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

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

来源：Cell Stem Cell, 2023, 30(8): 1072-+.

DOI：10.1016/j.stem.2023.07.001

• ACUTE MYELOID-LEUKEMIA
• TET-MEDIATED FORMATION
• MUTATIONS
• 5-METHYLCYTOSINE
• LEADS
• MOUSE
• BINDING
• VECTOR

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 defi-ciency 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 impor-tance of TET2 in leukemogenesis, leukemic blast cell migration/homing, and LSC self-renewal as an mRNA m5C demethylase.

• 单位
  上海交通大学; 中山大学; 浙江大学; 中国医科大学; 哈尔滨医科大学