Impaired V(D)J recombination and increased apoptosis among B cell precursors in the bone marrow of c-Abl-deficient mice.
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.
Lam
Queenie Lai Kwan
QL
Department of Pathology and Center of Infection and Immunology, The University of Hong Kong, Hong Kong, China.
Lo
Cherry Kam Chun
CK
Zheng
Bo-Jian
BJ
Ko
King-Hung
KH
Osmond
Dennis G
DG
Wu
Gillian E
GE
Rottapel
Robert
R
Lu
Liwei
L
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
D007143:Immunoglobulin Heavy Chains; D016315:Proto-Oncogene Proteins c-abl; D045567:VDJ Recombinases