Regulation of H3K4me3 breadth and MYC expression by the SETD1B catalytic domain in MLL-rearranged leukemia

Shintaro Izumi; Ko Ohtani; Makoto Matsumoto; Seito Shibata; Bahityar Rahmutulla; Masaki Fukuyo; Mitsutaka Nishimoto; Hideo Miyagawa; Emiko Sakaida; Koutaro Yokote; Issay Kitabayashi; Kimi Araki; Atsushi Kaneda; Takayuki Hoshii

doi:10.1038/s41375-025-02638-y

Regulation of H3K4me3 breadth and MYC expression by the SETD1B catalytic domain in MLL-rearranged leukemia

Leukemia. 2025 May 8. doi: 10.1038/s41375-025-02638-y. Online ahead of print.

Authors

Shintaro Izumi^{1

2}, Ko Ohtani^{1

2}, Makoto Matsumoto¹, Seito Shibata¹, Bahityar Rahmutulla¹, Masaki Fukuyo¹, Mitsutaka Nishimoto³, Hideo Miyagawa⁴, Emiko Sakaida², Koutaro Yokote², Issay Kitabayashi⁵, Kimi Araki^{6

7}, Atsushi Kaneda^{1

8}, Takayuki Hoshii⁹

Affiliations

¹ Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba-shi, Chiba, Japan.
² Department of Endocrinology, Hematology and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan.
³ Department of Hematology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
⁴ Preventive Medicine and Environmental Health, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
⁵ Oncology Innovation Center/ Center for Translational Research, Fujita Health University, Aichi, Japan.
⁶ Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
⁷ Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, Japan.
⁸ Health and Disease Omics Center, Chiba University, Chiba, Japan.
⁹ Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba-shi, Chiba, Japan. hoshiit@chiba-u.jp.

PMID: 40341256
DOI: 10.1038/s41375-025-02638-y

Abstract

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^G12D-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.

Abstract

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