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The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T- cell acute lymphoblastic leukemia: A report from the Children's Oncology Group
We explored the impact of mutations in the NOTCH1, FBW7 and PTEN genes on prognosis and downstream signaling in a well-defined cohort of 47 pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients. In T-ALL lymphoblasts, we identified high frequency mutations in NOTCH1 (n=16), FBW7 (n=5) and P...
Autores principales: | , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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2009
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726275/ https://www.ncbi.nlm.nih.gov/pubmed/19340001 http://dx.doi.org/10.1038/leu.2009.64 |
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author | Gedman, Amanda Larson Chen, Qing Desmoulin, Sita Kugel Ge, Yubin LaFiura, Katherine Haska, Christina L. Cherian, Christina Devidas, Meenakshi Linda, Stephen B. Taub, Jeffrey W. Matherly, Larry H. |
author_facet | Gedman, Amanda Larson Chen, Qing Desmoulin, Sita Kugel Ge, Yubin LaFiura, Katherine Haska, Christina L. Cherian, Christina Devidas, Meenakshi Linda, Stephen B. Taub, Jeffrey W. Matherly, Larry H. |
author_sort | Gedman, Amanda Larson |
collection | PubMed |
description | We explored the impact of mutations in the NOTCH1, FBW7 and PTEN genes on prognosis and downstream signaling in a well-defined cohort of 47 pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients. In T-ALL lymphoblasts, we identified high frequency mutations in NOTCH1 (n=16), FBW7 (n=5) and PTEN (n=26). NOTCH1 mutations resulted in 1.3-3.3-fold increased transactivation of a HES1 reporter construct over wild-type NOTCH1; mutant FBW7 resulted in further augmentation of reporter gene activity. NOTCH1 and FBW7 mutations were accompanied by increased median transcripts for NOTCH1 target genes (HES1, DELTEX1, cMYC). However, none of these mutations were associated with treatment outcome. Elevated HES1, DELTEX1 and cMYC transcripts were associated with significant increases in transcript levels of several chemotherapy relevant genes, including MDR1, ABCC5, reduced folate carrier, asparagine synthetase, thiopurine methyltranserase, Bcl-2 and dihydrofolate reductase. PTEN transcripts positively correlated with HES1 and cMYC transcript levels. Our results suggest that (1) multiple factors should be considered with attempting to identify molecular-based prognostic factors for pediatric T-ALL, and (2) depending on the NOTCH1 signaling status, modifications in the types or dosing of standard chemotherapy drugs for T-ALL, or combinations of agents capable of targeting NOTCH1, AKT and/or mTOR with standard chemotherapy agents may be warranted. |
format | Text |
id | pubmed-2726275 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
record_format | MEDLINE/PubMed |
spelling | pubmed-27262752010-02-01 The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T- cell acute lymphoblastic leukemia: A report from the Children's Oncology Group Gedman, Amanda Larson Chen, Qing Desmoulin, Sita Kugel Ge, Yubin LaFiura, Katherine Haska, Christina L. Cherian, Christina Devidas, Meenakshi Linda, Stephen B. Taub, Jeffrey W. Matherly, Larry H. Leukemia Article We explored the impact of mutations in the NOTCH1, FBW7 and PTEN genes on prognosis and downstream signaling in a well-defined cohort of 47 pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients. In T-ALL lymphoblasts, we identified high frequency mutations in NOTCH1 (n=16), FBW7 (n=5) and PTEN (n=26). NOTCH1 mutations resulted in 1.3-3.3-fold increased transactivation of a HES1 reporter construct over wild-type NOTCH1; mutant FBW7 resulted in further augmentation of reporter gene activity. NOTCH1 and FBW7 mutations were accompanied by increased median transcripts for NOTCH1 target genes (HES1, DELTEX1, cMYC). However, none of these mutations were associated with treatment outcome. Elevated HES1, DELTEX1 and cMYC transcripts were associated with significant increases in transcript levels of several chemotherapy relevant genes, including MDR1, ABCC5, reduced folate carrier, asparagine synthetase, thiopurine methyltranserase, Bcl-2 and dihydrofolate reductase. PTEN transcripts positively correlated with HES1 and cMYC transcript levels. Our results suggest that (1) multiple factors should be considered with attempting to identify molecular-based prognostic factors for pediatric T-ALL, and (2) depending on the NOTCH1 signaling status, modifications in the types or dosing of standard chemotherapy drugs for T-ALL, or combinations of agents capable of targeting NOTCH1, AKT and/or mTOR with standard chemotherapy agents may be warranted. 2009-04-02 2009-08 /pmc/articles/PMC2726275/ /pubmed/19340001 http://dx.doi.org/10.1038/leu.2009.64 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Gedman, Amanda Larson Chen, Qing Desmoulin, Sita Kugel Ge, Yubin LaFiura, Katherine Haska, Christina L. Cherian, Christina Devidas, Meenakshi Linda, Stephen B. Taub, Jeffrey W. Matherly, Larry H. The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T- cell acute lymphoblastic leukemia: A report from the Children's Oncology Group |
title | The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T- cell acute lymphoblastic leukemia: A report from the Children's Oncology Group |
title_full | The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T- cell acute lymphoblastic leukemia: A report from the Children's Oncology Group |
title_fullStr | The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T- cell acute lymphoblastic leukemia: A report from the Children's Oncology Group |
title_full_unstemmed | The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T- cell acute lymphoblastic leukemia: A report from the Children's Oncology Group |
title_short | The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T- cell acute lymphoblastic leukemia: A report from the Children's Oncology Group |
title_sort | impact of notch1, fbw7 and pten mutations on prognosis and downstream signaling in pediatric t- cell acute lymphoblastic leukemia: a report from the children's oncology group |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726275/ https://www.ncbi.nlm.nih.gov/pubmed/19340001 http://dx.doi.org/10.1038/leu.2009.64 |
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