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Molecular mechanisms involved in the relapse of T‐cell acute lymphoblastic leukemia (T‐ ALL ) are not fully understood, although activating  NOTCH 1 signaling due to   NOTCH 1/ FBXW 7  alterations is a major oncogenic driver. To unravel the relevance of   NOTCH 1/ FBXW 7  mutations associated with relapse, we performed whole–exome 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–based deep sequencing.   NOTCH 1/ FBXW 7  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–rich ( PEST)  domain alterations were the most frequent at relapse (54.5%). Comparison between non–relapsed 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   NOTCH 1  “switching” characterized by different   NOTCH 1  mutations in a major clone between diagnosis and relapse samples in 2 out of 11 diagnosis‐relapse paired cases analyzed. We found another   NOTCH 1  “switching” case in a previously reported Berlin‐Frankfurt‐Münster cohort (n = 13), indicating  NOTCH 1 importance in both the development and progression of T‐ ALL . Despite the limitations of having a small sample size and a non–minimal residual disease–based protocol, our results suggest that the presence of   NOTCH 1  mutations might contribute to the disease relapse of T‐ ALL .

NOTCH 1 pathway activating mutations and clonal evolution in pediatric T‐cell acute lymphoblastic leukemia