Mechanisms of resistance in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors.

Up to date, two major mechanisms have been proposed as an explanation for myeloid cells expansion in chronic myeloid leukemia (CML). One is a reduced susceptibility of hematopoietic stem or progenitor cells to apoptosis, while the other one is an increased activity within the hematopoietic progenitor cell population. The aim of the study was to identify specific features of functional activity, proliferation rates and differentiation potential of CML hematopoietic progenitor cells of patients treated with tyrosine kinase inhibitors (TKI) by identifying number of Ki-67, Bcl-2 and CD34 positive cells in bone marrow, as well as in vitro colony-forming unit assay in patients with different response to the TKI therapy. Our results indicated that there was a significant decline in proliferation activity of HSCs and HPCs in group of patients with optimal response to the TKI therapy. Correlation analysis, performed on individual basis for patients independently of response to the TKI therapy demonstrated that there was a negative correlation (ρ=0.7648) between the number of Ki67+ and CD34+ cells. As to colony to cluster ratio our results showed, that there is a correlation (ρ=0.6783) between CCR index and number of bone marrow cells with Philadelphia chromosome. It was indicated, that index of maturation correlates with level of bone marrow cells, containing Philadelphia chromosome, so as with percentage of CD34+, Bcl-2+, Pgp-170+ and Ki67+ cells in bone marrow of CML patients. In summary, obtained results suggest that different mechanisms (bcr-abl dependent and independent) may be involved in CML progression process in the same time. Disease prognosis should be preferably carried out on an individual basis.