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

Author

Listed:
  • Qianze Dong

    (Case Western Reserve University)

  • Yan Xiu

    (Case Western Reserve University
    Louis Stokes Veterans Affairs Medical Center)

  • 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
    China Medical 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
    Louis Stokes Veterans Affairs Medical Center
    University Hospitals Cleveland Medical Center)

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.

Suggested Citation

  • 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, 2022. "HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33861-1
    DOI: 10.1038/s41467-022-33861-1
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