The leukemic cells in a large proportion of individuals with a form of leukemia known as T-ALL have mutations in the NOTCH1 gene. These mutations lead to the generation of Notch1 proteins that have increased activity, however, it is not known whether they have sufficient increased activity to actually initiate the disease.
New data, generated by a team of researchers, at the University of Pennsylvania School of Medicine, Philadelphia, and Brigham and Women’s Hospital, Boston, have now indicated that only uncommon T-ALL-associated NOTCH1 mutations have the ability to induce cells to become leukemic in mice (these uncommon mutations generated Notch1 proteins with far greater increased activity than the Notch1 proteins generated by the more common mutations).
However, although the more common mutations were not themselves able to induce cells to become leukemic in mice, they were able to accelerate the onset of leukemia induced by other genetic mutations.
The authors therefore suggest that all T-ALL leukemic cells with mutations in the NOTCH1 gene are “addicted” to Notch and that this study provides support for the evaluation of Notch signaling pathway inhibitors as a treatment for leukemia.
“Leukemia-associated NOTCH1 alleles are weak tumor initiators but accelerate K-ras-initiated leukemia”
Mark Y. Chiang, Lanwei Xu, Olga Shestova, Gavin Histen, Sarah L’Heureux, Candice Romany, M. Eden Childs, Phyllis A. Gimotty, Jon C. Aster and Warren S. Pear
J. Clin. Invest. doi:10.1172/JCI35090
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The Journal of Clinical Investigation (JCI) is the publication of the American Society for Clinical Investigation, an honor society of physician-scientists.
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