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.
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 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.
Nakagawa
Rinako
R
Division of Immunology, Infection and Inflammation, Western Infirmary, University of Glasgow, Scotland, United Kingdom.
Soh
Jae Won
JW
Michie
Alison M
AM
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes / Q000201:enzymology / Q000473:pathology; D002471:Cell Transformation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000201:enzymology* / Q000473:pathology; D015448:Leukemia, B-Cell / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D051571:Protein Kinase C-alpha