De Yebenes V.G.,CSIC - National Center for Metallurgical Research |
Bartolome-Izquierdo N.,CSIC - National Center for Metallurgical Research |
Nogales-Cadenas R.,Functional Bioinformatics Group |
Perez-Duran P.,CSIC - National Center for Metallurgical Research |
And 10 more authors.
Blood | Year: 2014
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 downregulates 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. © 2014 by The American Society of Hematology.