acute Myeloid Leukemia; DNA Epigenetics; DNA Epigenome; Therapeutics

PMID:
30975912
DOI:
10.3324/haematol.2018.208835
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