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

Department of Experimental, Diagnostic and Specialty Medicine, Hematology/Oncology “L. e A. Seràgnoli”, University of Bologna, 40138 Bologna, Italy
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Int. J. Mol. Sci. 2019, 20(24), 6141; https://doi.org/10.3390/ijms20246141
Received: 5 November 2019 / Revised: 29 November 2019 / Accepted: 4 December 2019 / Published: 5 December 2019
(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias 2.0)
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. View Full-Text
Keywords: chronic myeloid leukemia; blastic phase; BCR-ABL1; tyrosine kinase inhibitors; resistance; persistence chronic myeloid leukemia; blastic phase; BCR-ABL1; tyrosine kinase inhibitors; resistance; persistence
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MDPI and ACS Style

Bavaro, L.; Martelli, M.; Cavo, M.; Soverini, S. Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update. Int. J. Mol. Sci. 2019, 20, 6141.

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