Activating Notch1 Mutations in Mouse Models of T-ALL.

NOTCH1 was discovered through its involvement in the t(7;9) chromosomal translocation found in less than 1% of T-ALLs. Recent studies have demonstrated a broader involvement of NOTCH1 in human T-ALL. The majority of T-ALL patients have activating mutations that disrupt either the heterodimerization domain or the PEST domain of NOTCH1. We sought to determine whether these mutations are also acquired in mouse models of T-ALL. We have sequenced the heterodimerization domain and PEST domain of notch1 in our mouse model of TAL1-induced leukemia and have found that 74% of the tumors harbor activating mutations in notch1. Cell lines derived from these tumors undergo G₀/G₁ arrest and often apoptosis when treated with a γ-secretase inhibitor (DAPT). In addition, we found activating notch1 mutations in 38% of thymic lymphomas that occur in mice deficient for various combinations of the H2AX, p53 and Rag2 genes. Thus, notch1 mutations are often acquired as a part of the molecular pathogenesis of T-ALL occurring in mice predisposed to develop the disease because they are transgenic for overexpression of the tal1 oncogene or because they have lost key tumor suppressor genes known to promote genomic instability.