K-RasG12D–induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to γ-secretase inhibitors

T Kindler, MG Cornejo, C Scholl, J Liu… - Blood, The Journal …, 2008 - ashpublications.org
T Kindler, MG Cornejo, C Scholl, J Liu, DS Leeman, JE Haydu, S Fröhling, BH Lee…
Blood, The Journal of the American Society of Hematology, 2008ashpublications.org
To study the impact of oncogenic K-Ras on T-cell leukemia/lymphoma development and
progression, we made use of a conditional K-RasG12D murine knockin model, in which
oncogenic K-Ras is expressed from its endogenous promoter. Transplantation of whole
bone marrow cells that express oncogenic K-Ras into wild-type recipient mice resulted in a
highly penetrant, aggressive T-cell leukemia/lymphoma. The lymphoblasts were composed
of a CD4/CD8 double-positive population that aberrantly expressed CD44. Thymi of primary …
Abstract
To study the impact of oncogenic K-Ras on T-cell leukemia/lymphoma development and progression, we made use of a conditional K-RasG12D murine knockin model, in which oncogenic K-Ras is expressed from its endogenous promoter. Transplantation of whole bone marrow cells that express oncogenic K-Ras into wild-type recipient mice resulted in a highly penetrant, aggressive T-cell leukemia/lymphoma. The lymphoblasts were composed of a CD4/CD8 double-positive population that aberrantly expressed CD44. Thymi of primary donor mice showed reduced cellularity, and immunophenotypic analysis demonstrated a block in differentiation at the double-negative 1 stage. With progression of disease, approximately 50% of mice acquired Notch1 mutations within the PEST domain. Of note, primary lymphoblasts were hypersensitive to γ-secretase inhibitor treatment, which is known to impair Notch signaling. This inhibition was Notch-specific as assessed by down-regulation of Notch1 target genes and intracellular cleaved Notch. We also observed that the oncogenic K-Ras-induced T-cell disease was responsive to rapamycin and inhibitors of the RAS/MAPK pathway. These data indicate that patients with T-cell leukemia with K-Ras mutations may benefit from therapies that target the NOTCH pathway alone or in combination with inhibition of the PI3K/AKT/MTOR and RAS/MAPK pathways.
ashpublications.org