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Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways
Although long-term survival in pediatric acute lymphoblastic leukemia (ALL) currently exceeds 90%, some subgroups, defined by specific genomic aberrations, respond poorly to treatment. We previously reported that leukemias harboring deletions or mutations affecting the B-cell transcription factor IK...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9478899/ https://www.ncbi.nlm.nih.gov/pubmed/36119546 http://dx.doi.org/10.3389/fonc.2022.905665 |
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author | Butler, Miriam Vervoort, Britt M.T. van Ingen Schenau, Dorette S. Jongeneel, Lieneke van der Zwet, Jordy C.G. Marke, René Meijerink, Jules P.P. Scheijen, Blanca van der Meer, Laurens T. van Leeuwen, Frank N. |
author_facet | Butler, Miriam Vervoort, Britt M.T. van Ingen Schenau, Dorette S. Jongeneel, Lieneke van der Zwet, Jordy C.G. Marke, René Meijerink, Jules P.P. Scheijen, Blanca van der Meer, Laurens T. van Leeuwen, Frank N. |
author_sort | Butler, Miriam |
collection | PubMed |
description | Although long-term survival in pediatric acute lymphoblastic leukemia (ALL) currently exceeds 90%, some subgroups, defined by specific genomic aberrations, respond poorly to treatment. We previously reported that leukemias harboring deletions or mutations affecting the B-cell transcription factor IKZF1 exhibit a tumor cell intrinsic resistance to glucocorticoids (GCs), one of the cornerstone drugs used in the treatment of ALL. Here, we identified increased activation of both AKT and ERK signaling pathways as drivers of GC resistance in IKZF1-deficient leukemic cells. Indeed, combined pharmacological inhibition of AKT and ERK signaling effectively reversed GC resistance in IKZF1-deficient leukemias. As inhibitors for both pathways are under clinical investigation, their combined use may enhance the efficacy of prednisolone-based therapy in this high-risk patient group. |
format | Online Article Text |
id | pubmed-9478899 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-94788992022-09-17 Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways Butler, Miriam Vervoort, Britt M.T. van Ingen Schenau, Dorette S. Jongeneel, Lieneke van der Zwet, Jordy C.G. Marke, René Meijerink, Jules P.P. Scheijen, Blanca van der Meer, Laurens T. van Leeuwen, Frank N. Front Oncol Oncology Although long-term survival in pediatric acute lymphoblastic leukemia (ALL) currently exceeds 90%, some subgroups, defined by specific genomic aberrations, respond poorly to treatment. We previously reported that leukemias harboring deletions or mutations affecting the B-cell transcription factor IKZF1 exhibit a tumor cell intrinsic resistance to glucocorticoids (GCs), one of the cornerstone drugs used in the treatment of ALL. Here, we identified increased activation of both AKT and ERK signaling pathways as drivers of GC resistance in IKZF1-deficient leukemic cells. Indeed, combined pharmacological inhibition of AKT and ERK signaling effectively reversed GC resistance in IKZF1-deficient leukemias. As inhibitors for both pathways are under clinical investigation, their combined use may enhance the efficacy of prednisolone-based therapy in this high-risk patient group. Frontiers Media S.A. 2022-09-02 /pmc/articles/PMC9478899/ /pubmed/36119546 http://dx.doi.org/10.3389/fonc.2022.905665 Text en Copyright © 2022 Butler, Vervoort, van Ingen Schenau, Jongeneel, van der Zwet, Marke, Meijerink, Scheijen, van der Meer and van Leeuwen https://creativecommons.org/licenses/by/4.0/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) and the copyright owner(s) 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 | Oncology Butler, Miriam Vervoort, Britt M.T. van Ingen Schenau, Dorette S. Jongeneel, Lieneke van der Zwet, Jordy C.G. Marke, René Meijerink, Jules P.P. Scheijen, Blanca van der Meer, Laurens T. van Leeuwen, Frank N. Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways |
title | Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways |
title_full | Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways |
title_fullStr | Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways |
title_full_unstemmed | Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways |
title_short | Reversal of IKZF1-induced glucocorticoid resistance by dual targeting of AKT and ERK signaling pathways |
title_sort | reversal of ikzf1-induced glucocorticoid resistance by dual targeting of akt and erk signaling pathways |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9478899/ https://www.ncbi.nlm.nih.gov/pubmed/36119546 http://dx.doi.org/10.3389/fonc.2022.905665 |
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