Notch-1 is a transmembrane receptor protein that directs T-cell differentiation. Gain-of-function mutations in Notch-1 have been reported in more than 50% of human T-cell acute lymphoblastic leukemia (T-ALL). The current study was undertaken to characterize mutations in the heterodimerization (HD) domain and proline, glutamic acid, serine, threonine-rich (PEST) domain of the Notch-1 receptor. RNA was isolated from peripheral blood/bone marrow of 15 de novo T-ALL subjects; the Notch-1 HD and PEST regions were amplified and sequenced. Overall six patients (40%) had at least one Notch-1 mutation, 2/15 (13%) in the HD and 4/15 (27%) in the PEST domain. None of the samples showed simultaneous mutations in HD and PEST domains. Mutations were seen in 4/10 adult patients (40%); in the pediatric cohort 2/5 (40%) had mutations both of which were in the PEST domain. Of the different mutations, two have been previously reported and the other four are novel. A high incidence of Notch-1 mutations has been seen; unlike other studies, a higher frequency of mutations was found in PEST domain. The current study also served to identify four novel mutants that add new insights into the genetic heterogeneity of T-ALL. More ongoing larger studies are warranted to elucidate the molecular pathogenesis of T-ALL that arises in this part of the world.
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