miR-217 is an oncogene that enhances the germinal center reaction.
microRNAs are a class of regulators of gene expression that have been shown critical for a great number of biological processes; however, little is known of their role in germinal center (GC) B cells. Although the GC reaction is crucial to ensure a competent immune response, GC B cells are also the origin of most human lymphomas, presumably due to bystander effects of the immunoglobulin gene remodeling that takes place at these sites. Here we report that miR-217 is specifically upregulated in GC B cells. Gain- and loss-of-function mouse models reveal that miR-217 is a positive modulator of the GC response that increases the generation of class-switched antibodies and the frequency of somatic hypermutation. We find that miR-217 down-regulates the expression of a DNA damage response and repair gene network and in turn stabilizes Bcl-6 expression in GC B cells. Importantly, miR-217 overexpression also promotes mature B-cell lymphomagenesis; this is physiologically relevant as we find that miR-217 is overexpressed in aggressive human B-cell lymphomas. Therefore, miR-217 provides a novel molecular link between the normal GC response and B-cell transformation.
B Cell Biology Laboratory, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain;
Virginia G
VG
de Yébenes
B Cell Biology Laboratory, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain;
Nahikari
N
Bartolomé-Izquierdo
Functional Bioinformatics Group, National Center for Biotechnology-Consejo Superior de Investigaciones Científicas, Madrid, Spain;
Rubén
R
Nogales-Cadenas
B Cell Biology Laboratory, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain;
Pablo
P
Pérez-Durán
B Cell Biology Laboratory, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain;
Sonia M
SM
Mur
Genomica del Cancer, Instituto de Investigación y Formación Marqués de Valdecilla, Santander, Spain;
Nerea
N
Martínez
Genomica del Cancer, Instituto de Investigación y Formación Marqués de Valdecilla, Santander, Spain;
Lorena
L
Di Lisio
Laboratory of Molecular Immunology, The Rockefeller University, New York, NY; and.
Davide F
DF
Robbiani
Functional Bioinformatics Group, National Center for Biotechnology-Consejo Superior de Investigaciones Científicas, Madrid, Spain;
Alberto
A
Pascual-Montano
Comparative Pathology Unit, Spanish National Cancer Research Centre, Madrid, Spain.
Marta
M
Cañamero
Genomica del Cancer, Instituto de Investigación y Formación Marqués de Valdecilla, Santander, Spain;
Miguel A
MA
Piris
B Cell Biology Laboratory, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain;
Almudena R
AR
Ramiro
D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D053263:Gene Regulatory Networks; D018858:Germinal Center / Q000502:physiology*; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D046228:Microarray Analysis; D009857:Oncogenes / Q000502:physiology*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics
C000591813:MIRN-217 microRNA, mouse; D035683:MicroRNAs; D051560:Proto-Oncogene Proteins c-bcl-6