2. Academic Validation
  3. A critical role of nuclear m6A reader YTHDC1 in leukemogenesis by regulating MCM complex-mediated DNA replication

A critical role of nuclear m6A reader YTHDC1 in leukemogenesis by regulating MCM complex-mediated DNA replication

  • Blood. 2021 Dec 30;138(26):2838-2852. doi: 10.1182/blood.2021011707.
Yue Sheng 1,  Jiangbo Wei 2 3,  Fang Yu 1,  Huanzhou Xu 4,  Chunjie Yu 1,  Qiong Wu 1,  Yin Liu 1,  Lei Li 5 6,  Xiao-Long Cui 2 3,  Xueying Gu 7,  Bin Shen 7,  Wei Li 5,  Yong Huang 8,  Sumita Bhaduri-McIntosh 4 9,  Chuan He 2 3,  Zhijian Qian 1
Affiliations

Affiliations

  • 1 Department of Medicine, UF Health Cancer Center, University of Florida, Gainesville, FL.
  • 2 Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL.
  • 3 Howard Hughes Medical Institute, The University of Chicago, Chicago, IL.
  • 4 Division of Infectious Disease, Department of Pediatrics, University of Florida, Gainesville, FL.
  • 5 Department of Biological Chemistry, School of Medicine, University of California, Irvine, CA.
  • 6 Institute of Systems and Physical Biology, Shenzhen Bay Laboratory, Shenzhen, China.
  • 7 State Key Laboratory of Reproductive Medicine, Center for Global Health, Gusu School, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing, China.
  • 8 Department of Medicine, University of Virginia, Charlottesville, VA; and.
  • 9 Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL.
PMID: 34255814 DOI: 10.1182/blood.2021011707
Abstract

YTHDC1 has distinct functions as a nuclear N6-methyladenosine (m6A) reader in regulating RNA metabolism. Here we show that YTHDC1 is overexpressed in acute myeloid leukemia (AML) and that it is required for the proliferation and survival of human AML cells. Genetic deletion of YTHDC1 markedly blocks AML development and maintenance as well as self-renewal of leukemia stem cells (LSCs) in vivo in mice. We found that YTHDC1 is also required for normal hematopoiesis and hematopoietic stem and progenitor cell (HSPC) maintenance in vivo. Notably, YTHDC1 haploinsufficiency reduces self-renewal of LSCs but not HSPCs in vivo. YTHDC1 knockdown has a strong inhibitory effect on proliferation of primary AML cells. Mechanistically, YTHDC1 regulates leukemogenesis through MCM4, which is a critical regulator of DNA replication. Our study provides compelling evidence that shows an oncogenic role and a distinct mechanism of YTHDC1 in AML.

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