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The Challenge of Targeting Notch in Hematologic Malignancies

Notch signaling can play oncogenic and tumor suppressor roles depending on cell type. Hematologic malignancies encompass a wide range of transformed cells, and consequently the roles of Notch are diverse in these diseases. For example Notch is a potent T-cell oncogene, with >50% of T-cell acute l...

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Autores principales: Hernandez Tejada, Fiorela N., Galvez Silva, Jorge R., Zweidler-McKay, Patrick A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051192/
https://www.ncbi.nlm.nih.gov/pubmed/24959528
http://dx.doi.org/10.3389/fped.2014.00054
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author Hernandez Tejada, Fiorela N.
Galvez Silva, Jorge R.
Zweidler-McKay, Patrick A.
author_facet Hernandez Tejada, Fiorela N.
Galvez Silva, Jorge R.
Zweidler-McKay, Patrick A.
author_sort Hernandez Tejada, Fiorela N.
collection PubMed
description Notch signaling can play oncogenic and tumor suppressor roles depending on cell type. Hematologic malignancies encompass a wide range of transformed cells, and consequently the roles of Notch are diverse in these diseases. For example Notch is a potent T-cell oncogene, with >50% of T-cell acute lymphoblastic leukemia (T-ALL) cases carry activating mutations in the Notch1 receptor. Targeting Notch signaling in T-ALL with gamma-secretase inhibitors, which prevent Notch receptor activation, has shown pre-clinical activity, and is under evaluation clinically. In contrast, Notch signaling inhibits acute myeloblastic leukemia growth and survival, and although targeting Notch signaling in AML with Notch activators appears to have pre-clinical activity, no Notch agonists are clinically available at this time. As such, despite accumulating evidence about the biology of Notch signaling in different hematologic cancers, which provide compelling clinical promise, we are only beginning to target this pathway clinically, either on or off. In this review, we will summarize the evidence for oncogenic and tumor suppressor roles of Notch in a wide range of leukemias and lymphomas, and describe therapeutic opportunities for now and the future.
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spelling pubmed-40511922014-06-23 The Challenge of Targeting Notch in Hematologic Malignancies Hernandez Tejada, Fiorela N. Galvez Silva, Jorge R. Zweidler-McKay, Patrick A. Front Pediatr Pediatrics Notch signaling can play oncogenic and tumor suppressor roles depending on cell type. Hematologic malignancies encompass a wide range of transformed cells, and consequently the roles of Notch are diverse in these diseases. For example Notch is a potent T-cell oncogene, with >50% of T-cell acute lymphoblastic leukemia (T-ALL) cases carry activating mutations in the Notch1 receptor. Targeting Notch signaling in T-ALL with gamma-secretase inhibitors, which prevent Notch receptor activation, has shown pre-clinical activity, and is under evaluation clinically. In contrast, Notch signaling inhibits acute myeloblastic leukemia growth and survival, and although targeting Notch signaling in AML with Notch activators appears to have pre-clinical activity, no Notch agonists are clinically available at this time. As such, despite accumulating evidence about the biology of Notch signaling in different hematologic cancers, which provide compelling clinical promise, we are only beginning to target this pathway clinically, either on or off. In this review, we will summarize the evidence for oncogenic and tumor suppressor roles of Notch in a wide range of leukemias and lymphomas, and describe therapeutic opportunities for now and the future. Frontiers Media S.A. 2014-06-10 /pmc/articles/PMC4051192/ /pubmed/24959528 http://dx.doi.org/10.3389/fped.2014.00054 Text en Copyright © 2014 Hernandez Tejada, Galvez Silva and Zweidler-McKay. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pediatrics
Hernandez Tejada, Fiorela N.
Galvez Silva, Jorge R.
Zweidler-McKay, Patrick A.
The Challenge of Targeting Notch in Hematologic Malignancies
title The Challenge of Targeting Notch in Hematologic Malignancies
title_full The Challenge of Targeting Notch in Hematologic Malignancies
title_fullStr The Challenge of Targeting Notch in Hematologic Malignancies
title_full_unstemmed The Challenge of Targeting Notch in Hematologic Malignancies
title_short The Challenge of Targeting Notch in Hematologic Malignancies
title_sort challenge of targeting notch in hematologic malignancies
topic Pediatrics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4051192/
https://www.ncbi.nlm.nih.gov/pubmed/24959528
http://dx.doi.org/10.3389/fped.2014.00054
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