Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 207, Issue 6, Pages 1209-1221Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20091299
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Funding
- National Institutes of Health/National Cancer Institute [R01CA104348, 5R01CA085573, R01CA137060, R01CA139032, R21CA152497]
- Leukemia and Lymphoma Society [6132-09, 6097-10]
- V Foundation for Cancer Research
- William Laurence and Blanche Hughes Foundation
- Stand Up to Cancer-American Association for Cancer Research Innovative Research [IRG00909]
- Deutsche Forschungsgemeinschaft [MU1616/5-1]
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BCL6 protects germinal center ( GC) B cells against DNA damage-induced apoptosis during somatic hypermutation and class-switch recombination. Although expression of BCL6 was not found in early IL-7-dependent B cell precursors, we report that IL-7R alpha-Stat5 signaling negatively regulates BCL6. Upon productive V-H-DJ(H) gene rearrangement and expression of a. heavy chain, however, activation of pre-B cell receptor signaling strongly induces BCL6 expression, whereas IL-7R alpha-Stat5 signaling is attenuated. At the transition from IL-7-dependent to -independent stages of B cell development, BCL6 is activated, reaches expression levels resembling those in GC B cells, and protects pre-B cells from DNA damage-induced apoptosis during immunoglobulin (Ig) light chain gene recombination. In the absence of BCL6, DNA breaks during Ig light chain gene rearrangement lead to excessive up-regulation of Arf and p53. As a consequence, the pool of new bone marrow immature B cells is markedly reduced in size and clonal diversity. We conclude that negative regulation of Arf by BCL6 is required for pre-B cell self-renewal and the formation of a diverse polyclonal B cell repertoire.
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