title: Impaired V(D)J recombination and increased apoptosis among B cell precursors in the bone marrow of c-Abl-deficient mice.
abstract: 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.
authors.affiliation: Department of Pathology and Center of Infection and Immunology, The University of Hong Kong, Hong Kong, China.
authors.forename: Queenie Lai Kwan
authors.initials: QL
authors.lastname: Lam
authors.forename: Cherry Kam Chun
authors.initials: CK
authors.lastname: Lo
authors.forename: Bo-Jian
authors.initials: BJ
authors.lastname: Zheng
authors.forename: King-Hung
authors.initials: KH
authors.lastname: Ko
authors.forename: Dennis G
authors.initials: DG
authors.lastname: Osmond
authors.forename: Gillian E
authors.initials: GE
authors.lastname: Wu
authors.forename: Robert
authors.initials: R
authors.lastname: Rottapel
authors.forename: Liwei
authors.initials: L
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D015322:Gene Rearrangement, B-Lymphocyte; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D038041:Lymphopoiesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D016315:Proto-Oncogene Proteins c-abl / Q000172:deficiency* / Q000235:genetics; D011995:Recombination, Genetic; D045567:VDJ Recombinases / Q000378:metabolism
chemical_list: D007143:Immunoglobulin Heavy Chains; D016315:Proto-Oncogene Proteins c-abl; D045567:VDJ Recombinases