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 WunderlichJames 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

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1072-1090.e10
JournalCell Stem Cell
Volume30
Issue number8
DOIs
StatePublished - Aug 3 2023

Keywords

  • CXCR4
  • RNA 5-methylcytosine methylation
  • TET2
  • TSPAN13
  • YBX1
  • bone marrow microenvironment
  • homing
  • leukemia stem cell
  • migration
  • self-renewal

ASJC Scopus subject areas

  • Genetics
  • Molecular Medicine
  • Cell Biology

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