Blocking SETD2 Enhances the Therapeutic Efficiency of Menin Inhibitor in MLL ‐Fusion Leukemia

During transcriptional elongation, the histone methyltransferase SETD2 binds to RNA polymerase II and deposits trimethylation marks at histone H3 lysine 36 (H3K36me3). However, the role of SETD2 in MLL-fusion leukemia has remained controversial over the past decade. Here, through genotyping of loss-of-function SETD2 mutations, we define the genetic basis for SETD2 acting as a haploinsufficient tumor suppressor in this disease. Then, we demonstrate that gene amplification and high expression of SETD2 are associated with poor prognosis, supporting the double-sided roles of SETD2 in this kind of acute leukemia. Next, we show that inhibitors of SETD2 (EZM0414) and menin (Revumenib) have synergistic efficacy against MLL-fusion and NPM1-mut leukemia and make prominent induction of cell cycle arrest, differentiation, and apoptosis. Moreover, SETD2 inhibition sensitizes leukemia cells to menin inhibitor through decreasing H3K36me3 marks, and combination therapy dramatically inhibits transcription of the canonical targeted genes, whose function may account for these phenotypic changes. The mode of action of this combined treatment is due to the attenuated both H3K36me3 at gene body regions and H3K4me3 at gene promoter regions. Finally, we clarify that the combined-drug treatment delays MLL-fusion leukemia progression in vivo. Taken together, these findings establish the simultaneously blocking of transcription elongation and initiation by epigenetic inhibitors as a promising therapeutic strategy for these aggressive leukemias.