Activating Notch1 mutations in mouse models of T-ALL.
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.
O'Neil
Jennifer
J
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Calvo
Jennifer
J
McKenna
Keith
K
Krishnamoorthy
Veena
V
Aster
Jon C
JC
Bassing
Craig H
CH
Alt
Frederick W
FW
Kelliher
Michelle
M
Look
A Thomas
AT
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D017209:Apoptosis; D016282:Aspartic Acid Endopeptidases; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016193:G1 Phase; D006657:Histones / Q000235:genetics / Q000502:physiology; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D051881:Receptor, Notch1 / Q000235:genetics*; D016192:Resting Phase, Cell Cycle; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D013953:Thymus Neoplasms / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D010450:Endopeptidases; D004791:Enzyme Inhibitors; D006657:Histones; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; D016159:Tumor Suppressor Protein p53; C497761:NOTCH1 protein, human; C499308:Rag2 protein, mouse; C489366:Tal1 protein, mouse; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; C475961:gamma-H2AX protein, mouse