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Haematologica 2020 Volume 105(1):148-160
Acute Myeloid Leukemia
Homoharringtonine exhibits potent anti-tumor effect and modulates DNA epigenome in acute myeloid leukemia by targeting SP1/TET1/5hmC
Chenying Li,1,2,3,* Lei Dong,2,3,* Rui Su,2,3,* Ying Bi,4 Ying Qing,2,3
Xiaolan Deng,2,3,5 Yile Zhou,1 Chao Hu,1 Mengxia Yu,1 Hao Huang,6
Xi Jiang,2,3,7 Xia Li,1 Xiao He,1 Dongling Zou,2,3,8 Chao Shen,2,3 Li Han,2,5 Miao Sun,9 Jennifer Skibbe,2 Kyle Ferchen,2 Xi Qin,2,3 Hengyou Weng,2,3 Huilin Huang,2,3 Chunxiao Song,4 Jianjun Chen2,3 and Jie Jin1
1Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, China; 2Department of Systems Biology & the Gehr Family Center for Leukemia Research, Beckman Research Institute of City of Hope, Monrovia, CA, USA; 3Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, USA; 4Ludwig Institute for Cancer Research & Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 5School of Pharmacy, China Medical University, Shenyang, Liaoning, China; 6Division of Gynecologic Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; 7Department of Pharmacology, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou, Zhejiang, China; 8Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China; 9Department of Pediatrics, University of Cincinnati College of Medicine; Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
*CL, LD and RS contributed equally to this work.
ABSTRACT
Homoharringtonine, a plant alkaloid, has been reported to suppress protein synthesis and has been approved by the US Food and Drug Administration for the treatment of chronic myeloid leukemia. Here we show that in acute myeloid leukemia (AML), homoharringtonine potently inhibits cell growth/viability and induces cell cycle arrest and apoptosis, significantly inhibits disease progression in vivo, and substantially prolongs survival of mice bearing murine or human AML. Strikingly, homo- harringtonine treatment dramatically decreases global DNA 5-hydrox- ymethylcytosine abundance through targeting the SP1/TET1 axis, and TET1 depletion mimics homoharringtonine's therapeutic effects in AML. Our further 5hmC-seq and RNA-seq analyses, followed by a series of vali- dation and functional studies, suggest that FLT3 is a critical down-stream target of homoharringtonine/SP1/TET1/5hmC signaling, and suppression of FLT3 and its downstream targets (e.g. MYC) contributes to the high sen- sitivity of FLT3-mutated AML cells to homoharringtonine. Collectively, our studies uncover a previously unappreciated DNA epigenome-related mech- anism underlying the potent antileukemic effect of homoharringtonine, which involves suppression of the SP1/TET1/5hmC/FLT3/MYC signaling pathways in AML. Our work also highlights the particular promise of clin- ical application of homoharringtonine to treat human AML with FLT3 mutations, which accounts for more than 30% of total cases of AML.
Introduction
Homoharringtonine (HHT, also known as omacetaxine mepesuccinate) is a cyto- toxic alkaloid originally isolated from the cephalotaxus hainanensis.1 It has been approved by the US Food and Drug Administration (FDA) for treatment of chronic myeloid leukemia (CML) with resistance and/or intolerance to imatinib or other
Correspondence:
JIE JIN
jiej0503@zju.edu.cn
JIANJUN CHEN
jianchen@coh.org
Received: October 8, 2018. Accepted: April 9, 2019. Pre-published: April 11, 2019.
doi:10.3324/haematol.2018.208835
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