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Blood. 2015 Apr 30;125(18):2806-14. doi: 10.1182/blood-2014-10-608448. Epub 2015 Mar 17.

Therapeutic targeting of HES1 transcriptional programs in T-ALL.

Author information

1
Institute for Cancer Genetics, Columbia University, New York, NY;
2
Institute for Virus Research, Kyoto University, Kyoto, Japan; and.
3
Institute for Cancer Genetics, Columbia University, New York, NY; Department of Pathology and Department of Pediatrics, Columbia University Medical Center, New York, NY.

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.

PMID:
25784680
PMCID:
PMC4424629
DOI:
10.1182/blood-2014-10-608448
[Indexed for MEDLINE]
Free PMC Article

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