title: c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma.
abstract: Human acute T-cell lymphoblastic leukemias and lymphomas (T-ALL) are commonly associated with gain-of-function mutations in Notch1 that contribute to T-ALL induction and maintenance. Starting from an expression-profiling screen, we identified c-myc as a direct target of Notch1 in Notch-dependent T-ALL cell lines, in which Notch accounts for the majority of c-myc expression. In functional assays, inhibitors of c-myc interfere with the progrowth effects of activated Notch1, and enforced expression of c-myc rescues multiple Notch1-dependent T-ALL cell lines from Notch withdrawal. The existence of a Notch1-c-myc signaling axis was bolstered further by experiments using c-myc-dependent murine T-ALL cells, which are rescued from withdrawal of c-myc by retroviral transduction of activated Notch1. This Notch1-mediated rescue is associated with the up-regulation of endogenous murine c-myc and its downstream transcriptional targets, and the acquisition of sensitivity to Notch pathway inhibitors. Additionally, we show that primary murine thymocytes at the DN3 stage of development depend on ligand-induced Notch signaling to maintain c-myc expression. Together, these data implicate c-myc as a developmentally regulated direct downstream target of Notch1 that contributes to the growth of T-ALL cells.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Weng
authors.forename: John M
authors.initials: JM
authors.lastname: Millholland
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yashiro-Ohtani
authors.forename: Marie Laure
authors.initials: ML
authors.lastname: Arcangeli
authors.forename: Arthur
authors.initials: A
authors.lastname: Lau
authors.forename: Carol
authors.initials: C
authors.lastname: Wai
authors.forename: Cristina
authors.initials: C
authors.lastname: Del Bianco
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Rodriguez
authors.forename: Hong
authors.initials: H
authors.lastname: Sai
authors.forename: John
authors.initials: J
authors.lastname: Tobias
authors.forename: Yueming
authors.initials: Y
authors.lastname: Li
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolfe
authors.forename: Cathy
authors.initials: C
authors.lastname: Shachaf
authors.forename: Dean
authors.initials: D
authors.lastname: Felsher
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Blacklow
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
authors.forename: Jon C
authors.initials: JC
authors.lastname: Aster
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000378:metabolism*; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism
chemical_list: C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1