TET2-mediated MRNA Demethylation Regulates Leukemia Stem Cell Homing and Self-renewal

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2023 Aug 4

PMID 37541212

Authors

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

Affiliations

Soon will be listed here.

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 (mC) modification in TSPAN13 mRNA; YBX1 specifically recognizes the mC 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 mC demethylase.

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