PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development

Phosphoinositide‐dependent kinase‐1 (PDK1) controls the activation of a subset of AGC kinases. Using a conditional knockout of PDK1 in haematopoietic cells, we demonstrate that PDK1 is essential for B cell development. B‐cell progenitors lacking PDK1 arrested at the transition of pro‐B to pre‐B cells, due to a cell autonomous defect. Loss of PDK1 decreased the expression of the IgH chain in pro‐B cells due to impaired recombination of the IgH distal variable segments, a process coordinated by the transcription factor Pax5. The expression of Pax5 in pre‐B cells was decreased in PDK1 knockouts, which correlated with reduced expression of the Pax5 target genes IRF4 , IRF8 and Aiolos . As a result, Ccnd3 is upregulated in PDK1 knockout pre‐B cells and they have an impaired ability to undergo cell‐cycle arrest, a necessary event for Ig light chain rearrangement. Instead, these cells underwent apoptosis that correlated with diminished expression of the pro‐survival gene Bcl2A1. Reintroduction of both Pax5 and Bcl2A1 together into PDK1 knockout pro‐B cells restored their ability to differentiate in vitro into mature B cells. The conditional knockout of PDK1 in haematopoietic cells reveals an essential role in cell‐cycle arrest, differentiation, IgH recombination and the survival of B cells, which is mediated by the pro‐survival factor Bcl2A1 and the transcription factor Pax5.