UC San Diego

The development of effective therapeutics to treat patients with acute myeloid leukemia (AML) has been challenged by the heterogeneous molecular landscape of the disease. One strategy to overcome the variability of therapeutic efficacy is to identify and target a universal cellular process upon which cancer cells are particularly dependent. Malignant growth increases the demand for protein biosynthesis, which can unbalance protein homeostasis (proteostasis) in cancer cells. Consequently, malignant cells can become addicted to stress response pathways that help restore proteostasis and support survival in the face of proteotoxic stress. Heat shock factor 1 (HSF1) promotes various cancers by regulating proteostasis, metabolism, cell cycle, and multiple signaling pathways. However, the role of HSF1 in AML has not yet been thoroughly investigated and therapeutics targeting HSF1 have not been developed successfully. Here, we show that HSF1 inhibition exerts prominent anti-leukemic effects in vitro and in vivo. Genetic depletion of HSF1 in human AML cell lines significantly reduced cell growth and proliferation in vitro, slowed AML progression and extended survival in vivo, and dysregulated several oncogenic signaling pathways. In addition to its intrinsic anti-leukemic activity, HSF1 deletion sensitized AML cells to treatment with the proteasome inhibitor carfilzomib. Finally, we found that cysteamine, a type 2 transglutaminase inhibitor that restricts HSF1 activation, partially recapitulates the anti-leukemic effects of HSF1 ablation and produces supra-additive effects with carfilzomib. Together, our results indicate that human AML cells are highly dependent on HSF1 and propose HSF1 inhibition as an encouraging novel therapeutic avenue for treating AML.