Regulation of cell survival during B lymphopoiesis: suppressed apoptosis of pro-B cells in P53-deficient mouse bone marrow

Abstract

B cell development in mouse bone marrow (BM) is subject to quality controls that eliminate aberrant cells by apoptosis, but the intrinsic cellular mechanisms that mediate this negative B cell selection remain unclear. The p53 tumor suppressor transduces signals resulting in apoptosis and cell cycle arrest in cells that sustain DNA damage. Faulty V(D)J recombination in scid lymphocyte precursors activates a p53-dependent DNA damage checkpoint. In the present study, we have examined whether p53 is involved in apoptotic selection of normally developing B cells in BM. Double immunofluorescence labeling and flow cytometry were used to quantitate phenotypically defined B cell populations and their apoptotic rates in BM of homozygous p53-deficient mice. B220(+) mu(-) and terminal deoxynucleotidyl transferase (TdT)(+) pro-B cells were increased in both incidence and absolute number to controls. In contrast, pre-B cells were only slightly increased and the sIgM(+) B lymphocyte compartment remained essentially normal. The incidence of apoptosis among p53(-/-) pro-B cells was greatly reduced, both ex vivo and in short-term culture, whereas, apoptosis of pre-B cells and B lymphocytes was not significantly different from normal. The results indicate that p53 is actively involved as an apoptosis inducer at an early quality control checkpoint in B lymphopoiesis.