Research and Development, Super Religare Laboratories Ltd., Mumbai, India.
Oncol Res. 2010;19(2):99-104. doi: 10.3727/096504010x12864748215007.
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.
Notch-1 是一种跨膜受体蛋白，可指导 T 细胞分化。已有报道称，Notch-1 的功能获得性突变存在于超过 50%的人类 T 细胞急性淋巴细胞白血病（T-ALL）中。本研究旨在分析 Notch-1 受体的异二聚化（HD）结构域和脯氨酸、谷氨酸、丝氨酸、苏氨酸丰富（PEST）结构域的突变情况。从 15 例初发 T-ALL 患者的外周血/骨髓中提取 RNA；扩增并测序 Notch-1 的 HD 和 PEST 区域。总体而言，有 6 名患者（40%）至少存在 1 种 Notch-1 突变，其中 2/15（13%）发生在 HD 区域，4/15（27%）发生在 PEST 区域。没有样本同时出现 HD 和 PEST 区域的突变。在 10 例成年患者中有 4 例（40%）出现突变，5 例儿科患者中有 2 例（40%）出现突变，均发生在 PEST 区域。不同的突变中，有 2 个以前有报道过，另外 4 个是新的。 Notch-1 突变的发生率较高；与其他研究不同的是，PEST 区域的突变频率更高。本研究还鉴定了 4 种新的突变体，为 T-ALL 的遗传异质性提供了新的见解。需要开展更多的大型研究来阐明该地区发生的 T-ALL 的分子发病机制。
