TET2-mediated mRNA demethylation regulates leukemia stem cell homing and self-renewal

Yangchan Li; Meilin Xue; Xiaolan Deng; Lei Dong; Le Xuan Truong Nguyen; Lili Ren; Li Han; Chenying Li; Jianhuang Xue; Zhicong Zhao; Wei Li; Ying Qing; Chao Shen; Brandon Tan; Zhenhua Chen; Keith Leung; Kitty Wang; Srividya Swaminathan; Ling Li; Mark Wunderlich; James C Mulloy; Xiaobo Li; Hao Chen; Bin Zhang; David Horne; Steven T Rosen; Guido Marcucci; Mingjiang Xu; Zejuan Li; Minjie Wei; Jingyan Tian; Baiyong Shen; Rui Su; Jianjun Chen

doi:10.1016/j.stem.2023.07.001

TET2-mediated mRNA demethylation regulates leukemia stem cell homing and self-renewal

Cell Stem Cell. 2023 Aug 3;30(8):1072-1090.e10. doi: 10.1016/j.stem.2023.07.001.

Authors

Yangchan Li¹, Meilin Xue², Xiaolan Deng³, Lei Dong³, Le Xuan Truong Nguyen⁴, Lili Ren⁵, Li Han⁶, Chenying Li⁷, Jianhuang Xue³, Zhicong Zhao³, Wei Li³, Ying Qing³, Chao Shen³, Brandon Tan³, Zhenhua Chen³, Keith Leung³, Kitty Wang³, Srividya Swaminathan⁸, Ling Li⁹, Mark Wunderlich¹⁰, James C Mulloy¹⁰, Xiaobo Li¹¹, Hao Chen¹², Bin Zhang⁹, David Horne¹³, Steven T Rosen¹⁴, Guido Marcucci⁹, Mingjiang Xu¹⁵, Zejuan Li¹⁶, Minjie Wei¹⁷, Jingyan Tian¹⁸, Baiyong Shen¹⁹, Rui Su²⁰, Jianjun Chen²¹

Affiliations

¹ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China.
² Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
³ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
⁴ Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA; Department of Hematological Malignancies Translational Science, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
⁵ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Pathology, Harbin Medical University, Harbin 150081, China.
⁶ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110001, Liaoning, China.
⁷ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Hematology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 31003, Zhejiang, China.
⁸ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Pediatrics, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
⁹ Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA; Department of Hematological Malignancies Translational Science, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA.
¹⁰ Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
¹¹ Department of Pathology, Harbin Medical University, Harbin 150081, China.
¹² Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
¹³ City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
¹⁴ Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA; City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; Department of Hematology/Hematopoietic Cell Transplantation, City of Hope, Duarte, CA 91010, USA.
¹⁵ Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA.
¹⁶ Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, USA.
¹⁷ Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang 110001, Liaoning, China.
¹⁸ State Key Laboratory of Medical Genomics, Clinical Trial Center, Shanghai Institute of Endocrine and Metabolic Diseases, Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: tianjypaper@163.com.
¹⁹ Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. Electronic address: shenby@shsmu.edu.cn.
²⁰ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. Electronic address: rsu@coh.org.
²¹ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA 91010, USA; City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. Electronic address: jianchen@coh.org.

Abstract

TET2 is recurrently mutated in acute myeloid leukemia (AML) and its deficiency promotes leukemogenesis (driven by aggressive oncogenic mutations) and enhances leukemia stem cell (LSC) self-renewal. However, the underlying cellular/molecular mechanisms have yet to be fully understood. Here, we show that Tet2 deficiency significantly facilitates leukemogenesis in various AML models (mediated by aggressive or less aggressive mutations) through promoting homing of LSCs into bone marrow (BM) niche to increase their self-renewal/proliferation. TET2 deficiency in AML blast cells increases expression of Tetraspanin 13 (TSPAN13) and thereby activates the CXCR4/CXCL12 signaling, leading to increased homing/migration of LSCs into BM niche. Mechanistically, TET2 deficiency results in the accumulation of methyl-5-cytosine (m⁵C) modification in TSPAN13 mRNA; YBX1 specifically recognizes the m⁵C modification and increases the stability and expression of TSPAN13 transcripts. Collectively, our studies reveal the functional importance of TET2 in leukemogenesis, leukemic blast cell migration/homing, and LSC self-renewal as an mRNA m⁵C demethylase.

Keywords: CXCR4; RNA 5-methylcytosine methylation; TET2; TSPAN13; YBX1; bone marrow microenvironment; homing; leukemia stem cell; migration; self-renewal.

Publication types

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

MeSH terms

Bone Marrow / metabolism
Carcinogenesis / metabolism
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Demethylation
Dioxygenases* / metabolism
Humans
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / metabolism
Neoplastic Stem Cells / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Stem Cells / metabolism
Tetraspanins / metabolism

Substances

RNA, Messenger
TSPAN13 protein, human
Tetraspanins
TET2 protein, human
DNA-Binding Proteins
Dioxygenases

Abstract

Publication types

MeSH terms

Substances

Grants and funding