Analysis of gene expression profiles in an imatinib-resistant cell line, KCL22/SR

Stem Cells. 2003;21(3):315-21. doi: 10.1634/stemcells.21-3-315.


The BCR/ABL tyrosine kinase inhibitor, imatinib, has shown substantial effects in blast crises of chronic myelogenous leukemia. However, most patients relapse after an initial clinical response, indicating that drug resistance is a major problem for patients being treated with imatinib. In this study, we generated a new imatinib-resistant BCR/ABL-positive cell line, KCL22/SR. The 50% inhibitory concentration of imatinib was 11-fold higher in KCL22/SR than in the imatinib-sensitive parental cell line, KCL22. However, KCL22/SR showed no mutations in the BCR/ABL gene and no increase in the levels of BCR/ABL protein and P-glycoprotein. Furthermore, the level of phosphorylated BCR/ABL protein was suppressed by imatinib treatment, suggesting that mechanisms independent of BCR/ABL signaling are involved in the imatinib resistance in KCL22/SR cells. DNA microarray analyses demonstrated that the signal transduction-related molecules, RAS p21 protein activator and RhoA, which could affect Ras signaling, and a surface tumor antigen, L6, were upregulated, while c-Myb and activin A receptor were downregulated in KCL22/SR cells. Furthermore, imatinib treatment significantly suppressed the level of phosphorylated p44/42 in KCL22 cells but not in KCL22/SR cells, even when BCR/ABL was inhibited by imatinib. These results suggest that various mechanisms, including disturbance of Ras-mitogen-activated protein kinase signaling, are involved in imatinib resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Benzamides
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Fusion Proteins, bcr-abl / drug effects
  • Fusion Proteins, bcr-abl / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Expression Regulation, Neoplastic / genetics*
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / immunology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / drug effects
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation / drug effects
  • Mutation / genetics
  • Oligonucleotide Array Sequence Analysis
  • Phosphorylation / drug effects
  • Piperazines / pharmacology*
  • Pyrimidines / pharmacology*
  • Secondary Prevention
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • ras Proteins / drug effects
  • ras Proteins / metabolism


  • Antineoplastic Agents
  • Benzamides
  • Piperazines
  • Pyrimidines
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • ras Proteins