【摘 要】
：
B-cell receptor (BCR) signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL).We tested whether blocking BCR signaling with dasatinib, an inhibitor of SRC kinase, w
【机 构】
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Pathology and Laboratory Medicine;Molecular Hematopathology Laboratory Weill Cornell Medical College
【出 处】
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BIT‘s2nd Annual World Cancer Congess-2009 (2009第二届癌症大会)
论文部分内容阅读
B-cell receptor (BCR) signaling plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL).We tested whether blocking BCR signaling with dasatinib, an inhibitor of SRC kinase, would interfere with the signaling cascade and cause death of leukemic cells.CLL B cells from 38 cases were treated ex vivo with a low dose of dasatinib.Cell viability was reduced by 2-90%, with an average reduction of ~50% on day four of culture.The drug induces CLL cell death via the intrinsic apoptotic pathway mediated by reactive oxygen species.Phosphorylation of SRC family kinases was inhibited by dasatinib in both good and poor responders.As opposed to SRC family kinases, activities of two downstream molecules, SYK and PLC gamma Z, correlate well with the apoptotic response of CLL cells to dasatinib.Thus, they may serve as potential biomarkers to predict dasatinib therapeutic response in patients.Moreover, those CLL cases with unfavorable prognostic parameters by IGHV, ZAP-70 and chromosomal abnormalities were more sensitive to the drug.Based on the current and published data, we propose a novel central BCR model to provide a possible molecular explanation that links together currently known associations among IGHV, ZAP-70, BCR signaling, dasatinib response and clinical outcome.
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