Prognostic significance of the correlation between the expression of CD180 and chromosomal abnormalities in Chronic Lymphocytic Leukemia

Author: Natia Davitashvili
Keywords: Chronic Lymphocytic Leukemia (CLL);toll-like receptors (TLR);FISH-method;Flow cytometry;
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Chronic Lymphocytic Leukemia (CLL) is the clonal expansion of CD20+CD5+CD23+ cells in peripheral lymphoid organs, tissues and bone marrow. CLL is the most frequent adult leukaemia in the Western World, incuding Georgia. CLL cells are driven by (auto)antigen(s) through the B cell receptor (BCR) and are regulated by the variety of signals received from the microenvironment, including toll-like receptors (TLR). These could act as bio switchers, defining the ultimate fate of the leukaemic cells at the given stage in disease progression and the efficiency of treatment. We have previously shown, that approximately 60% of CLL samples express CD180. We also indicated that whilst BCR-mediated signalling in CLL cells is predominantly anti-apoptotic and pro-survival, CD180 ligation with a monoclonal antibody (mAb) leads to a dichotomy of intracellular signal transduction: pro-survival/anti-apoptotic BTK/PI3K/AKT or pro-apoptotic p38MAPK pathway. Even more importantly, pre-treatment of CLL cells with anti-CD180 mAb redirects IgM-mediated signalling from the pro-survival towards the pro-apoptotic. The prognosis of CLL has been linked to the genomic changes, with certain chromosomal aberrations increasingly being associated with the resistance to the treatment with PK inhibitors. In this proposal we are planning to study CD180 expression patterns in CLL cells from peripheral blood and lymph nodes correlate with chromosomal aberrations of established prognostic significance, phenotypic and clinical data, and the disease outcome. We will establish the effect of CD180 on the susceptibility to the PK inhibitors of BCR-mediated signalling in CLL cells with chromosomal aberrations of prognostic significance, phenotype and clinical behaviour. The proposed research will also allow us to determine how CD180 enhances prediction and influences CLL cell susceptibility to molecular therapies and thus optimizes the precision therapy, improves the disease prognosis and the cost-efficiency of the treatment.