Beyond BCR::ABL1-The Role of Genomic Analyses in the Management of CML
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Updated: Jul 2, 2025
Comprehensive DNA Methylation Analysis Using a Methyl-CpG-binding Domain Capture-based Method in Chronic Lymphocytic Leukemia Patients
Published on: June 16, 2017
Susan Branford1,2,3, Adelina Fernandes1,3, NurHezrin Shahrin1
1Department of Genetics and Molecular Pathology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
Abstract:
Chronic myeloid leukemia (CML) is a model of genomically based diagnosis and management where BCR::ABL1 is successfully targeted by tyrosine kinase inhibitor (TKI) therapy in most patients. The dynamics of BCR::ABL1 transcript decline during therapy is a dependable biomarker of response, relapse, and drug resistance. Missense mutations acquired within the BCR::ABL1 kinase domain that disrupt TKI binding can evolve during therapy and are frequently detected in patients for whom TKI treatment fails. Importantly, specific BCR::ABL1 missense mutations are targetable alterations and direct therapeutic decisions based on the individual mutant TKI sensitivity profile. Nevertheless, BCR::ABL1 mutations are only implicated in approximately half of the cases of acquired resistance. Furthermore, not all patients with a single BCR::ABL1 mutation that is predicted to be sensitive to a specific TKI will experience a response when switched to that TKI. Progression to blast phase heralds independence from BCR::ABL1, and this phase of the disease is notoriously difficult to treat. The independent drivers of resistance and disease progression have long been investigated to both predict progression and to find targets for therapeutic intervention. Recent data reaffirm that drug resistance and disease progression is a mutation-driven process in CML, and somatic variants in genes that are known to drive acute myeloid and lymphoid leukemia have been detected in patients in the advanced phases of CML. Genomic testing over the last few decades for patients with blood cancer has revealed of variety of genomic aberrations that drive disease. Consequently, incorporation of genomic factors into patient management for a range of blood cancers has led to the implementation of high-throughput gene testing to detect clinically actionable variants. Is it time to integrate broader genomic screening into clinical management strategies for patients with CML?
Insights
Chronic myeloid leukemia (CML) treatment relies on BCR-ABL1 targeting. While mutations cause resistance, broader genomic screening may improve management of advanced CML phases.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Chronic myeloid leukemia (CML) management often targets the BCR-ABL1 fusion gene with tyrosine kinase inhibitors (TKIs).
- BCR-ABL1 transcript levels serve as a biomarker for treatment response, relapse, and resistance.
- Acquired mutations in the BCR-ABL1 kinase domain can lead to TKI resistance, but only explain about half of resistance cases.
Purpose of the Study:
- To investigate the role of broader genomic profiling in managing CML, particularly in advanced phases.
- To explore whether genomic testing beyond BCR-ABL1 mutations can identify drivers of resistance and disease progression.
- To assess the potential for integrating comprehensive genomic screening into CML clinical management strategies.
Main Methods:
- Review of recent data on genomic alterations in CML, including somatic variants in genes associated with acute leukemias.
- Analysis of the utility of high-throughput gene testing in identifying clinically actionable variants in blood cancers.
- Discussion of the implications of genomic findings for predicting CML progression and therapeutic interventions.
Main Results:
- BCR-ABL1 mutations are implicated in resistance to TKI therapy, but do not account for all cases.
- Disease progression in CML, especially to blast phase, can be driven by genetic alterations independent of BCR-ABL1.
- Somatic variants common in acute myeloid and lymphoid leukemia have been identified in advanced CML phases.
Conclusions:
- While BCR-ABL1 mutations are important, they do not fully explain TKI resistance or disease progression in CML.
- Broader genomic screening may uncover additional therapeutic targets and improve the prediction of disease progression.
- Integrating comprehensive genomic testing into CML management could enhance personalized treatment strategies and outcomes.
