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

Abstract

Evaluation of: Kindler T, Cornejo MG, Scholl C et al. K-Ras^G12D-induced T-cell lymphoblastic lymphoma/leukemias harbor Notch-1 mutations and are sensitive to γ-secretase inhibitors. Blood 15, 112(8), 3373–3382 (2008).

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 γ-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.

Keywords::

• γ-secretase inhibitor
• Kras
• Notch mutations
• Ras signaling
• T-cell acute lymphoblastic leukemia

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.