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Review
. 2019 Dec 5;20(24):6141.
doi: 10.3390/ijms20246141.

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

Luana Bavaro  1 , Margherita Martelli  1 , Michele Cavo  1 , Simona Soverini  1
Affiliations
Review

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

Luana Bavaro et al. Int J Mol Sci. .

Abstract

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.

Keywords: BCR-ABL1; blastic phase; chronic myeloid leukemia; persistence; resistance; tyrosine kinase inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of BCR-ABL1-dependent mechanisms. High BCR-ABL1 expression and activity in chronic myeloid leukemia (CML) implicate alteration of the normal cellular and genetic characteristics leading to transformation and progression to advanced phases.
Figure 2
Figure 2
The role of BCR-ABL1 in the genomic instability. High levels of BCR-ABL1 are responsible for the generation of reactive oxygen species (ROS) and stimulate unfaithful DNA repair mechanisms (HRR= homologous recombination repair, NHEJ = nonhomologous end-joining, SSA = single-cell annealing) thus leading to increased DNA damage.
Figure 3
Figure 3
Persistence of LSCs: BCR-ABL1 kinase-dependent and -independent pathways.
See this image and copyright information in PMC

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