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Activating Notch1 mutations in mouse models of T-ALL
Jennifer O'Neil1, Jennifer Calvo, Keith McKenna
1Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Blood
|September 17, 2005
Summary
Activating NOTCH1 mutations are common in mouse models of T-cell acute lymphocytic leukemia (T-ALL). These NOTCH1 mutations drive T-ALL development and can be targeted with gamma-secretase inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Activating mutations in NOTCH1 are frequently observed in human T-cell acute lymphocytic leukemia (T-ALL).
- The role of NOTCH1 mutations in the pathogenesis of T-ALL in mouse models requires further investigation.
Purpose of the Study:
- To investigate the occurrence and functional significance of NOTCH1 mutations in mouse models of T-ALL.
- To determine if NOTCH1 mutations are acquired during leukemogenesis in genetically altered mice.
Main Methods:
- Sequencing of the heterodimerization and PEST domains of Notch1 in mouse T-ALL tumors.
- Treatment of T-ALL cell lines with a gamma-secretase inhibitor to assess Notch1 pathway dependency.
- Analysis of Notch1 mutations in thymic lymphomas from mice with genetic deficiencies (H2AX, Tp53, Rag2).
Main Results:
- Activating NOTCH1 mutations were found in 74% of tumors in a TAL1-induced mouse model of T-ALL.
- T-ALL cell lines with NOTCH1 mutations exhibited G(0)/G(1) arrest and apoptosis upon gamma-secretase inhibitor treatment.
- Activating NOTCH1 mutations were identified in 31% of thymic lymphomas in mice with combined H2AX, Tp53, and Rag2 deficiencies.
Conclusions:
- NOTCH1 mutations are frequently acquired during the molecular pathogenesis of T-ALL in mice with predisposing genetic alterations.
- NOTCH1 signaling is crucial for the survival of T-ALL cells in these mouse models.
- These findings support the relevance of mouse models for studying T-ALL and potential therapeutic strategies targeting the NOTCH1 pathway.