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Blood, 15 January 2006, Vol. 107, No. 2, pp. 781-785.
Prepublished online as a Blood First Edition Paper on September 15, 2005; DOI 10.1182/blood-2005-06-2553.
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NEOPLASIA
Brief report
Activating Notch1 mutations in mouse models of T-ALL
Jennifer O'Neil,
Jennifer Calvo,
Keith McKenna,
Veena Krishnamoorthy,
Jon C. Aster,
Craig H. Bassing,
Frederick W. Alt,
Michelle Kelliher, and
A. Thomas Look
From the Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Howard Hughes Medical Institute, The Children's Hospital, Department of Genetics, Harvard Medical School and The Center for Blood Research, Boston, MA.
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 G0/G1 arrest and apoptosis when treated with a  -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. (Blood. 2006;107:781-785)
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