Role of heat shock transcription factors (HSFs) in hematological malignancies

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Abstract Among the human hematological malignancies, acute leukemia types including acute myeloid leukemia (AML) accounts for 4% of all cancer deaths worldwide and 6% of cancer in the US population. AML is the second most common type of diagnosed leukemia in pediatric and adult populations but most frequently occurs in adults accounting for about 30% of all leukemia cases. Inductive therapy generally involves intensive and genotoxic chemotherapy that can lead to high remission rates (>80%), but the long-term survival rates for AML subtypes are only 30-50%. Indeed, the prognosis of primary resistant and relapsed leukemia in pediatric and elderly populations remains very poor. Currently, there is a strong rationale for immune intervention in cancers, including hematological malignancies, but recent clinical trials have demonstrated that the benefits of immunotherapy are relegated to a small fraction (~20%) of cancer patients, including those with AML. This prompts the need for greater understanding of the mechanisms underlying leukemic cell plasticity and adaptation, as well as developing novel therapeutic approaches to achieve more effective and selective cure rates for primary drug-resistant and relapsed leukemia. Hsf1, as the master activator of the classical heat shock response and guardian of the proteome, has been implicated in the pathogenesis of cancer. Our preclinical studies have revealed the existence of a coordinated, Hsf1-dependent protein homeostatic and metabolic program that, when inactivated, can lead to cancer regression and, in particular, effective leukemia inhibition. Encouragingly, our recent studies unveiled a highly novel and clinically significant role for Hsf1 inhibition in metabolic reprogramming and enhancement of anti-tumor T cell immunity. This may provide a new approach to improve leukemia treatment by improving the anti-tumor immune capacity targeting Hsf1 activity. We propose that by inhibiting supportive non- oncogene addiction pathways, interfering with tumor-promoting metabolic reprogramming, and improving the predicted power of anti-tumor immunity through targeting of Hsf1 activity, we can develop a valid strategy for therapeutic interventions in leukemia. Our experimental strategy entails the following two major approaches: 1. Determine the impact of Hsf1 deletion on AML induction and explore its therapeutic potential for advanced chemotherapy-resistant AML, and 2. Investigate the therapeutic impact of Hsf1 deletion on improved MHC- restricted TCR or chimeric antigen receptor (CAR)-T cell-based immunotherapy for primary and drug resistant/relapsed human AMLs. In summary, the long-term translational goal of the project is to test the potential of Hsf1 targeting in human AML. It will also provide proof-of-concept for targeting Hsf1-mediated metabolic programs for immunotherapeutic application of chemotherapy-resistant hematological malignancies.