Alterations in functional properties of bone marrow stem cells in chronic myeloid leukemia patients with different response to tyrosine kinase inhibitors treatment
M. Diachenko1, N. Bilko1, I. Dyagil2
1National University of Kyiv-Mohyla Academy, Center of Molecular and Cell Research, Kyiv, Ukraine
2National Research Center for Radiation Medicine NAMS of Ukraine, Kyiv, Ukraine
Introduction: It has been revealed the relative quiescence and resultant therapeutic resistance of primitive chronic myeloid leukemia (CML) progenitor cells providing a basis for identifying the hematopoietic developmental stage of chronic phase initiating events, such as altered stem cell differentiation and survival. This survival advantage is largely mediated by leukemic stem cells (LSCs) microenvironment. Aim: The aim of this study was to determine the functional characteristics of hemopoietic and mesenchymal stem cells from CML patients with different response to the tyrosine kinase inhibitor (TKi) Imatinib (Novartis). Patients and Methods: All 32 patients who were treated with TKi between 0 and 41 month have undergone cytogenetic analysis for the Philadelphia chromosome as well as in vitro assays: CFU-A in the semisolid agar and suspension cultures. According to the TKi therapy response patients were divided into groups: with optimal response (no Ph+ cells), suboptimal response (Ph+ > 0%) and the group of patients who received hydroxyurea before TKi treatment. Results: The functional activity of bone marrow progenitor cells of patients with an optimal response to therapy was significantly lower (p <0.05) compared to patients with resistance to the therapy (the average CFU-GM numbers 29.3 and 79.3, respectively). Leukemic progenitor cells from CML patients were able to survive in stroma-free suspension culture without any additional growth factors supplementation during 21 day (median survival of 10 days). Such autonomous growth, not typical for normal cells, could be explained by autocrine mechanisms in primitive leukemia cells. Mesenchymal stem cells (MSCs) from CML patients with suboptimal response to TKi therapy showed 6 fold increases in proliferation rate compared to MSCs from bone marrow of patients with optimal response, suggesting that stem cell microenvironment is also involved in transformation process. Conclusions: Our data indicate the presence of individual response to the TKi therapy in CML’s patients that is probably associated with specific changes in the population of stem and progenitor cells due to alterations of their functional activity. Further researches of leukemic stem cells and their niche would allow better understanding of mechanisms of drug resistance and disease progression.
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