在伴随MLL基因重排的急性髓系白血病（MLL-AML）中，白血病干细胞（LSCs）持续的自我更新是其难治复发的主要原因之一，DOT1L可通过组蛋白甲基化介导MLL靶基因高表达调控LSCs自我更新，已经作为临床治疗MLL白血病的靶点。DNA损伤应答反应关键分子ATM作为辅助靶点能够调节AML细胞存活，我们前期研究显示，ATM缺失导致DOT1L蛋白水平下调从而使小鼠MLL-AML LSCs的自我更新能力显著下降，此外，DOT1L的抑制同时导致ATM表达水平的降低。基于此，我们提出ATM-DOT1L正反馈调控MLL LSCs自我更新能力的科学假说。我们将解析ATM维持DOT1L稳定性的分子机制，阐明DOT1L调节ATM表达的分子基础，证实靶向DOT1L稳定性和活性更有效抑制MLL-AML LSCs自我更新，为基于DOT1L的稳定性和活性靶向LSCs自我更新的MLL-AML治疗提供有效的参考依据。

In acute myeloid leukemia with MLL rearrangement (MLL-AML), the continuous self-renewal of leukemia stem cells (LSCs) is one of the key reasons for its refractory recurrence. DOT1L can regulate the self-renewal of LSCs through histone methylation mediated high expression of MLL target genes, and has been used as a target for clinical treatment of MLL leukemia. ATM, a key molecule in DNA damage response, acts as an auxiliary target to regulate AML cell survival. Our present study showed that ATM deficiency led to the down-regulation of DOT1L at the protein level, which significantly reduced the self-renewal ability of murine MLL-AML LSCs. In addition, the inhibition of DOT1L also resulted in a decrease in ATM expression. Based on this, we propose a scientific hypothesis that the positive feedback of ATM-DOT1L regulates the self-renewal ability of MLL LSCs. We will decipher the molecular mechanism of ATM maintaining the stability of DOT1L, clarify the molecular basis of DOT1L regulating ATM expression, and confirm that simultaneously targeting the stability and activity of DOT1L is more effective in suppressing the self-renewal of MLL-AML LSCs. We would provide a strong evidence for the treatment of MLL-AML by targeting LSCs self-renewal based on the stability and activity of DOT1L.