Molecular Monitoring of Chronic Myeloid Leukemia Treated with Imatinib Mesylate

University dissertation from Göteborg University

Abstract: The BCR-ABL fusion gene product is a constitutively activated tyrosine kinase, which is fundamental in the pathogenesis of chronic myeloid leukemia (CML). Imatinib mesylate (imatinib, Glivec® or Gleevec®), a small molecule inhibitor of the BCR-ABL tyrosine kinase, is now the first-line treatment for all newly diagnosed chronic phase CML patients. Imatinib treatment results in a high frequency of complete cytogenetic response (CCgR). Patients in CCgR can be further stratified by the degree of minimal residual disease, measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The present thesis deals with different aspects on molecular monitoring of imatinib treated CML patients. By serially analyzing peripheral blood and bone marrow BCR-ABL transcript levels using qRT-PCR in CML patients commencing imatinib therapy, we found that the major decline in BCR-ABL transcripts occurred within 6 months after start of imatinib treatment. An apparent plateau in BCR-ABL transcript level seems to have been reached after 12-15 months of imatinib treatment, which indicates a stable number of remaining BCR-ABL positive cells. To search for markers associated with molecular response in CML patients treated with imatinib, we studied the mRNA expression of apoptosis-related genes in peripheral blood nucleated cells from chronic phase CML patients commencing imatinib treatment. We found that a lower BAD expression at diagnosis correlates with a better molecular response at 12 months of imatinib therapy. Studies of BCR-ABL kinase domain mutations in imatinib treated CML patients revealed that point mutations were mainly associated with acquired resistance, but not with cytogenetic or molecular disease persistence in CML patients without signs of increasing leukemia burden. Finally we studied ?off-target? effects of imatinib on peripheral blood on T-lymphocytes. We found that therapeutic doses of imatinib alter the expression of apoptosis related genes in CD3+ lymphocytes and change the phenotype of CD4+CD28+ T-helper cells.

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