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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2540-2543.
Prepublished online as a Blood First Edition Paper on November 10, 2005; DOI 10.1182/blood-2005-07-3013.
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NEOPLASIA
Brief report
Notch1 mutations are important for leukemic transformation in murine models of precursor-T leukemia/lymphoma
Ying-Wei Lin,
Rebecca A. Nichols,
John J. Letterio, and
Peter D. Aplan
From the Genetics Branch and Laboratory for Cell Regulation and Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
NOTCH1 is frequently mutated in human precursor T-cell lymphoblastic leukemia/lymphoma (pre-T LBL). In the current study, we found that 13 of 19 cell lines and 29 of 49 primary tumors from SCL/LMO1, OLIG2/LMO1, OLIG2, LMO1, NUP98/HOXD13, and p27-/-/SMAD3+/- mice had Notch1 mutations in either the heterodimerization (HD) or the glutamic acid/serine/threonine (PEST) domain but not both. Thymocytes from clinically healthy SCL/LMO1 mice aged 5 weeks did not have Notch1 mutations, whereas thymocytes from clinically healthy SCL/LMO1 mice aged 8 to 12 weeks did have Notch1 mutations and formed tumors upon transplantation into nude mice. Remarkably, all of the HD domain mutations that we identified were single-base substitutions, whereas all of the PEST domain mutations were insertions or deletions, half of which mapped to 1 of 2 mutational "hot spots." Taken together, these findings indicate that Notch1 mutations are very frequent events that are acquired relatively early in the process of leukemic transformation and are important for leukemic cell growth. (Blood. 2006;107: 2540-2543)
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