Dicer Ablation Affects Antibody Diversity and Cell Survival in the B Lymphocyte Lineage

Summary To explore the role of Dicer-dependent control mechanisms in B lymphocyte development, we ablated this enzyme in early B cell progenitors. This resulted in a developmental block at the pro- to pre-B cell transition. Gene-expression profiling revealed a miR-17∼92 signature in the 3′UTRs of genes upregulated in Dicer-deficient pro-B cells; a top miR-17∼92 target, the proapoptotic molecule Bim, was highly upregulated. Accordingly, B cell development could be partially rescued by ablation of Bim or transgenic expression of the prosurvival protein Bcl-2. This allowed us to assess the impact of Dicer deficiency on the V(D)J recombination program in developing B cells. We found intact Ig gene rearrangements in immunoglobulin heavy (IgH) and κ chain loci, but increased sterile transcription and usage of D H elements of the DSP family in IgH, and increased N sequence addition in Igκ due to deregulated transcription of the terminal deoxynucleotidyl transferase gene.