Therapeutic targeting of HES1 transcriptional programs in T-ALL.

Blood
Stephanie A SchnellAdolfo A Ferrando

Abstract

Oncogenic activation of NOTCH1 signaling plays a central role in the pathogenesis of T-cell acute lymphoblastic leukemia, with mutations on this signaling pathway affecting more than 60% of patients at diagnosis. However, the transcriptional regulatory circuitries driving T-cell transformation downstream of NOTCH1 remain incompletely understood. Here we identify Hairy and Enhancer of Split 1 (HES1), a transcriptional repressor controlled by NOTCH1, as a critical mediator of NOTCH1-induced leukemogenesis strictly required for tumor cell survival. Mechanistically, we demonstrate that HES1 directly downregulates the expression of BBC3, the gene encoding the PUMA BH3-only proapoptotic factor in T-cell acute lymphoblastic leukemia. Finally, we identify perhexiline, a small-molecule inhibitor of mitochondrial carnitine palmitoyltransferase-1, as a HES1-signature antagonist drug with robust antileukemic activity against NOTCH1-induced leukemias in vitro and in vivo.

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Citations

May 3, 2016·Current Opinion in Hematology·Mark Y ChiangIvan Maillard
Jan 25, 2017·Blood·Marta Sanchez-Martin, Adolfo Ferrando
Sep 6, 2017·International Journal of Molecular Sciences·Deborah BongiovanniErich Piovan
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Oct 2, 2019·Cold Spring Harbor Perspectives in Medicine·Francesca GianniAdolfo Ferrando
Apr 19, 2018·Frontiers in Immunology·Erich PiovanPaola Zanovello
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Nov 23, 2019·Journal of Hematology & Oncology·Boheng Li, Wee-Joo Chng
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Sep 15, 2020·Blood Cancer Discovery·Anna C McCarterMark Y Chiang

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