Related Experiment Video
Updated: Dec 21, 2025
Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype
Published on: June 17, 2022
Cytogenetic and molecular mechanisms of resistance to imatinib
1III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany.
Abstract:
Selective inhibition of the BCR-ABL tyrosine kinase by imatinib (Gleevec) (formerly STI571) is a promising new therapeutic strategy in patients with chronic myelogenous leukemia (CML). Despite significant hematologic and cytogenetic responses, resistance occurs in patients with chronic phase (CP) and advanced disease. A cohort of 72 patients with CML in myeloid blast crisis (BC) (n = 34), lymphoid BC (n = 2), accelerated phase (AP) (n = 16), CP (n = 18), and BCR-ABL(+) acute lymphoblastic leukemia (ALL) (n = 2) resistant to imatinib were investigated. Median levels of BCR-ABL transcripts, determined by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR), were not significantly changed at the time of resistance, but seven of 55 patients showed a greater than 10-fold increase in BCR-ABL levels. Genomic amplification of BCR-ABL was found in two of 32 patients evaluated by fluorescence in situ hybridization (FISH). Additional chromosomal aberrations were observed in 19 of 36 patients and point mutations of the ABL tyrosine kinase domain resulting in reactivation of the BCR-ABL tyrosine kinase were detected in 29 of 72 patients. Resistance may be caused by BCR-ABL-independent or BCR-ABL-dependent mechanisms. A thorough evaluation of resistant cases is required to suggest therapeutic measures in the individual case. Clonal selection of resistant cells harboring a BCR-ABL mutation might be reversed by stopping imatinib therapy and switching to chemotherapy. Combination therapy from the start of treatment to reduce the frequency of resistance is currently being evaluated with several drugs.
Insights
Imatinib resistance in chronic myelogenous leukemia (CML) can arise from BCR-ABL mutations or amplification. Evaluating these mechanisms is crucial for guiding imatinib therapy and exploring combination treatments.
Area of Science:
- Oncology
- Hematology
- Molecular Biology
Background:
- Imatinib (Gleevec) offers a targeted therapy for chronic myelogenous leukemia (CML) by inhibiting the BCR-ABL tyrosine kinase.
- Therapeutic resistance to imatinib is a significant clinical challenge in CML patients, even those in early disease phases.
Purpose of the Study:
- To investigate the mechanisms of imatinib resistance in a cohort of CML patients across different disease phases.
- To identify genetic alterations and molecular changes associated with imatinib resistance.
Main Methods:
- Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) to measure BCR-ABL transcript levels.
- Fluorescence in situ hybridization (FISH) to detect genomic amplification of BCR-ABL.
- Analysis of ABL tyrosine kinase domain point mutations and additional chromosomal aberrations.
Main Results:
- Point mutations in the ABL tyrosine kinase domain were detected in 29 of 72 patients, leading to BCR-ABL reactivation.
- Genomic amplification of BCR-ABL was observed in 2 of 32 patients.
- Increased BCR-ABL transcript levels (>10-fold) were noted in 7 of 55 patients, while others showed stable levels.
Conclusions:
- Imatinib resistance in CML can be driven by BCR-ABL-dependent mechanisms, such as mutations and amplification, or BCR-ABL-independent pathways.
- Comprehensive molecular evaluation of resistant cases is essential for personalized therapeutic strategies.
- Strategies like switching to chemotherapy or combination therapy are being explored to overcome or prevent imatinib resistance.
