title: Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKCα subversion induces up-regulation of PKCβII expression in B lymphocytes.
abstract: Overwhelming evidence identifies the microenvironment as a critical factor in the development and progression of chronic lymphocytic leukemia, underlining the importance of developing suitable translational models to study the pathogenesis of the disease. We previously established that stable expression of kinase dead protein kinase C alpha in hematopoietic progenitor cells resulted in the development of a chronic lymphocytic leukemia-like disease in mice. Here we demonstrate that this chronic lymphocytic leukemia model resembles the more aggressive subset of chronic lymphocytic leukemia, expressing predominantly unmutated immunoglobulin heavy chain genes, with upregulated tyrosine kinase ZAP-70 expression and elevated ERK-MAPK-mTor signaling, resulting in enhanced proliferation and increased tumor load in lymphoid organs. Reduced function of PKCα leads to an up-regulation of PKCβII expression, which is also associated with a poor prognostic subset of human chronic lymphocytic leukemia samples. Treatment of chronic lymphocytic leukemia-like cells with the selective PKCβ inhibitor enzastaurin caused cell cycle arrest and apoptosis both in vitro and in vivo, and a reduction in the leukemic burden in vivo. These results demonstrate the importance of PKCβII in chronic lymphocytic leukemia-like disease progression and suggest a role for PKCα subversion in creating permissive conditions for leukemogenesis.
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow The Babraham Institute, Cambridge.
authors.forename: Rinako
authors.initials: R
authors.lastname: Nakagawa
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow MRC Centre for Regenerative Medicine, University of Edinburgh.
authors.forename: Milica
authors.initials: M
authors.lastname: Vukovic
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Tarafdar
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow.
authors.forename: Emilio
authors.initials: E
authors.lastname: Cosimo
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow.
authors.forename: Karen
authors.initials: K
authors.lastname: Dunn
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow.
authors.forename: Alison M
authors.initials: AM
authors.lastname: McCaig
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow.
authors.forename: Ailsa
authors.initials: A
authors.lastname: Holroyd
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London.
authors.forename: Fabienne
authors.initials: F
authors.lastname: McClanahan
authors.affiliation: Department of Haemato-Oncology, King's College London, UK.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Ramsay
authors.affiliation: Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London.
authors.forename: John G
authors.initials: JG
authors.lastname: Gribben
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow Alison.Michie@glasgow.ac.uk.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Michie
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D017254:Leukemic Infiltration / Q000473:pathology; D008221:Lymphoid Tissue / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011379:Prognosis; D064546:Protein Kinase C beta / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014161:Transduction, Genetic; D047368:Tumor Burden / Q000187:drug effects; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D047428:Protein Kinase Inhibitors; D051746:ZAP-70 Protein-Tyrosine Kinase; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha