Activating Notch1 mutations in mouse models of T-ALL

Blood. 2006 Jan 15;107(2):781-5. doi: 10.1182/blood-2005-06-2553. Epub 2005 Sep 15.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Animals
  • Apoptosis
  • Aspartic Acid Endopeptidases
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / physiology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Disease Models, Animal*
  • Endopeptidases / chemistry
  • Enzyme Inhibitors / pharmacology
  • Female
  • G1 Phase
  • Histones / genetics
  • Histones / physiology
  • Humans
  • Leukemia-Lymphoma, Adult T-Cell / genetics*
  • Lymphoma / genetics*
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation / genetics*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology
  • Receptor, Notch1 / genetics*
  • Resting Phase, Cell Cycle
  • T-Cell Acute Lymphocytic Leukemia Protein 1
  • Thymus Neoplasms / genetics*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / physiology

Substances

  • 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