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

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.