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; Chen Zhao

doi:10.1038/s41467-022-33861-1

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

Journal article

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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, …

Nature communications, Vol.13(1), pp.6107-6107

10/16/2022

DOI: 10.1038/s41467-022-33861-1

PMCID: PMC9573868

PMID: 36245043

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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.

Cell Self Renewal - genetics

Heat Shock Transcription Factors - genetics

Heat Shock Transcription Factors - metabolism

Humans

Leukemia, Myeloid, Acute - genetics

Leukemia, Myeloid, Acute - metabolism

Neoplastic Stem Cells - metabolism

Succinate Dehydrogenase - metabolism

Transcription Factors - genetics

Transcription Factors - metabolism

Details

Title: Subtitle: HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia
Creators: Qianze Dong - Case Western Reserve University
Yan Xiu - Department of Pathology, Louis Stokes Veterans Affairs Medical Center, Cleveland, OH, 44106, USA
Yang Wang - Case Western Reserve University
Christina Hodgson - MAWD Pathology Group, Kansas City, MO, 66215, USA
Nick Borcherding - Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, 63110, USA
Craig Jordan - Division of Hematology, University of Colorado Anschutz Campus, Denver, CO, 80045, USA
Jane Buchanan - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52240, USA
Eric Taylor - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52240, USA
Brett Wagner - University of Iowa
Mariah Leidinger - Department of Pathology, University of Iowa, Iowa City, IA, 52242, USA
Carol Holman - Department of Pathology, University of Iowa, Iowa City, IA, 52242, USA
Dennis J Thiele - Sisu Pharma, Inc., Chapel Hill, NC, 27514, USA
Sean O'Brien - Sisu Pharma, Inc., Chapel Hill, NC, 27514, USA
Hai-Hui Xue - Hackensack University Medical Center
Jinming Zhao - Department of Pathology, China Medical University, 77 Puhe Rd, Shenbei Xinqu, Shenyang Shi, 110122, Liaoning Sheng, China
Qingchang Li - Department of Pathology, China Medical University, 77 Puhe Rd, Shenbei Xinqu, Shenyang Shi, 110122, Liaoning Sheng, China
Howard Meyerson - University Hospitals of Cleveland
Brendan F Boyce - University of Rochester Medical Center
Chen Zhao - University Hospitals of Cleveland
Resource Type: Journal article
Publication Details: Nature communications, Vol.13(1), pp.6107-6107
DOI: 10.1038/s41467-022-33861-1
PMID: 36245043
PMCID: PMC9573868
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: F30 DK127845 / NIDDK NIH HHS R01 CA237006 / NCI NIH HHS R01 DK104998 / NIDDK NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 10/16/2022
Academic Unit: Dermatology; Molecular Physiology and Biophysics; Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984383903402771

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