Activating Notch1 mutations in mouse models of T-ALL.

Abstract	Recent studies have demonstrated that most patients with T-cell acute lymphocytic leukemia (T-ALL) have activating mutations in NOTCH1. We sought to determine whether these mutations are also acquired in mouse models of T-ALL. We sequenced the heterodimerization domain and the PEST domain of Notch1 in our mouse model of TAL1-induced leukemia and found that 74% of the tumors harbor activating mutations in Notch1. Cell lines derived from these tumors undergo G(0)/G(1) arrest and apoptosis when treated with a gamma-secretase inhibitor. In addition, we found activating Notch1 mutations in 31% of thymic lymphomas that occur in mice deficient for various combinations of the H2AX, Tp53, and Rag2 genes. Thus, Notch1 mutations are often acquired as a part of the molecular pathogenesis of T-ALLs that develop in mice with known predisposing genetic alterations.
Authors	Jennifer O'Neil, Jennifer Calvo, Keith McKenna, Veena Krishnamoorthy, Jon C Aster, Craig H Bassing, Frederick W Alt, Michelle Kelliher, A Thomas Look
Journal	Blood (Blood) Vol. 107 Issue 2 Pg. 781-5 (Jan 15 2006) ISSN: 0006-4971 [Print] United States
PMID	16166587 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References	Basic Helix-Loop-Helix Transcription Factors DNA-Binding Proteins Enzyme Inhibitors H2AX protein, mouse Histones NOTCH1 protein, human Proto-Oncogene Proteins Rag2 protein, mouse Receptor, Notch1 T-Cell Acute Lymphocytic Leukemia Protein 1 Tal1 protein, mouse Tumor Suppressor Protein p53 Amyloid Precursor Protein Secretases Endopeptidases Aspartic Acid Endopeptidases BACE1 protein, human Bace1 protein, mouse
Topics	Amyloid Precursor Protein Secretases Animals Apoptosis Aspartic Acid Endopeptidases Basic Helix-Loop-Helix Transcription Factors (genetics, physiology) DNA-Binding Proteins (genetics, physiology) Disease Models, Animal Endopeptidases (chemistry) Enzyme Inhibitors (pharmacology) Female G1 Phase Histones (genetics, physiology) Humans Leukemia-Lymphoma, Adult T-Cell (genetics) Lymphoma (genetics) Male Mice Mice, Transgenic Mutation (genetics) Proto-Oncogene Proteins (genetics, physiology) Receptor, Notch1 (genetics) Resting Phase, Cell Cycle T-Cell Acute Lymphocytic Leukemia Protein 1 Thymus Neoplasms (genetics) Tumor Suppressor Protein p53 (genetics, physiology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!