International Immunology Advance Access originally published online on January 17, 2007
International Immunology 2007 19(3):267-276; doi:10.1093/intimm/dxl143
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Impaired V(D)J recombination and increased apoptosis among B cell precursors in the bone marrow of c-Abl-deficient mice
1 Department of Pathology and Center of Infection and Immunology, The University of Hong Kong, Hong Kong, China
2 Department of Anatomy and Cell Biology, McGill University, Montreal, Canada
3 Faculty of Pure and Applied Science, York University, Ontario, Canada
4 Ontario Cancer Institute and Department of Immunology, University of Toronto, Ontario, Canada
Correspondence to: L. Lu; E-mail: liweilu{at}hkucc.hku.hk
Previous studies on c-Abl-deficient mice have shown high post-natal mortality and lymphopenia. However, the mechanisms by which c-Abl may influence B lymphopoiesis remain obscure. In this study, we analyzed B cell sub-populations at various differentiation stages in the bone marrow (BM) of c-Abl-deficient mice. Phenotypic analyses revealed that c-Abl–/– pro-B cells were reduced to half of normal incidence and absolute number, while pre-B cells showed an even greater reduction. Both c-Abl–/– pro-B and pre-B cell populations showed considerably elevated apoptosis ex vivo and in short-term culture but their cell cycle progression was not impaired. In contrast, apoptosis of immature IgM+IgD– B lymphocytes remained at normal control levels. Inhibition of c-Abl activity by STI571 in normal BM cultures significantly increased apoptosis in B cell precursors while the survival of immature B cells was not affected. To determine whether c-Abl deficiency affects Ig heavy-chain rearrangement, we found that the frequency of V(D)J recombination was markedly reduced by 15-fold in c-Abl–/– pro-B cells compared with the control values. However, no perturbation in the levels of signal-end recombination intermediates was found. Taken together, we propose that c-Abl mediates a stage-specific anti-apoptotic response in precursor B cells and is required for efficient V(D)J recombination during B cell development.
Keywords: B cell development, bone marrow, c-Abl, V(D)J recombination
* Equal contributions.
Received 29 August 2006, accepted 18 December 2006.
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