title: 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.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY;
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Schnell
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY;
authors.forename: Alberto
authors.initials: A
authors.lastname: Ambesi-Impiombato
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY;
authors.forename: Marta
authors.initials: M
authors.lastname: Sanchez-Martin
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY;
authors.forename: Laura
authors.initials: L
authors.lastname: Belver
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY;
authors.forename: Luyao
authors.initials: L
authors.lastname: Xu
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY;
authors.forename: Yue
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Institute for Virus Research, Kyoto University, Kyoto, Japan; and.
authors.forename: Ryoichiro
authors.initials: R
authors.lastname: Kageyama
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY; Department of Pathology and Department of Pediatrics, Columbia University Medical Center, New York, NY.
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D020868:Gene Silencing; D018390:Gene Targeting / Q000379:methods*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D058990:Molecular Targeted Therapy; D010480:Perhexiline / Q000627:therapeutic use; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000628:therapy*; D051881:Receptor, Notch1 / Q000235:genetics; D000072056:Transcription Factor HES-1
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D010480:Perhexiline; D051881:Receptor, Notch1; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human