C-terminal mutation of Nucleophosmin 1 (NPM1^C+) was thought to be a primary driving event in acute myeloid leukemia (AML) that reprograms leukemic-associated transcription programs to transform hematopoietic stem and progenitor cells (HSPCs). However, molecular mechanisms underlying NPM1^C+-driven leukemogenesis remain elusive. Here, we report that NPM1^C+ activates signature HOX genes and reprograms cell cycle regulators by altering CTCF-driven topologically associated domains (TADs). Hematopoietic-specific NPM1^C+ knock-in alters TAD topology leading to disrupted regulation of the cell cycle as well as aberrant chromatin accessibility and homeotic gene expression, which results in myeloid differentiation block. Restoration of NPM1 within the nucleus re-establishes differentiation programs by reorganizing TADs critical for myeloid TFs and cell cycle regulators that switch the oncogenic MIZ1/MYC regulatory axis in favor of interacting with coactivator NPM1/p300, and prevents NPM1^C+-driven leukemogenesis. In sum, our data reveal that NPM1^C+ reshapes CTCF-defined TAD topology to reprogram signature leukemic transcription programs required for cell cycle progression and leukemic transformation.

核磷蛋白 1 ( NPM1 ^C+ )的 C 端突变被认为是急性髓系白血病 (AML) 的主要驱动事件，它会重新编程白血病相关转录程序以转化造血干细胞和祖细胞 (HSPC)。然而，NPM1 ^C+驱动的白血病发生的分子机制仍然难以捉摸。在这里，我们报告NPM1 ^C+通过改变 CTCF 驱动的拓扑相关域 (TAD) 激活标志性 HOX 基因并重新编程细胞周期调节因子。造血特异性NPM1 ^C+敲入会改变 TAD 拓扑结构，导致细胞周期调节破坏以及染色质可及性和同源异型基因表达异常，从而导致骨髓分化阻断。细胞核内 NPM1 的恢复通过重组对髓系 TF 和细胞周期调节因子至关重要的 TAD 来重新建立分化程序，这些调节因子可切换致癌 MIZ1/MYC 调节轴，有利于与共激活因子 NPM1/p300 相互作用，并防止 NPM1 C+ 驱动的白血病^发生。总之，我们的数据表明，NPM1 ^C+重塑了 CTCF 定义的 TAD 拓扑，以重新编程细胞周期进展和白血病转化所需的标志性白血病转录程序。