Subversion of protein kinase C alpha signaling in hematopoietic progenitor cells results in the generation of a B-cell chronic lymphocytic leukemia-like population in vivo

Nakagawa, R., Soh, J.W. and Michie, A.M. (2006) Subversion of protein kinase C alpha signaling in hematopoietic progenitor cells results in the generation of a B-cell chronic lymphocytic leukemia-like population in vivo. Cancer Research, 66(1), pp. 527-534. (doi: 10.1158/0008-5472.CAN-05-0841)

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Abstract

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-CIA, 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 alpha (PKC alpha-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 alpha 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 alpha-regulated transformation events.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Michie, Dr Alison
Authors: Nakagawa, R., Soh, J.W., and Michie, A.M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Research
ISSN:0008-5472

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