Izumi Shintaro, Ohtani Ko, Matsumoto Makoto, Shibata Seito, Rahmutulla Bahityar, Fukuyo Masaki, Nishimoto Mitsutaka, Miyagawa Hideo, Sakaida Emiko, Yokote Koutaro, Kitabayashi Issay, Araki Kimi, Kaneda Atsushi, Hoshii Takayuki
Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba-shi, Chiba, Japan.
Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Leukemia. 2025 May 8. doi: 10.1038/s41375-025-02638-y.
Histone H3 lysine 4 trimethylation (H3K4me3) is abundant in mixed-lineage leukemia-rearranged (MLL-r) acute myeloid leukemia (AML) cells; however, the responsible enzymes and their roles remain unclear. This study aimed to identify the modifier responsible for high H3K4me3 modification in MLL-r leukemia and its downstream targets essential for the cell proliferation. Here, we performed a CRISPR-tiling screen against known H3K4 methylation modifiers in an MLL-r AML model. Disrupting the SETD1B catalytic SET domain caused depletion of FLT3-ITD or Nras-expressing AML cells, and gene expression downregulation, particularly in the MYC pathway. SETD1B SET domain loss results in a significant decrease in H3K4me3 breadth. Exogenous MYC expression or disrupting H3K4 demethylase KDM5C significantly restored growth defects in SETD1B SET domain-mutant cells. These data indicated that SETD1B was required for H3K4me3 breadth and MYC expression. Thus, a thorough understanding of SETD1B-mediated H3K4me3 breadth is critical for developing markers and therapies for MYC-dependent leukemia subtypes.
组蛋白H3赖氨酸4三甲基化（H3K4me3）在混合谱系白血病重排（MLL-r）急性髓系白血病（AML）细胞中含量丰富；然而，相关酶及其作用仍不清楚。本研究旨在确定MLL-r白血病中导致高H3K4me3修饰的调节因子及其对细胞增殖至关重要的下游靶点。在此，我们在MLL-r AML模型中针对已知的H3K4甲基化调节因子进行了CRISPR平铺筛选。破坏SETD1B催化SET结构域会导致FLT3-ITD或表达Nras的AML细胞耗竭以及基因表达下调，尤其是在MYC途径中。SETD1B SET结构域缺失导致H3K4me3宽度显著降低。外源性MYC表达或破坏H3K4去甲基化酶KDM5C可显著恢复SETD1B SET结构域突变细胞中的生长缺陷。这些数据表明，SETD1B是H3K4me3宽度和MYC表达所必需的。因此，深入了解SETD1B介导的H3K4me3宽度对于开发针对MYC依赖性白血病亚型的标志物和治疗方法至关重要。
