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Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects

Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. Despite the enormous progress in ALL therapy, resulting in achieving a 5-year survival rate of up to 90%, the ambitious goal of reaching a 100% survival rate is still being pursued. A typical ALL treatment includes thre...

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Autores principales: Kośmider, Kamil, Karska, Katarzyna, Kozakiewicz, Agata, Lejman, Monika, Zawitkowska, Joanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8999045/
https://www.ncbi.nlm.nih.gov/pubmed/35409154
http://dx.doi.org/10.3390/ijms23073795
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author Kośmider, Kamil
Karska, Katarzyna
Kozakiewicz, Agata
Lejman, Monika
Zawitkowska, Joanna
author_facet Kośmider, Kamil
Karska, Katarzyna
Kozakiewicz, Agata
Lejman, Monika
Zawitkowska, Joanna
author_sort Kośmider, Kamil
collection PubMed
description Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. Despite the enormous progress in ALL therapy, resulting in achieving a 5-year survival rate of up to 90%, the ambitious goal of reaching a 100% survival rate is still being pursued. A typical ALL treatment includes three phases: remission induction and consolidation and maintenance, preceded by a prednisone prephase. Poor prednisone response (PPR) is defined as the presence of ≥1.0 × 10(9) blasts/L in the peripheral blood on day eight of therapy and results in significantly frequent relapses and worse outcomes. Hence, identifying risk factors of steroid resistance and finding methods of overcoming that resistance may significantly improve patients’ outcomes. A mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) pathway seems to be a particularly attractive target, as its activation leads to steroid resistance via a phosphorylating Bcl-2-interacting mediator of cell death (BIM), which is crucial in the steroid-induced cell death. Several mutations causing activation of MAPK-ERK were discovered, notably the interleukin-7 receptor (IL-7R) pathway mutations in T-cell ALL and rat sarcoma virus (Ras) pathway mutations in precursor B-cell ALL. MAPK-ERK pathway inhibitors were demonstrated to enhance the results of dexamethasone therapy in preclinical ALL studies. This report summarizes steroids’ mechanism of action, resistance to treatment, and prospects of steroids therapy in pediatric ALL.
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spelling pubmed-89990452022-04-12 Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects Kośmider, Kamil Karska, Katarzyna Kozakiewicz, Agata Lejman, Monika Zawitkowska, Joanna Int J Mol Sci Review Acute lymphoblastic leukemia (ALL) is the most common malignancy among children. Despite the enormous progress in ALL therapy, resulting in achieving a 5-year survival rate of up to 90%, the ambitious goal of reaching a 100% survival rate is still being pursued. A typical ALL treatment includes three phases: remission induction and consolidation and maintenance, preceded by a prednisone prephase. Poor prednisone response (PPR) is defined as the presence of ≥1.0 × 10(9) blasts/L in the peripheral blood on day eight of therapy and results in significantly frequent relapses and worse outcomes. Hence, identifying risk factors of steroid resistance and finding methods of overcoming that resistance may significantly improve patients’ outcomes. A mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-ERK) pathway seems to be a particularly attractive target, as its activation leads to steroid resistance via a phosphorylating Bcl-2-interacting mediator of cell death (BIM), which is crucial in the steroid-induced cell death. Several mutations causing activation of MAPK-ERK were discovered, notably the interleukin-7 receptor (IL-7R) pathway mutations in T-cell ALL and rat sarcoma virus (Ras) pathway mutations in precursor B-cell ALL. MAPK-ERK pathway inhibitors were demonstrated to enhance the results of dexamethasone therapy in preclinical ALL studies. This report summarizes steroids’ mechanism of action, resistance to treatment, and prospects of steroids therapy in pediatric ALL. MDPI 2022-03-30 /pmc/articles/PMC8999045/ /pubmed/35409154 http://dx.doi.org/10.3390/ijms23073795 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Kośmider, Kamil
Karska, Katarzyna
Kozakiewicz, Agata
Lejman, Monika
Zawitkowska, Joanna
Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects
title Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects
title_full Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects
title_fullStr Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects
title_full_unstemmed Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects
title_short Overcoming Steroid Resistance in Pediatric Acute Lymphoblastic Leukemia—The State-of-the-Art Knowledge and Future Prospects
title_sort overcoming steroid resistance in pediatric acute lymphoblastic leukemia—the state-of-the-art knowledge and future prospects
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8999045/
https://www.ncbi.nlm.nih.gov/pubmed/35409154
http://dx.doi.org/10.3390/ijms23073795
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