RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia

Chao Shen; Yue Sheng; Allen C Zhu; Sean Robinson; Xi Jiang; Lei Dong; Huiying Chen; Rui Su; Zhe Yin; Wei Li; Xiaolan Deng; Yinhuai Chen; Yueh-Chiang Hu; Hengyou Weng; Huilin Huang; Emily Prince; Christopher R Cogle; Miao Sun; Bin Zhang; Chun-Wei Chen; Guido Marcucci; Chuan He; Zhijian Qian; Jianjun Chen

doi:10.1016/j.stem.2020.04.009

RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia

Cell Stem Cell. 2020 Jul 2;27(1):64-80.e9. doi: 10.1016/j.stem.2020.04.009. Epub 2020 May 12.

Authors

Chao Shen¹, Yue Sheng², Allen C Zhu³, Sean Robinson¹, Xi Jiang⁴, Lei Dong¹, Huiying Chen¹, Rui Su¹, Zhe Yin⁵, Wei Li¹, Xiaolan Deng¹, Yinhuai Chen⁶, Yueh-Chiang Hu⁶, Hengyou Weng¹, Huilin Huang¹, Emily Prince¹, Christopher R Cogle², Miao Sun⁷, Bin Zhang⁸, Chun-Wei Chen¹, Guido Marcucci⁸, Chuan He⁹, Zhijian Qian¹⁰, Jianjun Chen¹¹

Affiliations

¹ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
² Department of Medicine and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32608, USA.
³ Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Medical Scientist Training Program/Committee on Cancer Biology, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA.
⁴ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Pharmacology, and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Institute of Hematology, Zhejiang University, and Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou 310058, Zhejiang Province, China.
⁵ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Thoracic Surgery, Chongqing Cancer Hospital, Chongqing 400030, China.
⁶ Transgenic Animal and Genome Editing Facility, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
⁷ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
⁸ Department of Hematologic Malignancies Translational Science, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
⁹ Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, Medical Scientist Training Program/Committee on Cancer Biology, Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.
¹⁰ Department of Medicine and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32608, USA. Electronic address: zhijian.qian@medicine.ufl.edu.
¹¹ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. Electronic address: jianchen@coh.org.

Abstract

N⁶-methyladenosine (m⁶A), the most abundant internal modification in mRNA, has been implicated in tumorigenesis. As an m⁶A demethylase, ALKBH5 has been shown to promote the development of breast cancer and brain tumors. However, in acute myeloid leukemia (AML), ALKBH5 was reported to be frequently deleted, implying a tumor-suppressor role. Here, we show that ALKBH5 deletion is rare in human AML; instead, ALKBH5 is aberrantly overexpressed in AML. Moreover, its increased expression correlates with poor prognosis in AML patients. We demonstrate that ALKBH5 is required for the development and maintenance of AML and self-renewal of leukemia stem/initiating cells (LSCs/LICs) but not essential for normal hematopoiesis. Mechanistically, ALKBH5 exerts tumor-promoting effects in AML by post-transcriptional regulation of its critical targets such as TACC3, a prognosis-associated oncogene in various cancers. Collectively, our findings reveal crucial functions of ALKBH5 in leukemogenesis and LSC/LIC self-renewal/maintenance and highlight the therapeutic potential of targeting the ALKBH5/m⁶A axis.

Keywords: ALKBH5; MYC; P21; TACC3; acute myeloid leukemia; hematopoietic stem cells (HSCs); leukemia stem cells (LSCs/LICs); m(6)A modification; normal hematopoiesis; prognosis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

AlkB Homolog 5, RNA Demethylase / genetics
Carcinogenesis / genetics
Cell Self Renewal*
Humans
Leukemia, Myeloid, Acute* / genetics
Microtubule-Associated Proteins
Neoplastic Stem Cells

Substances

Microtubule-Associated Proteins
TACC3 protein, human
ALKBH5 protein, human
AlkB Homolog 5, RNA Demethylase

Abstract

Publication types

MeSH terms

Substances

Grants and funding