SETD1A Interacts with Cyclin K to Promote Leukemia Cell Survival

Histone 3 lysine 4 (H3K4) methylation has important functions in transcriptional regulation and cancer, and H3K4 methylation is catalyzed by SET domain–containing proteins including SETD1A, SETD1B, and MLL1–4, each of which are found in multiprotein histone methyltransferase (HMT) complexes. These SET domain–containing proteins are frequently mutated or rearranged in leukemia, but it is not clear if the methyltransferase activity is required for leukemia cell survival or if there is redundancy between HMTs. Hoshii and colleagues performed an shRNA screen, depleting individual MLL/SET complex subunits to determine which are required for the growth of MLL-AF9 acute myeloid leukemia (AML) cells and determined that SETD1A was required for leukemia cell growth in vitro and in vivo. However, the SETD1A SET domain and methyltransferase activity were not required for leukemia cell growth. Instead, a domain termed the functional location on SETD1A (FLOS) was essential for leukemia cell survival. Disrupting SETD1A reduced expression of DNA damage response genes including FANCD2, thereby suppressing the DNA damage response and inducing apoptosis of AML cells in a p53-dependent manner. Mechanistically, the SETD1A FLOS domain interacted with cyclin K, which is required for regulation of CDK12/13 kinase activity and controls transcription of multiple DNA damage response genes, and this association was required for leukemia cell growth. Despite the homology with SETD1A, SETD1B did not associate with cyclin K, indicating a nonredundant function for SETD1A in leukemia cell growth. Further, in human MLL-AF9 leukemia cells, treatment with the CDK12/13 inhibitor THZ531 induced apoptosis, indicating a cell-cycle dependent requirement for cyclin K/CDK12 control of DNA damage repair genes. Collectively, these findings reveal an essential role for SETD1A in leukemia cell survival that is independent of its H3K4 methyltransferase activity and suggest the potential for therapeutic targeting of SETD1A and cyclin K complexes in AML.

Hoshii T, Cifani P, Feng Z, Huang CH, Koche R, Chen CW, et al. A non-catalytic function of SETD1A regulates cyclin K and the DNA damage response. Cell 2018;172:1007–21.

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