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Chronic Lymphocytic Leukemia

Recruitment of PKC-βII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70

Abstract

ZAP-70 is a key signaling molecule in T cells. It couples the antigen-activated T-cell receptor to downstream signaling pathways. Its expression in leukemic B-cells derived from a subgroup of patients with chronic lymphocytic leukemia (CLL) is associated with an aggressive course of the disease. However, its implication for the pathogenesis of aggressive CLL is still unclear. In this study, we show that the expression of ZAP-70 enhances the signals associated with the B-cell receptor, recruiting protein kinase C-βII (PKC-βII) into lipid raft domains. Subsequently, PKC-βII is activated and shuttles from the plasma membrane to the mitochondria. We unravel that the antiapoptotic protein Bcl-2 and its antagonistic BH3-protein BimEL are putative substrates for PKC-βII. PKC-βII-mediated phosphorylation of Bcl-2 augments its antiapoptotic function by increasing its ability to sequester more pro-apoptotic BimEL. In addition, the phosphorylation of BimEL by PKC-βII leads to its proteasomal degradation. These changes confer leukemic cells to a more antiapoptotic state with aggressiveness of the disease. Most importantly, these molecular changes can be therapeutically targeted with the small molecule inhibitor Enzastaurin. We provide evidence that this compound is highly active in leukemic cells and augments the cytotoxic effects of standard chemotherapeutic drugs.

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Acknowledgements

We thank Burkhard Schmidt for his continuous support of our work. In addition, we are very grateful for the blood donations of our patients, who keep encouraging us to follow up our basic research. Finally, we thank Lilly Corporation for providing Enzastaurin for our ex vivo experiments. CMzB provided experimental concept and wrote the paper; MW and GL performed experiments and analysis of data; MO and YF performed experiments; TD provided experimental concept; CB provided analysis of data, CP provided conceptional design; IR performed planning of experiments, analyzed data, performed experimental concept and wrote the paper. This work was supported by grants from the Deutsche Forschungsgemeinschaft (IR) (SFB TRR 54 TP C03) and (MZB) (DFG ME 1913/3-1) and a grant from the Deutsche Jose Carreras Leukämie Stiftung (DJCLS ;R 05/17) (TD).

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Correspondence to I Ringshausen.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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zum Büschenfelde, C., Wagner, M., Lutzny, G. et al. Recruitment of PKC-βII to lipid rafts mediates apoptosis-resistance in chronic lymphocytic leukemia expressing ZAP-70. Leukemia 24, 141–152 (2010). https://doi.org/10.1038/leu.2009.216

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