Modulation of PKC-α promotes lineage reprogramming of committed B lymphocytes

Nakagawa, R., Vukovic, M., Cosimo, E. and Michie, A. M. (2012) Modulation of PKC-α promotes lineage reprogramming of committed B lymphocytes. European Journal of Immunology, 42(4), pp. 1005-1015. (doi: 10.1002/eji.201141442)

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Publisher's URL: http://dx.doi.org/10.1002/eji.201141442

Abstract

During hematopoietic lineage development, HSCs sequentially commit towards 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 towards other hematopoietic lineages, in addition to generating progenitor B cell lymphomas. Our previous studies showed that subversion of PKCα in developing B cells transforms B lineage cells. Here we demonstrate that PKCα modulation in committed CD19+ B lymphocytes also promotes lineage conversion towards myeloid, NK and T cell lineages upon Notch ligation. This occurs via a reduction in Pax5 expression resulting from a downregulation of E47, a product of the E2A gene. T cell lineage commitment is 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 carry Igh gene rearrangements reminiscent of their B cell origin. Our findings suggest that modulation of PKCα induces hematopoietic lineage plasticity in committed B lineage cells by perturbing expression of critical B lineage transcription factors, and deregulation of PKCα activity/expression represents a potential mechanism for lineage trans-differentiation during malig

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Michie, Dr Alison and Cosimo, Dr Emilio and Vukovic, Ms Milica and Nakagawa, Dr Rinako
Authors: Nakagawa, R., Vukovic, M., Cosimo, E., and Michie, A. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:European Journal of Immunology
Journal Abbr.:Eur. J. Immunol.
Publisher:Wiley-VCH Verlag
ISSN:0014-2980
ISSN (Online):1521-4141
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
444831Defining the cellular origin of chronic lymphocytic leukaemiaAlison MichieMedical Research Council (MRC)G0601099Institute of Cancer Sciences
450701Defining the cellular origin of chronic lymphocytic leukaemiaAlison MichieLeukaemia & Lymphoma Research (LRF)07023Institute of Cancer Sciences