title: Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc.
abstract: Recent work with mouse models and human leukemic samples has shown that gain-of-function mutation(s) in Notch1 is a common genetic event in T-cell acute lymphoblastic leukemia (T-ALL). The Notch1 receptor signals through a gamma-secretase-dependent process that releases intracellular Notch1 from the membrane to the nucleus, where it forms part of a transcriptional activator complex. To identify Notch1 target genes in leukemia, we developed mouse T-cell leukemic lines that express intracellular Notch1 in a doxycycline-dependent manner. Using gene expression profiling and chromatin immunoprecipitation, we identified c-myc as a novel, direct, and critical Notch1 target gene in T-cell leukemia. c-myc mRNA levels are increased in primary mouse T-cell tumors that harbor Notch1 mutations, and Notch1 inhibition decreases c-myc mRNA levels and inhibits leukemic cell growth. Retroviral expression of c-myc, like intracellular Notch1, rescues the growth arrest and apoptosis associated with gamma-secretase inhibitor treatment or Notch1 inhibition. Consistent with these findings, retroviral insertional mutagenesis screening of our T-cell leukemia mouse model revealed common insertions in either notch1 or c-myc genes. These studies define the Notch1 molecular signature in mouse T-ALL and importantly provide mechanistic insight as to how Notch1 contributes to human T-ALL.
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Vishva Mitra
authors.initials: VM
authors.lastname: Sharma
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Calvo
authors.forename: Kyle M
authors.initials: KM
authors.lastname: Draheim
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Cunningham
authors.forename: Nicole
authors.initials: N
authors.lastname: Hermance
authors.forename: Levi
authors.initials: L
authors.lastname: Beverly
authors.forename: Veena
authors.initials: V
authors.lastname: Krishnamoorthy
authors.forename: Manoj
authors.initials: M
authors.lastname: Bhasin
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Capobianco
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Kelliher
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015458:Leukemia, T-Cell / Q000378:metabolism*; D051379:Mice; D016254:Mutagenesis, Insertional; D020411:Oligonucleotide Array Sequence Analysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
chemical_list: D053829:Amyloid Precursor Protein Secretases; D051792:Basic Helix-Loop-Helix Proteins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C489428:Myc protein, mouse; C497762:Notch1 protein, mouse; C489366:Tal1 protein, mouse