Cargando…
The EphB6 receptor is overexpressed in pediatric T cell acute lymphoblastic leukemia and increases its sensitivity to doxorubicin treatment
While impressive improvements have been achieved in T-ALL therapy, current treatment approaches fail in approximately 25% of patients and these patients have limited treatment options. Another significant group of patients is being overtreated, which causes long-lasting side effects. Identification...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676711/ https://www.ncbi.nlm.nih.gov/pubmed/29116180 http://dx.doi.org/10.1038/s41598-017-15200-3 |
_version_ | 1783277108478345216 |
---|---|
author | El Zawily, Amr McEwen, Emily Toosi, Behzad Vizeacoumar, Frederick S. Freywald, Tanya Vizeacoumar, Franco J. Freywald, Andrew |
author_facet | El Zawily, Amr McEwen, Emily Toosi, Behzad Vizeacoumar, Frederick S. Freywald, Tanya Vizeacoumar, Franco J. Freywald, Andrew |
author_sort | El Zawily, Amr |
collection | PubMed |
description | While impressive improvements have been achieved in T-ALL therapy, current treatment approaches fail in approximately 25% of patients and these patients have limited treatment options. Another significant group of patients is being overtreated, which causes long-lasting side effects. Identification of molecules controlling drug resistance in T-ALL is crucial for treatment optimisation in both scenarios. We report here the EphB6 receptor is frequently overexpressed in T-ALL. Remarkably, our observations indicate that EphB6 acts in T-ALL cells to enhance sensitivity to a DNA-damaging drug, doxorubicin, as interruption of EphB6 activity interferes with the efficiency of doxorubicin-induced eradication of T-ALL cells in cell culture and in xenograft animals. This effect relies on the protection of Akt kinase signaling, while Akt inhibition combined with doxorubicin application produces synergistic effects on the elimination of EphB6-deficient T-ALL cells. These data imply that EphB6 suppresses T-ALL resistance by interfering with Akt activity. Our observations highlight a novel role for EphB6 in reducing drug resistance of T-ALL and suggest that doxorubicin treatment should produce better results if personalised based on EphB6 levels. If successfully verified in clinical studies, this approach should improve outcomes for T-ALL patients resistant to current therapies and for patients, who are being overtreated. |
format | Online Article Text |
id | pubmed-5676711 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-56767112017-11-15 The EphB6 receptor is overexpressed in pediatric T cell acute lymphoblastic leukemia and increases its sensitivity to doxorubicin treatment El Zawily, Amr McEwen, Emily Toosi, Behzad Vizeacoumar, Frederick S. Freywald, Tanya Vizeacoumar, Franco J. Freywald, Andrew Sci Rep Article While impressive improvements have been achieved in T-ALL therapy, current treatment approaches fail in approximately 25% of patients and these patients have limited treatment options. Another significant group of patients is being overtreated, which causes long-lasting side effects. Identification of molecules controlling drug resistance in T-ALL is crucial for treatment optimisation in both scenarios. We report here the EphB6 receptor is frequently overexpressed in T-ALL. Remarkably, our observations indicate that EphB6 acts in T-ALL cells to enhance sensitivity to a DNA-damaging drug, doxorubicin, as interruption of EphB6 activity interferes with the efficiency of doxorubicin-induced eradication of T-ALL cells in cell culture and in xenograft animals. This effect relies on the protection of Akt kinase signaling, while Akt inhibition combined with doxorubicin application produces synergistic effects on the elimination of EphB6-deficient T-ALL cells. These data imply that EphB6 suppresses T-ALL resistance by interfering with Akt activity. Our observations highlight a novel role for EphB6 in reducing drug resistance of T-ALL and suggest that doxorubicin treatment should produce better results if personalised based on EphB6 levels. If successfully verified in clinical studies, this approach should improve outcomes for T-ALL patients resistant to current therapies and for patients, who are being overtreated. Nature Publishing Group UK 2017-11-07 /pmc/articles/PMC5676711/ /pubmed/29116180 http://dx.doi.org/10.1038/s41598-017-15200-3 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article El Zawily, Amr McEwen, Emily Toosi, Behzad Vizeacoumar, Frederick S. Freywald, Tanya Vizeacoumar, Franco J. Freywald, Andrew The EphB6 receptor is overexpressed in pediatric T cell acute lymphoblastic leukemia and increases its sensitivity to doxorubicin treatment |
title | The EphB6 receptor is overexpressed in pediatric T cell acute lymphoblastic leukemia and increases its sensitivity to doxorubicin treatment |
title_full | The EphB6 receptor is overexpressed in pediatric T cell acute lymphoblastic leukemia and increases its sensitivity to doxorubicin treatment |
title_fullStr | The EphB6 receptor is overexpressed in pediatric T cell acute lymphoblastic leukemia and increases its sensitivity to doxorubicin treatment |
title_full_unstemmed | The EphB6 receptor is overexpressed in pediatric T cell acute lymphoblastic leukemia and increases its sensitivity to doxorubicin treatment |
title_short | The EphB6 receptor is overexpressed in pediatric T cell acute lymphoblastic leukemia and increases its sensitivity to doxorubicin treatment |
title_sort | ephb6 receptor is overexpressed in pediatric t cell acute lymphoblastic leukemia and increases its sensitivity to doxorubicin treatment |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676711/ https://www.ncbi.nlm.nih.gov/pubmed/29116180 http://dx.doi.org/10.1038/s41598-017-15200-3 |
work_keys_str_mv | AT elzawilyamr theephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment AT mcewenemily theephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment AT toosibehzad theephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment AT vizeacoumarfredericks theephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment AT freywaldtanya theephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment AT vizeacoumarfrancoj theephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment AT freywaldandrew theephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment AT elzawilyamr ephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment AT mcewenemily ephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment AT toosibehzad ephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment AT vizeacoumarfredericks ephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment AT freywaldtanya ephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment AT vizeacoumarfrancoj ephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment AT freywaldandrew ephb6receptorisoverexpressedinpediatrictcellacutelymphoblasticleukemiaandincreasesitssensitivitytodoxorubicintreatment |