During B lymphocyte development, pro-B cells that fail to rearrange an immunoglobulin heavy (IgH) chain allele productively are thought to undergo developmental arrest and death, but because these cells are short-lived in vivo they are not well characterized. Transgenic mice expressing the apoptosis regulatory gene bcl-xL in the B lineage developed large expansions of pro-B cells in bone marrow. V(D)J rearrangements in the expanded population were nearly all nonproductive, 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 immunoglobulin rearrangements occurs by apoptosis, and bcl-xL can deliver a strong survival signal at the pro-B stage. This analysis also demonstrates that immunoglobulin gene rearrangement is less precise than previously appreciated.
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).