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Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TK...

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Autores principales: Bavaro, Luana, Martelli, Margherita, Cavo, Michele, Soverini, Simona
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940932/
https://www.ncbi.nlm.nih.gov/pubmed/31817512
http://dx.doi.org/10.3390/ijms20246141
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author Bavaro, Luana
Martelli, Margherita
Cavo, Michele
Soverini, Simona
author_facet Bavaro, Luana
Martelli, Margherita
Cavo, Michele
Soverini, Simona
author_sort Bavaro, Luana
collection PubMed
description Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, some patients may not respond (primary resistance) or may relapse after an initial response (secondary resistance). In a small proportion of cases, development of resistance is accompanied or shortly followed by progression from chronic to blastic phase (BP), characterized by a dismal prognosis. Evolution from CP into BP is a multifactorial and probably multistep phenomenon. Increase in BCR-ABL1 transcript levels is thought to promote the onset of secondary chromosomal or genetic defects, induce differentiation arrest, perturb RNA transcription, editing and translation that together with epigenetic and metabolic changes may ultimately lead to the expansion of highly proliferating, differentiation-arrested malignant cells. A multitude of studies over the past two decades have investigated the mechanisms underlying the closely intertwined phenomena of drug resistance and disease progression. Here, we provide an update on what is currently known on the mechanisms underlying progression and present the latest acquisitions on BCR-ABL1-independent resistance and leukemia stem cell persistence.
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spelling pubmed-69409322020-01-09 Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update Bavaro, Luana Martelli, Margherita Cavo, Michele Soverini, Simona Int J Mol Sci Review Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, some patients may not respond (primary resistance) or may relapse after an initial response (secondary resistance). In a small proportion of cases, development of resistance is accompanied or shortly followed by progression from chronic to blastic phase (BP), characterized by a dismal prognosis. Evolution from CP into BP is a multifactorial and probably multistep phenomenon. Increase in BCR-ABL1 transcript levels is thought to promote the onset of secondary chromosomal or genetic defects, induce differentiation arrest, perturb RNA transcription, editing and translation that together with epigenetic and metabolic changes may ultimately lead to the expansion of highly proliferating, differentiation-arrested malignant cells. A multitude of studies over the past two decades have investigated the mechanisms underlying the closely intertwined phenomena of drug resistance and disease progression. Here, we provide an update on what is currently known on the mechanisms underlying progression and present the latest acquisitions on BCR-ABL1-independent resistance and leukemia stem cell persistence. MDPI 2019-12-05 /pmc/articles/PMC6940932/ /pubmed/31817512 http://dx.doi.org/10.3390/ijms20246141 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Bavaro, Luana
Martelli, Margherita
Cavo, Michele
Soverini, Simona
Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update
title Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update
title_full Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update
title_fullStr Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update
title_full_unstemmed Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update
title_short Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update
title_sort mechanisms of disease progression and resistance to tyrosine kinase inhibitor therapy in chronic myeloid leukemia: an update
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940932/
https://www.ncbi.nlm.nih.gov/pubmed/31817512
http://dx.doi.org/10.3390/ijms20246141
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