Shcherbina V. Cell surface receptors and cytokines as predictive factors associated with sensitivity of chronic lymphocytic leukemia B lymphocytes to cytostatics

We identified for the first time a relationship between the expression level of immunophenotypic markers of malignant B lymphocytes and their sensitivity to key cytostatics, which are the components of different chemotherapy schemes for CLL treatment – bendamustine (BEN), cyclophosphamide (CP) and fludarabine (FL). The cytotoxic effect of chemotherapeutics on CLL B lymphocytes was determined using a resazurin test, where the percentage of resazurin reduction is directly proportional to the percentage of viable cells. In particular, we found that a high level of sensitivity of CLL B lymphocytes to BEN is associated with the CD5M>, CD37M<, CD38- and CD40M< phenotype (p < 0.05). The better cytotoxic effect of CP on CLL B-lymphocytes ex vivo is observed in cases of high expression of CD5 and CD20 (M>, p = 0.01). The sensitivity of CLL B-lymphocytes to FL is not associated with the expression status of CD5, CD20, CD37, CD38 or CD40, but is significantly higher in the case of simultaneous expression of CD150 and CD180 on B-lymphocytes (p = 0.04). It should be noted that CD150+ phenotype of CLL B lymphocytes regardless of the expression status of CD180 is associated with an increase in cytotoxic effect under the simultaneous action of FL and CP as compared to FL and CP used as single agents (p < 0.05). The possibility of positive regulation of CD20 expression on the plasma membrane of CLL B lymphocytes by activating CD150 and CD180-mediated signaling pathways could be advantageous for optimizing anti-CD20 targeted therapy. Our study of the relationship between the sensitivity of CLL B lymphocytes to cytostatics and mRNA expression levels of IL-6, IL-10, CCL3 and CCL4, demonstrated several reliable patterns. Within the studied group of patients, the higher sensitivity of CLL B lymphocytes to FL and BEN is associated with high mRNA expression levels of CCL3 (M> 1.47 r.u.), CCL4 (M> 2.81 r.u.) and low mRNA expression level of IL-10 (M <1.08 r.u.). In contrast, low mRNA expression levels of IL-6 (M <0.22 r.u.) and IL-10 (M <1.08 r.u.) are associated with a high sensitivity of CLL B lymphocytes to FL and CP ex vivo.