An epigenetic enzyme may play a key role in a particularly aggressive form of acute myeloid leukaemia in laboratory models, Japanese researchers have reported.
The researchers, led by a team based at Chiba University, believe that drugs that target the enzyme, SETD1B, may offer an option to more effective treatments for the disease, especially when there a FLT3-ITD mutation is present.
The epigenetic modification H3K4me3 (histone H3 lysine 4 trimethylation) has already been linked to aggressive AML, but the different enzymes responsible for this modification was not yet clear. The research, published recently in the journal Leukemia, found the Setd1b gene to be responsible for broad H3K4me3 distribution in the genome of AML cells. This in turn affects the expression of MYC, a key cancer gene.
The researchers found that removing the enzyme’s catalytic domain seemed to slow cancer growth, especially where there were FLT3-ITD or NrasG12D mutations.
The team suggest that SETD1B-inhibiting drugs could lead to improved treatments for aggressive AMLs. Although not tested in this study, the team point to chaetocin, a compound that blocks enzymes similar to SETD1B, which could serve as the foundation for future drug development.
Study leader Dr Takayuki Hoshii said: “Patients with AML, especially with the FLT3-ITD mutation, often respond poorly to current therapies. Our findings are that the epigenetic regulator SETD1B protein supports aggressive cell proliferation in AML by promoting oncogenic MYC expression.
“The breadth of H3K4me3 is crucial for transcriptional consistency, and MYC expression appears highly dependent on both the quality and quantity of transcriptional elongation. Understanding SETD1B’s role in maintaining this epigenetic mark is critical for developing biomarkers and therapies for leukaemia subtypes and other MYC-driven cancers."
Source:
Izumi S, Ohtani K, Matsumoto M, Shibata S, Rahmutulla B, Fukuyo M, Nishimoto M, Miyagawa H, Sakaida E, Yokote K, Kitabayashi I, Araki K, Kaneda A, Hoshii T. (2025) “Regulation of H3K4me3 breadth and MYC expression by the SETD1B catalytic domain in MLL-rearranged leukemia.” Leukemia, 8 May 2025, doi: 10.1038/s41375-025-02638-y.
Link: https://www.nature.com/articles/s41375-025-02638-y
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