@article{dc9c7caaf49241688eb74e6001c218f1,
title = "TET2-mediated mRNA demethylation regulates leukemia stem cell homing and self-renewal",
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",
author = "Yangchan Li and Meilin Xue and Xiaolan Deng and Lei Dong and Nguyen, {Le Xuan Truong} and Lili Ren and Li Han and Chenying Li and Jianhuang Xue and Zhicong Zhao and Wei Li and Ying Qing and Chao Shen and Brandon Tan and Zhenhua Chen and Keith Leung and Kitty Wang and Srividya Swaminathan and Ling Li and Mark Wunderlich and Mulloy, {James C.} and Xiaobo Li and Hao Chen and Bin Zhang and David Horne and Rosen, {Steven T.} and Guido Marcucci and Mingjiang Xu and Zejuan Li and Minjie Wei and Jingyan Tian and Baiyong Shen and Rui Su and Jianjun Chen",
note = "Funding Information: We thank Dr. Gang (Greg) Wang for kindly providing MSCV-DNMT3AR882H and MSCV-DNMT3AR882H-NRASG12D. This work was supported in part by the National Institutes of Health (NIH) grants R01 CA214965 (to J.C.), R01 CA243386 (to J.C.), R01 CA236399 (to J.C.), R01 CA271497 (to J.C.), R01 DK124116 (to J.C.), and R01 CA280389 (to J.C.); the Simms/Mann Family Foundation (to J.C.); Leukemia Research Foundation New Investigator Research Grant (to R.S.); The Margaret E. Early Medical Research Trust (to R.S.); and AASLD Foundation grants PNC22-261362 (to R.S.) and T32 CA186895 (to B.T.). J.C. is a Leukemia & Lymphoma Society (LLS) Scholar. Z.L. is a Research Scholar of American Cancer Society. S.S. is a Scholar of the American Society of Hematology. R.S. and J.C. conceived and designed the entire project and supervised the research conducted in their laboratories; Y.L. M.X. X.D. L.X.T.N. L.R. L.H. C.L. J.X. Z.Z. W.L. Y.Q. C.S. B.T. M.X. K.L. K.W. R.S. and J.C. performed experiments and/or data analyses; L.D. performed the bioinformatics analysis; S.S. L.L. M.W. J.C.M. X.L. H.C. B.Z. D.H. S.T.R. G.M. Z.L. M.W. J.T. B.S. R.S. and J.C. contributed reagents/analytic tools and/or grant support; and Y.L. M.X. X.D. L.D. R.S. and J.C. wrote the paper. All authors discussed the results and commented on the manuscript. The authors declare no competing interests. Funding Information: We thank Dr. Gang (Greg) Wang for kindly providing MSCV-DNMT3A R882H and MSCV-DNMT3A R882H -NRAS G12D . This work was supported in part by the National Institutes of Health (NIH) grants R01 CA214965 (to J.C.), R01 CA243386 (to J.C.), R01 CA236399 (to J.C.), R01 CA271497 (to J.C.), R01 DK124116 (to J.C.), and R01 CA280389 (to J.C.); the Simms/Mann Family Foundation (to J.C.); Leukemia Research Foundation New Investigator Research Grant (to R.S.); The Margaret E. Early Medical Research Trust (to R.S.); and AASLD Foundation grants PNC22-261362 (to R.S.) and T32 CA186895 (to B.T.). J.C. is a Leukemia & Lymphoma Society (LLS) Scholar. Z.L. is a Research Scholar of American Cancer Society. S.S. is a Scholar of the American Society of Hematology. Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",
year = "2023",
month = aug,
day = "3",
doi = "10.1016/j.stem.2023.07.001",
language = "English (US)",
volume = "30",
pages = "1072--1090.e10",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "8",
}