CBFβ–SMMHC Activates MYC Enhancers to Promote Leukemogenesis

In approximately 8% of patients with acute myeloid leukemia (AML) a chromosomal inversion, inv(16)(p13;q22), results in expression of the CBFβ–SMMHC fusion oncoprotein. CBFβ is a stabilizing subunit that interacts with the transcription factor RUNX1, and the CBFβ–SMMHC fusion has a dominant-negative effect on RUNX1 activity. However, the role of CBFβ–SMMHC in oncogenesis remain poorly understood. Pulikkan and colleagues used a bivalent inhibitor of the CBFβ–SMMHC-RUNX1 interaction, AI-10-49, to elucidate the mechanism by which CBFβ–SMMHC inhibition induced apoptosis of inv(16) AML cells. RNA sequencing revealed that AI-10-49 treatment reduced MYC expression, resulting in apoptosis of inv(16) AML cells in vitro and in vivo. Mechanistically, AI-10-49 blocked the interaction between CBFβ–SMMHC and RUNX1, thereby freeing RUNX1 to globally enhance its DNA binding. Specifically, AI-10-49 treatment increased RUNX1 binding to three MYC enhancers, inducing RUNX1-mediated repression of MYC transcription. RUNX1 occupancy resulted in displacement of the SWI/SNF activating complex component BRG1 from MYC enhancers, replacing it with the polycomb repressive complex component RING1B, providing a mechanism for RUNX1-mediated MYC repression without disruption of the enhancer or promoter architecture. Further, AI-10-49 cooperated with the bromodomain inhibitor JQ1 to reduce inv(16) leukemogenesis in vitro and in vivo. Taken together, these findings elucidate a mechanism by which RUNX1 suppresses MYC by promoting SWI/SNF eviction and RING1 bindings. CBFβ–SMMHC restrains RUNX1 activity to promote leukemogenesis, and may be a potential therapeutic target to suppress MYC expression in patients with inv(16) AML.

Pulikkan JA, Hegde M, Ahmad HM, Belaghzal H, Illendula A, Yu J, et al. CBFβ-SMMHC inhibition triggers apoptosis by disrupting MYC chromatin dynamics in acute myeloid leukemia. Cell 2018;174:172–86.

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