Therapeutic targeting of HES1 transcriptional programs in T-ALL

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use
  • Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / physiology
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cells, Cultured
  • Gene Expression Regulation, Leukemic* / drug effects
  • Gene Silencing
  • Gene Targeting / methods*
  • HEK293 Cells
  • Homeodomain Proteins / antagonists & inhibitors
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / physiology
  • Humans
  • Jurkat Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microarray Analysis
  • Molecular Targeted Therapy
  • Perhexiline / therapeutic use
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / therapy*
  • Receptor, Notch1 / genetics
  • Transcription Factor HES-1

Substances

  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • Receptor, Notch1
  • Transcription Factor HES-1
  • HES1 protein, human
  • Perhexiline