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.

• Authors: Stephanie A Schnell, Alberto Ambesi-Impiombato, Marta Sanchez-Martin, Laura Belver, Luyao Xu, Yue Qin, Ryoichiro Kageyama, Adolfo A Ferrando
• Journal: Blood (Blood) Vol. 125 Issue 18 Pg. 2806-14 (Apr 30 2015) ISSN: 1528-0020 [Electronic] United States
• PMID: 25784680 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society of Hematology.

Chemical References

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

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Basic Helix-Loop-Helix Transcription Factors (antagonists & inhibitors, genetics, physiology)
• Cell Survival (drug effects, genetics)
• Cells, Cultured
• Gene Expression Regulation, Leukemic (drug effects)
• Gene Silencing
• Gene Targeting (methods)
• HEK293 Cells
• Homeodomain Proteins (antagonists & inhibitors, genetics, 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, therapy)
• Receptor, Notch1 (genetics)
• Transcription Factor HES-1