HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia

Qianze Dong, Yan Xiu, Yang Wang, Christina Hodgson, Nick Borcherding, Craig Jordan, Jane Buchanan, Eric Taylor, Brett Wagner, Mariah Leidinger, Carol Holman, Dennis J. Thiele, Sean O’Brien, Hai-hui Xue, Jinming Zhao, Qingchang Li, Howard Meyerson, Brendan F. Boyce and Chen Zhao ()
Additional contact information
Qianze Dong: Case Western Reserve University
Yan Xiu: Case Western Reserve University
Yang Wang: Case Western Reserve University
Christina Hodgson: MAWD Pathology Group
Nick Borcherding: Washington University School of Medicine
Craig Jordan: University of Colorado Anschutz Campus
Jane Buchanan: University of Iowa
Eric Taylor: University of Iowa
Brett Wagner: University of Iowa
Mariah Leidinger: University of Iowa
Carol Holman: University of Iowa
Dennis J. Thiele: Sisu Pharma, Inc.
Sean O’Brien: Sisu Pharma, Inc.
Hai-hui Xue: Hackensack University Medical Center
Jinming Zhao: Case Western Reserve University
Qingchang Li: China Medical University
Howard Meyerson: University Hospitals Cleveland Medical Center
Brendan F. Boyce: University of Rochester Medical Center
Chen Zhao: Case Western Reserve University

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Acute myeloid leukemia (AML) is maintained by self-renewing leukemic stem cells (LSCs). A fundamental problem in treating AML is that conventional therapy fails to eliminate LSCs, which can reinitiate leukemia. Heat shock transcription factor 1 (HSF1), a central regulator of the stress response, has emerged as an important target in cancer therapy. Using genetic Hsf1 deletion and a direct HSF1 small molecule inhibitor, we show that HSF1 is specifically required for the maintenance of AML, while sparing steady-state and stressed hematopoiesis. Mechanistically, deletion of Hsf1 dysregulates multifaceted genes involved in LSC stemness and suppresses mitochondrial oxidative phosphorylation through downregulation of succinate dehydrogenase C (SDHC), a direct HSF1 target. Forced expression of SDHC largely restores the Hsf1 ablation-induced AML developmental defect. Importantly, the growth and engraftment of human AML cells are suppressed by HSF1 inhibition. Our data provide a rationale for developing efficacious small molecules to specifically target HSF1 in AML.

Date: 2022
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DOI: 10.1038/s41467-022-33861-1

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