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Dissertation zugänglich unter
Analysis of NOTCH1 Mutation Status in Precursor T-Cell Lymphoblastic Leukemia of Childhood: Prognostic Value and Correlation with Early Treatment Response.
NOTCH1 Mutationsstatus Analyse in Vorläufer T-Zellen lymphoblastische Leukämie im Kindesalter: prognostische Bedeutung und Korrelation mit initialen Therapieansprechens.
Gallo Llorente, Lucía
Dokument 1.pdf (2.163 KB)
Freie Schlagwörter (Englisch):
NOTCH1 , Mutation , T-ALL , prognosis , therapie response
44.81 , 44.48 , 44.67
Schneppenheim, Reinhard (Prof. Dr.)
Tag der mündlichen Prüfung:
Kurzfassung auf Englisch:
The presence of activating NOTCH1 mutations in about 60% of pediatric T-ALL and the fact that different studies have shown a favorable effect on early treatment response and long term outcome, originated the question of the prognostic implication in patients treated on German Co-Operative Study Group for Childhood Acute Lymphoblastic Leukemia study (COALL-92-97-03) protocols. We retrospectively investigated the prognostic relevance of NOTCH1 mutations for 133 pediatric patients enrolled in COALL-92-97-03 and analyzed the relationship with early treatment response [according to the incidence of high minimal residual disease (MRD) levels] and long term outcome.
Overall, 80 out of 133 (60.2%) patients were NOTCH1+. In 47/80 samples mutations were detected only in the HD domain (58.8%), in 11/80 in the PEST domain (13.8%) and in 19/80 in both domains (23.7%). Only one patient (1.25%) had a mutation in the TM domain. Noteworthy, are the two mutations (2.5%) found in the LNR repeat domain, a very rarely affected domain, which to our best knowledge, have not been previously described.
Statistical analysis of 127 patients failed to confirm a lower relapse rate (same incidence of relapse for both groups: 27% (12/50 NOTCH- versus 18/77 NOTCH+; p=0.95) and overall favorable effect of activating NOTCH1 mutations. However, NOTCH1 mutations were associated with low levels of MRD on day 29 (P=.009) but no correlation was found with levels of MRD on day 43.
In this study, 38 patients treated according the ALL IC-BFM protocol (Garrahan Hospital, Buenos Aires, Argentina) were included. When considering patients in the BFM-like cohort, mutations were associated with good prednisone response (P=.009); but no relationship with long-term prognosis.
Our data support the statement that the effect of NOTCH1 is generally treatment related and may depend on the intensity of the induction chemotherapy specifically. Therefore, they do not seem to improve our current risk-stratification strategies.
Of note, an in-frame mutation was found in the PEST domain (exon 34) that to date, has not been described, and does not follow the usual pattern of mutations in this domain, that normally lead to premature stop codons and a truncated PEST domain. The novel mutations found in exon 25, may contribute to a better understanding of the structure of the NOTCH1 negative regulatory region (NRR). Antibodies or small molecule inhibitors targeting the NRR of NOTCH1 might find future utility as targeted therapeutics in the management of T-ALL.