During B lymphocyte development, pro-B cells that fail to productively rearrange an immunoglobulin heavy chain allele are thought to undergo developmental arrest and death, but because these cells are short-lived in vivo they are not well characterized. In the present study, we have investigated the normal expression of the apoptosis regulatory gene bcl-XL during B cell development and have characterized the bone marrow phenotype of rapidlycl-XL in the B lineage. Bcl-x mRNA and protein are expressed at low levels in pre-pro-B cells, at high levels in late pro-B cells and pre-B cells, and again at low levels in mature cells. This pattern is essentially reciprocal to that of the bcl-2 gene. Transgenic mice expressing bcl-XL in the B lineage developed large expansions of pro-B cells in bone marrow. These pro-B cells expressed the cell surface markers B220 and CD43 and were long-lived in vitro. V(D)J rearrangements in the expanded population were nearly all non-productive, and DJH rearrangements were enriched for joints in DH reading frame 2 and for aberrant joints with extensive DH or JH deletions. Thus, the death of pro-B cells with failed Ig rearrangements occurs by apoptosis, and bcl-XL can deliver a strong survival signal at the pro-B stage. This analysis also demonstrates that Ig gene rearrangement is less precise than previously appreciated.
|Published - 1996
Bibliographical noteFunding Information:
The authors thank B. Van Ness and R. Perlmutter for plasmids, M. Hupke for assistance with flow sorting, R. Ehlenfeldt for transgenic work, and L. Staudt for review of the manuscript. This work was supported by grants from the National Institutes of Health (D. L. M., AI 31699 and AI 35296; R. R. H., AI 26782; M. S. S., HL 48702; T. W. B., AR 01959), the Cancer Research Institute (M. S. S., Investigator award), and the Arthritis Foundation (D. L. M., Investigator award; T. W. B., American College of Rheumatology Investigator and Minnesota chapter awards).