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BCL6 is critical for the development of a diverse primary B cell repertoire.

  • Author(s): Duy, Cihangir
  • Yu, J Jessica
  • Nahar, Rahul
  • Swaminathan, Srividya
  • Kweon, Soo-Mi
  • Polo, Jose M
  • Valls, Ester
  • Klemm, Lars
  • Shojaee, Seyedmehdi
  • Cerchietti, Leandro
  • Schuh, Wolfgang
  • Jäck, Hans-Martin
  • Hurtz, Christian
  • Ramezani-Rad, Parham
  • Herzog, Sebastian
  • Jumaa, Hassan
  • Koeffler, H Phillip
  • de Alborán, Ignacio Moreno
  • Melnick, Ari M
  • Ye, B Hilda
  • Müschen, Markus
  • et al.
Abstract

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-7Ralpha-Stat5 signaling negatively regulates BCL6. Upon productive VH-DJH gene rearrangement and expression of a mu heavy chain, however, activation of pre-B cell receptor signaling strongly induces BCL6 expression, whereas IL-7Ralpha-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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