TET2基因在急性髓系白血病（AML）中经常发生突变，其缺乏促进了白血病发生（由侵袭性致癌突变驱动）并增强了白血病干细胞（LSC）的自我更新能力。然而，其潜在的细胞/分子机制尚未完全理解。在这里，我们展示了Tet2缺乏明显促进了各种AML模型中的白血病发生（通过侵袭性或较不侵袭性突变介导），通过促进LSCs对骨髓（BM）微环境的迁移以增加其自我更新/增殖。AML爆发细胞中的TET2缺乏增加了Tetraspanin 13（TSPAN13）的表达，从而激活CXCR4 / CXCL12信号通路，导致LSCs对BM生境的迁移/迁入增加。在机制上，TET2缺陷导致TSPAN13 mRNA中甲基-5-胞嘧啶（m5C）修饰的积累；YBX1特异性识别m5C修饰，并增加TSPAN13转录本的稳定性和表达。总之，我们的研究揭示了TET2在白血病发生、白血病爆发细胞的迁移/迁入和LSCs自我更新中的功能重要性，作为mRNA m5C去甲基酶。版权所有©2023 Elsevier Inc. 保留所有权利。

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.Copyright © 2023 Elsevier Inc. All rights reserved.