The pathogenetic mechanism in hematological malignancies

The cellular and molecular changes of chronic myeloproliferative neoplasms (CMN) will be examined to achieve better diagnosis and detection of predisposition to progression of malignancy. The different experimental approaches in vitro and in vivo will be applied, using human material and animal models. The characterization of gene expression at the transcriptional and translational level will be observed in hematopoietic cells isolated from patients before and after therapy, which will clarify the complex molecular network in transformed cell. Mechanism of activation and inhibition of pre-defined signaling pathways and gene mutations, as well as the effect of cytostatic therapy and cytokine IL-8 in the signaling pathways, including JAK-STAT and NO/cGMP, will be examined in vitro. In addition to genetic mutations, the research will include the role of oxidative stress and tumor suppressor p53-activating ribosomal proteins in the mechanism of CMN. The tendency to thrombosis and angiogenesis in bone marrow will be determined by risk factors in the pathogenesis and progression of CMN. The genes expression and differentiation markers will be followed during ontogenesis of hematopoietic progenitors. In order to explain the etiology of CMN, the neuroendocrine regulation of hematopoiesis will be investigated in animal models under chronic stress. The project results will contribute to a better understanding of the pathogenesis of CMN and development of new therapeutic protocols.