title: Mutations in the HD and PEST domain of Notch-1 receptor in T-cell acute lymphoblastic leukemia: report of novel mutations from Indian population.
abstract: 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.
authors.affiliation: Research and Development, Super Religare Laboratories Ltd., Mumbai, India.
authors.forename: Aparna A
authors.initials: AA
authors.lastname: Bhanushali
authors.forename: Suresh
authors.initials: S
authors.lastname: Babu
authors.forename: Veera Raghavan
authors.initials: VR
authors.lastname: Thangapandi
authors.forename: Renjith
authors.initials: R
authors.lastname: Pillai
authors.forename: Pratiksha
authors.initials: P
authors.lastname: Chheda
authors.forename: Bibhu R
authors.initials: BR
authors.lastname: Das
mesh_terms: D000328:Adult; D001483:Base Sequence; D002648:Child; D006801:Humans; D007194:India; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000737:chemistry / Q000235:genetics*; D055815:Young Adult
chemical_list: D051881:Receptor, Notch1