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

Abstract

To study the impact of oncogenic K-Ras on T-cell leukemia/lymphoma development and progression, we made use of a conditional K-Ras(G12D) 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 gamma-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.

• Authors: Thomas Kindler, Melanie G Cornejo, Claudia Scholl, Jianing Liu, Dena S Leeman, J Erika Haydu, Stefan Fröhling, Benjamin H Lee, D Gary Gilliland
• Journal: Blood (Blood) Vol. 112 Issue 8 Pg. 3373-82 (Oct 15 2008) ISSN: 1528-0020 [Electronic] United States
• PMID: 18663146 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hyaluronan Receptors
• NOTCH1 protein, human
• Receptor, Notch1
• Amyloid Precursor Protein Secretases
• ras Proteins

Topics

• Amyloid Precursor Protein Secretases (antagonists & inhibitors)
• Animals
• Bone Marrow Cells (cytology)
• Cell Differentiation
• Gene Expression Regulation
• Genes, ras
• Humans
• Hyaluronan Receptors (biosynthesis)
• Leukemia, T-Cell (genetics)
• Lymphoma, T-Cell (genetics)
• Mice
• Mice, Transgenic
• Mutation
• Receptor, Notch1 (genetics)
• ras Proteins (physiology)