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

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.