title: Modulation of PKC-α promotes lineage reprogramming of committed B lymphocytes.
abstract: During hematopoietic lineage development, hematopoietic stem cells sequentially commit toward myeloid or lymphoid lineages in a tightly regulated manner, which under normal circumstances is irreversible. However, studies have established that targeted deletion of the B-lineage specific transcription factor, paired box gene 5 (Pax5), enables B cells to differentiate toward other hematopoietic lineages, in addition to generating progenitor B-cell lymphomas. Our previous studies showed that subversion of protein kinase C (PKC)-α in developing B cells transformed B-lineage cells. Here, we demonstrate that PKC-α modulation in committed CD19(+)  B lymphocytes also promoted lineage conversion toward myeloid, NK-, and T-cell lineages upon Notch ligation. This occurred via a reduction in Pax5 expression resulting from a downregulation of E47, a product of the E2A gene. T-cell lineage commitment was indicated by the expression of T-cell associated genes Ptcra, Cd3e, and gene rearrangement at the Tcrb gene locus. Importantly, the lineage-converted T cells carried Igh gene rearrangements reminiscent of their B-cell origin. Our findings suggest that modulation of PKC-α induces hematopoietic-lineage plasticity in committed B-lineage cells by perturbing expression of critical B-lineage transcription factors, and deregulation of PKC-α activity/expression represents a potential mechanism for lineage trans-differentiation during malignancies.
authors.affiliation: Institute of Cancer Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Rinako
authors.initials: R
authors.lastname: Nakagawa
authors.forename: Milica
authors.initials: M
authors.lastname: Vukovic
authors.forename: Emilio
authors.initials: E
authors.lastname: Cosimo
authors.forename: Alison M
authors.initials: AM
authors.lastname: Michie
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D054337:Cell Dedifferentiation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D054503:Lymphoid Progenitor Cells / Q000201:enzymology / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D023461:Myeloid Progenitor Cells / Q000201:enzymology / Q000276:immunology*; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D007143:Immunoglobulin Heavy Chains; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D051880:Receptors, Notch; D051571:Protein Kinase C-alpha