Gene Expression Profile of Chronic Myeloid Leukemia Innately Resistant to Imatinib

Background

After 12 months of treatment, most patients with chronic myeloid leukemia (CML) who receive imatinib as first-line therapy will have complete cytogenetic and molecular response. However, several patients will not exhibit molecular response, but their innate mechanism(s) of resistance remain poorly understood. We explored the molecular events involved in innate resistance in CML.

Patients and Methods

Five patients who were molecular nonresponders and 7 major responders were investigated by using the expression profile of a set of 380 genes. Multiple testing procedure, Significance Analysis of Microarrays, Empirical Bayes Analysis of Microarrays, False Discovery Rate, and support vector machine with linear kernel were used for comparative analysis.

Results

Three hundred twenty-three of 380 genes (85%) were overexpressed in the nonresponder group compared with the responders. After a very stringent statistical analysis, a list of 26 genes was identified, in which overexpression in nonresponders was highly statistically significant. These genes are involved in signal transduction and transcription factors, apoptosis, cell cycle, and adhesion. Discriminative power of the proposed gene set was estimated by 2 different statistical methods, which yielded a correct prediction of the drug response for each patient used as a test sample.

Conclusion

Our study identified a set of 26 genes involved in resistance to imatinib, which can be used as clinical predictors or therapeutic targets. We consider some of them of particular interest: IGFBP2, CDC37, MAPK3, ETS1, and PEA15. Epigenetic mechanisms, such as genome-wide promoter hypomethylation, might be involved as the basic mechanism for innate resistance in CML.