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Subversion of Protein Kinase C Signaling in Hematopoietic Progenitor Cells Results in the Generation of a B-Cell Chronic Lymphocytic Leukemia–Like Population In vivo

¹ Division of Immunology, Infection and Inflammation and ² Division of Cancer Science and Molecular Pathology, Section of Experimental Haematology, University of Glasgow, Scotland, United Kingdom and ³ Laboratory of Signal Transduction, Department of Chemistry, Inha University, Incheon, Korea

Requests for reprints: Alison M. Michie, Division of Immunology, Infection and Inflammation, Western Infirmary, University of Glasgow, Scotland G11 6NT, United Kingdom. Phone: 44-141-211-2161; Fax: 44-141-337-3217; E-mail: a.michie{at}udcf.gla.ac.uk.

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of long-lived mature B cells with the distinctive phenotype CD19^hi CD5⁺ CD23⁺ IgM^lo, which are refractory to apoptosis. An increased level of apoptosis has been observed on treatment of human B-CLL cells with protein kinase C (PKC) inhibitors, suggesting that this family of protein kinases mediate survival signals within B-CLL cells. Therefore, to investigate the ability of individual PKC isoforms to transform developing B cells, we stably expressed plasmids encoding PKC mutants in fetal liver–derived hematopoietic progenitor cells (HPC) from wild-type mice and then cultured them in B-cell generation systems in vitro and in vivo. Surprisingly, we noted that expression of a plasmid-encoding dominant-negative PKC (PKC-KR) in HPCs and subsequent culture both in vitro and in vivo resulted in the generation of a population of cells that displayed an enhanced proliferative capacity over untransfected cells and phenotypically resemble human B-CLL cells. In the absence of growth factors and stroma, these B-CLL-like cells undergo cell cycle arrest and, consistent with their ability to escape growth factor withdrawal-induced apoptosis, exhibited elevated levels of Bcl-2 expression. These studies therefore identify a unique oncogenic trigger for the development of a B-CLL-like disease resulting from the subversion of PKC signaling. Our findings uncover novel avenues not only for the study of the induction of leukemic B cells but also for the development of therapeutic drugs to combat PKC-regulated transformation events. (Cancer Res 2006; 66(1): 527-34)

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