Transcriptional regulation of early B cell development.

All blood cell types including mature B cells derive from pluripotent hematopoietic stem cells. The developmental cues responsible for guiding multipotent cells to the B cell fate remain to be fully elucidated. During recent years, it has become clear that firm commitment to the B cell fate requires the active suppression of differentiation potentials for alternative fates. Through the work of our laboratory and many others, it is now apparent that early B cell development and B-lineage commitment is controlled by a complex interplay between specific cytokine receptors and a variety of transcription factors. Whereas the transcription factor Pax5 has been touted as the chief transcriptional regulator of B-lineage commitment, our recent studies suggest that the B cell fate is established through the concerted action of several transcription factors including Early B cell Factor-1 (EBF). Notably, we recently found that EBF is able to suppress myeloid and T cell differentiation when introduced into multipotent Pax5(null/null) progenitors. Past work has also established that EBF expression is connected to the activity of the receptor for the cytokine IL-7. Therefore, the IL-7/EBF pathway plays a key and non-redundant role in establishing the B cell fate. This work provides a provisional model for understanding the molecular basis for B cell developmental biology. Furthermore, because aging leads to a decline in early B cell development and reduced IL-7 responsiveness, this work establishes a conceptual framework for understanding how and why aging leads to the loss of early B cell precursors.