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Prognostic Implications of Mutations in NOTCH1 and FBXW7 in Childhood T-ALL Treated According to the NOPHO ALL-1992 and ALL-2000 Protocols

Fogelstrand, Linda; Staffas, Anna; Wasslavik, Carina; Sjogren, Helene; Soderhall, Stefan; Frost, Britt-Marie; Forestier, Erik; Degerman, Sofie; Behrendtz, Mikael and Heldrup, Jesper LU , et al. (2014) In Pediatric Blood & Cancer 61(3). p.424-430
Abstract
BackgroundIn children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis. ProcedureWe analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes. ResultsForty-seven of the cases (59%) displayed mutations... (More)
BackgroundIn children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis. ProcedureWe analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes. ResultsForty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P=0.14) or event-free survival (EFS) (P=0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.21.9 (mean +/- SEM), MYB 8.7 +/- 0.8 (mean +/- SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 +/- 0.7, MYB 5.1 +/- 1.2, P=0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P=0.02) and EFS (P=0.028) was seen. ConclusionsIncreased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated. Pediatr Blood Cancer 2014;61:424-430. (c) 2013 Wiley Periodicals, Inc. (Less)
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keywords
cytogenetics and molecular genetics, FBXW7, NOTCH1, pediatric acute, lymphoblastic leukemia, prognosis
in
Pediatric Blood & Cancer
volume
61
issue
3
pages
424 - 430
publisher
John Wiley and Sons Inc.
external identifiers
  • wos:000329585300006
  • scopus:84892515823
ISSN
1545-5017
DOI
10.1002/pbc.24803
language
English
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yes
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b1f69e13-011a-4506-a59f-ba8e6313a1d8 (old id 4318835)
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2014-03-03 08:00:09
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2017-10-08 03:03:50
@article{b1f69e13-011a-4506-a59f-ba8e6313a1d8,
  abstract     = {BackgroundIn children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis. ProcedureWe analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes. ResultsForty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P=0.14) or event-free survival (EFS) (P=0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.21.9 (mean +/- SEM), MYB 8.7 +/- 0.8 (mean +/- SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 +/- 0.7, MYB 5.1 +/- 1.2, P=0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P=0.02) and EFS (P=0.028) was seen. ConclusionsIncreased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated. Pediatr Blood Cancer 2014;61:424-430. (c) 2013 Wiley Periodicals, Inc.},
  author       = {Fogelstrand, Linda and Staffas, Anna and Wasslavik, Carina and Sjogren, Helene and Soderhall, Stefan and Frost, Britt-Marie and Forestier, Erik and Degerman, Sofie and Behrendtz, Mikael and Heldrup, Jesper and Karrman, Kristina and Johansson, Bertil and Heyman, Mats and Abrahamsson, Jonas and Palmqvist, Lars},
  issn         = {1545-5017},
  keyword      = {cytogenetics and molecular genetics,FBXW7,NOTCH1,pediatric acute,lymphoblastic leukemia,prognosis},
  language     = {eng},
  number       = {3},
  pages        = {424--430},
  publisher    = {John Wiley and Sons Inc.},
  series       = {Pediatric Blood & Cancer},
  title        = {Prognostic Implications of Mutations in NOTCH1 and FBXW7 in Childhood T-ALL Treated According to the NOPHO ALL-1992 and ALL-2000 Protocols},
  url          = {http://dx.doi.org/10.1002/pbc.24803},
  volume       = {61},
  year         = {2014},
}