TY - JOUR
T1 - HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia
AU - Dong, Qianze
AU - Xiu, Yan
AU - Wang, Yang
AU - Hodgson, Christina
AU - Borcherding, Nick
AU - Jordan, Craig
AU - Buchanan, Jane
AU - Taylor, Eric
AU - Wagner, Brett
AU - Leidinger, Mariah
AU - Holman, Carol
AU - Thiele, Dennis J.
AU - O’Brien, Sean
AU - Xue, Hai hui
AU - Zhao, Jinming
AU - Li, Qingchang
AU - Meyerson, Howard
AU - Boyce, Brendan F.
AU - Zhao, Chen
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
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.
UR - https://www.scopus.com/pages/publications/85139856167
U2 - 10.1038/s41467-022-33861-1
DO - 10.1038/s41467-022-33861-1
M3 - Article
C2 - 36245043
AN - SCOPUS:85139856167
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6107
ER -