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Targeted Therapy Approaches in Leukemia

Inv(16) AML is an aggressive form of leukemia driven by the presence of a fusion protein that inhibits the activity of transcription factor RUNX1. This interaction is essential for the oncogenic function of the fusion protein and survival of the leukemic cells. We are interested in developing targeted therapeutic candidates that can eliminate leukemic stem cells by inhibiting fusion protein CBFß-SMMHC function by disrupting its interaction with RUNX1.

We have shown that AI-10-49, a small molecule inhibitor, successfully hinders CBFß-SMMHC/RUNX1 binding and represses MYC expression, inducing apoptosis of inv(16) AML cells and delaying leukemia in vivo (Illendula et al., Science 2015). Mechanistically, we demonstrated that the inhibitor interferes with SWI/SNF activating complexes at downstream enhancers by enabling  the formation of a RUNX1/PRC1 repressive complex, which displaces the SWI/SNF complex and hinders MYC expression (Pulikkan et al., Cell 2018).

Can we move AI-10-49 to the clinic? Our laboratory is combining genetic, pharmacologic, and biochemical approaches in cells and mouse models to develop a preclinical system for AI-10-49 delivery, as well as study its effects in combination with other drugs.