Therapeutic targeting of HES1 transcriptional programs in T-ALL.

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.

journal_name

Blood

journal_title

Blood

authors

Schnell SA,Ambesi-Impiombato A,Sanchez-Martin M,Belver L,Xu L,Qin Y,Kageyama R,Ferrando AA

doi

10.1182/blood-2014-10-608448

subject

Has Abstract

pub_date

2015-04-30 00:00:00

pages

2806-14

issue

18

eissn

0006-4971

issn

1528-0020

pii

blood-2014-10-608448

journal_volume

125

pub_type

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