Commitment to the B-lymphoid lineage depends on the transcription factor Pax5

Abstract

The Pax5 gene encoding the B-cell-specific activator protein (BSAP) is expressed within the haematopoietic system exclusively in the B-lymphoid lineage, where it is required in vivo for progression beyond the pro-B-cell stage. However, Pax5 is not essential for in vitro propagation of pro-B cells in the presence of interleukin-7 and stromal cells. Here we show that pro-B cells lacking Pax5 are also incapable of in vitro B-cell differentiation unless Pax5 expression is restored by retroviral transduction. Pax5-/- pro-B cells are not restricted in their lineage fate, as stimulation with appropriate cytokines induces them to differentiate into functional macrophages, osteoclasts, dendritic cells, granulocytes and natural killer cells. As expected for a clonogenic haematopoietic progenitor with lymphomyeloid developmental potential, the Pax5-/- pro-B cell expresses genes of different lineage-affiliated programmes, and restoration of Pax5 activity represses this lineage-promiscuous transcription. Pax5 therefore plays an essential role in B-lineage commitment by suppressing alternative lineage choices.

Loss of B cell identity correlates with loss of B cell-specific transcription factors in Hodgkin/Reed-Sternberg cells of classical Hodgkin lymphoma

“…The immunohistological data are, however, conflicting. In the light of the central importance of this transcription factor for maintaining B cell identity but also for preventing B cells from embarking on any non-B lineage developmental programme (Nutt et al, 1999;Horcher et al, 2001) and also of its cellular concentration (Wallin et al, 1998), we assessed PAX-5 expression semi-quantitatively in HRS cells from primary pathological tissues. Using immunohistology, we found expression of PAX-5 in HRS cells in 13/18 (72%) cases of classical HL.…”

The role of Smad signaling in hematopoiesis

“…Studies in knockout mouse models have elegantly demonstrated crucial roles of several transcription factors in early hematopoietic commitment steps and lineage outcome. For example, GATA-1 is required for erythroid and megakaryocytic development and Pax-5 for B-cell development (Pevny et al, 1991;Fujiwara et al, 1996;Shivdasani et al, 1997;Nutt et al, 1999;Rolink et al, 1999). The PU.1 and GATA-1 transcription factors have both been shown to have concentration-dependent effects on differentiation and lineage choice (Kulessa et al, 1995;DeKoter and Singh, 2000).…”

Molecular portraits of B cell lineage commitment

“…Before B cell differentiation in a sequence defined by the configuration of the Ig gene loci (3), the pluripotent progenitor cells undergo commitment to the B cell lineage (4), which critically relies on expression of the PAX5 transcription factor (5). Developmental progression of a committed B cell precursor including rearrangement of Ig D H to J H gene segments, depends on two transcription factors encoded by the E2A (6) and EBF (7) genes.…”