The effects of c-Abl mutation on developing B cell differentiation and survival.
c-Abl is a widely expressed Src family protein tyrosine kinase that is activated by chromosomal translocation in certain human leukemias. While shown in various experimental systems to regulate cell division and stress responses, its biological functions remain poorly understood. Although expressed at similar levels throughout B cell development, we found that the fraction of phosphorylated, active c-Abl peaks at the pro-B stage. We went on to perform a detailed analysis of B cell development in c-Abl-deficient mice. We confirmed a striking but variable decrease in pro- and pre-B cell numbers, a decrease in pre-B cell growth and an increase in pre-B cell apoptosis. This phenotype was not rescued by transgenic expression of a functional IgHC transgene and only partially rescued by the anti-apoptosis gene Bcl-x. Unlike their wild-type counterparts, c-Abl-deficient pre-B cells show a defect in Ca(2+) flux upon cross-linking of CD19, a co-receptor known to be involved in pre-B cell receptor signaling and failed to express CD25 on the cell surface. Despite these pre-B cell-signaling defects, selection for in-frame heavy-chain rearrangements was intact in the mutant mice. Remarkably, we were able to rescue the proliferative defect by culturing cells in vitro with large amounts of rIL-7. We conclude that c-Abl is required for normal B cell differentiation and survival.
Brightbill
Hans
H
Division of Immunology, Department of Molecular and Cell Biology, 439 Life Science Addition, University of California, Berkeley, CA 94720-3200, USA.
Schlissel
Mark S
MS
D000818:Animals; D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000235:genetics; D015851:Interleukin-7 / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D018941:Antigens, CD19; D015851:Interleukin-7; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D016315:Proto-Oncogene Proteins c-abl; D002118:Calcium