Heat Shock Transcription Factor 1 Specifically Regulates AML Stem Cell Self-Renewal

Acute myeloid leukemia (AML) is maintained by a small minority of self-renewing leukemic stem cells (LSCs). Defining and targeting key molecules specifically regulating LSCs hold promise for eradication of AML. Heat Shock transcription Factor 1 (HSF1), a master regulator of the heat-shock response and facilitates cancer cell growth, survival, and metastasis, has emerged as an important target in cancers. However, whether HSF1 is involved in the initiation and maintenance of AML remain unknown. Here, using conventional and conditional HSF1 knockout mice, we show that HSF1 is specifically required for both the initiation and maintenance of murine MLL-AF9-induced AML while sparing steady-state and stressed hematopoiesis. Mechanistically, deletion of HSF1 dysregulates multifaceted genes involved in LSC stemness, disrupts amino acid metabolism and inhibits mitochondrial oxidative phosphorylation mainly through downregulation of mitochondrial respiratory chain complex II. Importantly, we validate the efficacy of HSF1 inhibition in human AML and further reveal that HSF1 can be used as a malignant clinical marker to monitor the status of myeloid neoplasms. Collectively, our studies indicate that HSF1 is essential for maintaining AML stem cells and provide a scientific rationale for developing small molecules to specifically target HSF1 in myeloid leukemias.