Notch1 mutations are important for leukemic transformation in murine models of precursor-T leukemia/lymphoma.
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.
Lin
Ying-Wei
YW
Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 8901 Wisconsin Ave, Bethesda, MD 20889-5105, USA.
Nichols
Rebecca A
RA
Letterio
John J
JJ
Aplan
Peter D
PD
D000367:Age Factors; D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D015458:Leukemia, T-Cell / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051881:Receptor, Notch1 / Q000235:genetics*; D013950:Thymus Gland / Q000166:cytology
C497762:Notch1 protein, mouse; D051881:Receptor, Notch1