BCL6 is critical for the development of a diverse primary B cell repertoire.
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.
Duy
Cihangir
C
Childrens Hospital Los Angeles and Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90027, USA.
Yu
J Jessica
JJ
Nahar
Rahul
R
Swaminathan
Srividya
S
Kweon
Soo-Mi
SM
Polo
Jose M
JM
Valls
Ester
E
Klemm
Lars
L
Shojaee
Seyedmehdi
S
Cerchietti
Leandro
L
Schuh
Wolfgang
W
Jäck
Hans-Martin
HM
Hurtz
Christian
C
Ramezani-Rad
Parham
P
Herzog
Sebastian
S
Jumaa
Hassan
H
Koeffler
H Phillip
HP
de Alborán
Ignacio Moreno
IM
Melnick
Ari M
AM
Ye
B Hilda
BH
Müschen
Markus
M
D020727:ADP-Ribosylation Factors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D001483:Base Sequence; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D019610:Cytoprotection; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000276:immunology*; D015536:Down-Regulation / Q000235:genetics; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain / Q000235:genetics; D006801:Humans; D015851:Interleukin-7 / Q000378:metabolism; D038041:Lymphopoiesis; D051379:Mice; D008969:Molecular Sequence Data; D054420:Pre-B Cell Receptors / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics
C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D015851:Interleukin-7; D054420:Pre-B Cell Receptors; D051560:Proto-Oncogene Proteins c-bcl-6; D016271:Proto-Oncogene Proteins c-myc; D020727:ADP-Ribosylation Factors