PMID- 36245043 OWN - NLM STAT- MEDLINE DCOM- 20221021 LR - 20230412 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 13 IP - 1 DP - 2022 Oct 16 TI - HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia. PG - 6107 LID - 10.1038/s41467-022-33861-1 [doi] LID - 6107 AB - 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. CI - (c) 2022. The Author(s). FAU - Dong, Qianze AU - Dong Q AD - Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, USA. FAU - Xiu, Yan AU - Xiu Y AD - Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, USA. AD - Department of Pathology, Louis Stokes Veterans Affairs Medical Center, Cleveland, OH, 44106, USA. FAU - Wang, Yang AU - Wang Y AD - Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, USA. FAU - Hodgson, Christina AU - Hodgson C AD - MAWD Pathology Group, Kansas City, MO, 66215, USA. FAU - Borcherding, Nick AU - Borcherding N AD - Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, 63110, USA. FAU - Jordan, Craig AU - Jordan C AUID- ORCID: 0000-0003-0869-3465 AD - Division of Hematology, University of Colorado Anschutz Campus, Denver, CO, 80045, USA. FAU - Buchanan, Jane AU - Buchanan J AD - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52240, USA. FAU - Taylor, Eric AU - Taylor E AUID- ORCID: 0000-0003-4549-6567 AD - Department of Biochemistry, Carver College of Medicine, University of Iowa, Iowa City, IA, 52240, USA. FAU - Wagner, Brett AU - Wagner B AUID- ORCID: 0000-0002-0094-7259 AD - Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA, 52242, USA. FAU - Leidinger, Mariah AU - Leidinger M AD - Department of Pathology, University of Iowa, Iowa City, IA, 52242, USA. FAU - Holman, Carol AU - Holman C AUID- ORCID: 0000-0002-5748-9914 AD - Department of Pathology, University of Iowa, Iowa City, IA, 52242, USA. FAU - Thiele, Dennis J AU - Thiele DJ AD - Sisu Pharma, Inc., Chapel Hill, NC, 27514, USA. FAU - O'Brien, Sean AU - O'Brien S AD - Sisu Pharma, Inc., Chapel Hill, NC, 27514, USA. FAU - Xue, Hai-Hui AU - Xue HH AUID- ORCID: 0000-0002-9163-7669 AD - Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ, 07110, USA. FAU - Zhao, Jinming AU - Zhao J AD - Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, USA. AD - Department of Pathology, China Medical University, 77 Puhe Rd, Shenbei Xinqu, Shenyang Shi, 110122, Liaoning Sheng, China. FAU - Li, Qingchang AU - Li Q AUID- ORCID: 0000-0002-6317-7386 AD - Department of Pathology, China Medical University, 77 Puhe Rd, Shenbei Xinqu, Shenyang Shi, 110122, Liaoning Sheng, China. FAU - Meyerson, Howard AU - Meyerson H AD - Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA. FAU - Boyce, Brendan F AU - Boyce BF AD - Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, 14642, USA. FAU - Zhao, Chen AU - Zhao C AUID- ORCID: 0000-0003-3217-0269 AD - Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, USA. cxz545@case.edu. AD - Department of Pathology, Louis Stokes Veterans Affairs Medical Center, Cleveland, OH, 44106, USA. cxz545@case.edu. AD - Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, 44106, USA. cxz545@case.edu. LA - eng GR - R01 DK104998/DK/NIDDK NIH HHS/United States GR - P30 CA086862/CA/NCI NIH HHS/United States GR - I01 BX004255/BX/BLRD VA/United States GR - R01 CA237006/CA/NCI NIH HHS/United States GR - F30 DK127845/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20221016 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Heat Shock Transcription Factors) RN - EC 1.3.99.1 (Succinate Dehydrogenase) RN - 0 (Transcription Factors) RN - 0 (HSF1 protein, human) SB - IM MH - Humans MH - *Cell Self Renewal/genetics MH - Heat Shock Transcription Factors/genetics/metabolism MH - *Leukemia, Myeloid, Acute/genetics/metabolism MH - Neoplastic Stem Cells/metabolism MH - Succinate Dehydrogenase/metabolism MH - Transcription Factors/genetics/metabolism PMC - PMC9573868 COIS- D.J.T. and S.O. are employed by and hold equity in Sisu Pharma, Inc. The remaining authors declare no competing interests. EDAT- 2022/10/17 06:00 MHDA- 2022/10/19 06:00 PMCR- 2022/10/16 CRDT- 2022/10/16 23:19 PHST- 2021/12/16 00:00 [received] PHST- 2022/10/05 00:00 [accepted] PHST- 2022/10/16 23:19 [entrez] PHST- 2022/10/17 06:00 [pubmed] PHST- 2022/10/19 06:00 [medline] PHST- 2022/10/16 00:00 [pmc-release] AID - 10.1038/s41467-022-33861-1 [pii] AID - 33861 [pii] AID - 10.1038/s41467-022-33861-1 [doi] PST - epublish SO - Nat Commun. 2022 Oct 16;13(1):6107. doi: 10.1038/s41467-022-33861-1.