Modulation of PKC-α promotes lineage reprogramming of committed B lymphocytes.
Eur J Immunol
; 42(4): 1005-15, 2012 Apr.
Article
in En
| MEDLINE
| ID: mdl-22531924
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.
Full text:
1
Database:
MEDLINE
Main subject:
B-Lymphocytes
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Myeloid Progenitor Cells
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Protein Kinase C-alpha
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PAX5 Transcription Factor
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Lymphoid Progenitor Cells
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Cell Dedifferentiation
Limits:
Animals
Language:
En
Journal:
Eur J Immunol
Year:
2012
Type:
Article
Affiliation country:
United kingdom