Oncogenic Kras and Notch-1 cooperate in T-cell acute lymphoblastic leukemia/lymphoma

Mutations of the Ras family are one of the most common somatic events found in all human cancers, although they are relatively rare in T-cell acute lymphoblastic leukemia (T-ALL). In mice, conditional expression of oncogenic Kras(G12D) from its endogenous promoter causes a fatal myeloproliferative disorder, and only rarely a T-ALL-like disease. In the article being evaluated, the authors demonstrate that primary mice expressing oncogenic Kras have a block in T-cell differentiation at the double-negative 1 stage. Interestingly, most secondarily transplanted mice develop a fatal T-ALL-like disease. Sequencing of NOTCH-1 showed that 50% of these mice harbored truncating mutations in the PEST domain that would be predicted to activate Notch signaling. Cell lines established from some of the mice demonstrated sensitivity to gamma-secretase inhibition, suggesting that even when NOTCH-1 mutations occur as secondary collaborating events, tumors retain a dependency on this pathway that might be exploitable clinically.