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Modulation of PKC ‐α promotes lineage reprogramming of committed B lymphocytes
Author(s) -
Nakagawa Rinako,
Vukovic Milica,
Cosimo Emilio,
Michie Alison M.
Publication year - 2012
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.201141442
Subject(s) - biology , lineage (genetic) , haematopoiesis , lineage markers , microbiology and biotechnology , progenitor cell , myeloid , transcription factor , reprogramming , b cell , stem cell , gene , cancer research , genetics , antibody
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 ( P ax5), 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 CD 19 + B lymphocytes also promoted lineage conversion toward myeloid, NK ‐, and T ‐cell lineages upon N otch ligation. This occurred via a reduction in P ax5 expression resulting from a downregulation of E 47, a product of the E 2 A gene. T ‐cell lineage commitment was indicated by the expression of T ‐cell associated genes P tcra , C d3e , and gene rearrangement at the T crb gene locus. Importantly, the lineage‐converted T cells carried I gh 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.