Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata 997-0052, Japan.
Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
Cell Rep. 2020 Sep 29;32(13):108200. doi: 10.1016/j.celrep.2020.108200.
Uncontrolled self-renewal of hematopoietic progenitors induces leukemia. To self-renew, leukemia cells must continuously activate genes that were previously active in their mother cells. Here, we describe the circuitry of a transactivation system responsible for oncogenic self-renewal. MLL recruits RNA polymerase II (RNAP2) to unmethylated CpG-rich promoters by its CXXC domain and activates transcription by transcriptional regulators, including the AF4 family/ENL family/P-TEFb complex, DOT1L, and p300/CBP histone acetyl transferases. MOZ also targets a broad range of CpG-rich promoters through association with RNAP2 and MLL. Leukemic fusion proteins such as MOZ-TIF2 and MLL-AFX constitutively activate CpG-rich promoters by aberrantly recruiting p300/CBP. Pharmacological inhibition of MLL or DOT1L induces differentiation of MOZ-TIF2-transformed cells. These results reveal that activation of unmethylated CpG-rich promoters mediated by MLL is the central mechanism of oncogenic self-renewal in MOZ-rearranged leukemia and indicate that the molecularly targeted therapies intended for MLL-rearranged leukemia can be applied for MOZ-rearranged leukemia.
造血祖细胞的失控自我更新会引发白血病。为了自我更新，白血病细胞必须持续激活其母细胞中先前活跃的基因。在这里，我们描述了一个负责致癌性自我更新的转录激活系统的电路。MLL 通过其CXXC 结构域招募 RNA 聚合酶 II (RNAP2) 到未甲基化的富含 CpG 的启动子，并通过转录调节因子（包括 AF4 家族/ENL 家族/P-TEFb 复合物、DOT1L 和 p300/CBP 组蛋白乙酰转移酶）激活转录。MOZ 还通过与 RNAP2 和 MLL 的关联靶向广泛的富含 CpG 的启动子。MOZ-TIF2 和 MLL-AFX 等白血病融合蛋白通过异常募集 p300/CBP 来持续激活富含 CpG 的启动子。MLL 或 DOT1L 的药理学抑制诱导 MOZ-TIF2 转化细胞的分化。这些结果表明，MLL 介导的未甲基化富含 CpG 的启动子的激活是 MOZ 重排白血病中致癌性自我更新的核心机制，并表明针对 MLL 重排白血病的分子靶向治疗可应用于 MOZ 重排白血病。
