Activating Notch1 mutations in mouse models of T-ALL
Graduate School of Biomedical Sciences; Department of Cancer Biology; Department of Molecular Genetics and Microbiology
Medical Subject Headings
Amyloid Precursor Protein Secretases; Animals; Apoptosis; Aspartic Endopeptidases; Basic Helix-Loop-Helix Transcription Factors; DNA-Binding Proteins; *Disease Models, Animal; Endopeptidases; Enzyme Inhibitors; Female; G0 Phase; G1 Phase; Histones; Humans; Leukemia-Lymphoma, Adult T-Cell; Lymphoma; Male; Mice; Mice, Transgenic; Mutation; Proto-Oncogene Proteins; Receptor, Notch1; Thymus Neoplasms; Tumor Suppressor Protein p53
Life Sciences | Medicine and Health Sciences
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.
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Citation: Blood. 2006 Jan 15;107(2):781-5. Epub 2005 Sep 15. Link to article on publisher's site
O'Neil, Jennifer Elinor; Calvo, Jennifer Ann; McKenna, Keith; Krishnamoorthy, Veena; Aster, Jon C.; Bassing, Craig H.; Alt, Frederick W.; Kelliher, Michelle; and Look, A. Thomas, "Activating Notch1 mutations in mouse models of T-ALL" (2005). GSBS Student Publications. 913.