%0 Journal Article
%T NOTCH1 pathway activating mutations and clonal evolution in pediatric T©\cell acute lymphoblastic leukemia
%A Akira Oka
%A Atsushi Manabe
%A Junko Takita
%A Katsuyoshi Koh
%A Kenichi Yoshida
%A Masafumi Seki
%A Masaharu Akiyama
%A Masao Kobayashi
%A Satoru Miyano
%A Seishi Ogawa
%A Shunsuke Kimura
%A Toshihiko Imamura
%A Yasuhide Hayashi
%A Yuichi Shiraishi
%J Archive of "Cancer Science".
%D 2019
%R 10.1111/cas.13859
%X Molecular mechanisms involved in the relapse of T©\cell acute lymphoblastic leukemia (T©\ALL) are not fully understood, although activating NOTCH1 signaling due to NOTCH1/FBXW7 alterations is a major oncogenic driver. To unravel the relevance of NOTCH1/FBXW7 mutations associated with relapse, we performed whole¨Cexome sequencing in 30 pediatric T©\ALL cases, among which 11 diagnosis©\relapse paired cases were further investigated to track the clonal evolution of relapse using amplicon¨Cbased deep sequencing. NOTCH1/FBXW7 alterations were detected in 73.3% (diagnosis) and 72.7% (relapse) of cases. Single nucleotide variations in the heterodimerization domain were the most frequent (40.0%) at diagnosis, whereas proline, glutamic acid, serine, threonine¨Crich (PEST) domain alterations were the most frequent at relapse (54.5%). Comparison between non¨Crelapsed and relapsed cases at diagnosis showed a predominance of PEST alterations in relapsed cases (P = .045), although we failed to validate this in the TARGET cohort. Based on the clonal analysis of diagnosis©\relapse samples, we identified NOTCH1 ¡°switching¡± characterized by different NOTCH1 mutations in a major clone between diagnosis and relapse samples in 2 out of 11 diagnosis©\relapse paired cases analyzed. We found another NOTCH1 ¡°switching¡± case in a previously reported Berlin©\Frankfurt©\M¨¹nster cohort (n = 13), indicating NOTCH1 importance in both the development and progression of T©\ALL. Despite the limitations of having a small sample size and a non¨Cminimal residual disease¨Cbased protocol, our results suggest that the presence of NOTCH1 mutations might contribute to the disease relapse of T©\ALL
%K NOTCH1
%K pediatric leukemia
%K relapse
%K T©\cell acute lymphoblastic leukemia
%K whole¨Cexome sequencing
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361559/