Related Experiment Video
Updated: Aug 30, 2026
Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence
Published on: January 7, 2019
Comparative gene expression profile of chronic myeloid leukemia cells innately resistant to imatinib mesylate
Alex J Tipping1, Michael W Deininger, John M Goldman
1Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK.
Objective:
Resistance to imatinib mesylate monotherapy is clearly a barrier to successful treatment of chronic myeloid leukemia (CML) patients. In some patients, resistance arises due to powerful selective pressure on rare cells that carry amplified copies of the BCR-ABL fusion oncogene or point mutations in the Bcr-Abl tyrosine kinase domain that affect binding of the drug to the oncoprotein. However, in a proportion of patients neither mechanism operates, and resistance appears to be a priori, existing prior to exposure to the drug. These mechanisms of imatinib resistance are poorly understood and may be heterogeneous.
Materials And Methods:
We have previously described such innate resistance to imatinib in subclones of a myeloid leukemia cell line, KCL22, in which imatinib exposure inhibits the activity of Bcr-Abl and yet fails to induce apoptosis. We describe here whole-genome expression analysis of imatinib-sensitive and -resistant cells derived from the original KCL22 line, using Affymetrix microarray analysis.
Results:
We detected differential expression of 39 genes that correlate with the imatinib-resistant phenotype. The resistant cells overexpress several genes associated with the suppression of apoptosis or with conferral of a transformed phenotype.
Conclusion:
Amongst the differentially-expressed genes correlating with imatinib resistance, several suggest the activation of alternative pathway(s) that maintain viability and growth independently of Bcr-Abl kinase activity. Given the high rate of primary imatinib resistance in blast crisis, the potential of activating such alternative pathways appears to correlate with disease progression.
Insights
Imatinib resistance in chronic myeloid leukemia (CML) can occur without known genetic causes. Gene expression analysis revealed 39 differentially expressed genes in resistant cells, suggesting alternative survival pathways independent of BCR-ABL kinase activity.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Imatinib mesylate is a key treatment for chronic myeloid leukemia (CML).
- Primary resistance to imatinib is a significant clinical challenge.
- Mechanisms of innate imatinib resistance in CML are not fully understood.
Purpose of the Study:
- To investigate the molecular mechanisms underlying innate imatinib resistance in CML.
- To identify genes and pathways associated with imatinib resistance independent of BCR-ABL mutations or amplification.
Main Methods:
- Whole-genome expression analysis using Affymetrix microarrays.
- Comparison of gene expression profiles between imatinib-sensitive and -resistant KCL22 myeloid leukemia cell lines.
- Identification of differentially expressed genes correlating with imatinib resistance.
Main Results:
- 39 genes showed differential expression correlating with the imatinib-resistant phenotype.
- Resistant cells exhibited overexpression of genes involved in apoptosis suppression and cellular transformation.
- Gene expression changes suggest activation of alternative survival pathways.
Conclusions:
- Alternative signaling pathways may maintain cell viability and growth independently of BCR-ABL kinase activity in imatinib-resistant CML.
- Activation of these alternative pathways could be linked to disease progression and blast crisis.
- Understanding these pathways may offer new therapeutic strategies for resistant CML.
