Activating Notch1 mutations in mouse models of T-ALL
Graduate School of Biomedical Sciences; Department of Cancer Biology; Department of Molecular Genetics and Microbiology
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.
DOI of Published Version
Blood. 2006 Jan 15;107(2):781-5. Epub 2005 Sep 15. Link to article on publisher's site
O'Neil JE, Calvo JA, McKenna K, Krishnamoorthy V, Aster JC, Bassing CH, Alt FW, Kelliher M, Look AT. (2005). Activating Notch1 mutations in mouse models of T-ALL. Morningside Graduate School of Biomedical Sciences Student Publications. https://doi.org/10.1182/blood-2005-06-2553. Retrieved from https://escholarship.umassmed.edu/gsbs_sp/913