Chronic lymphocytic leukemia (CLL) is a malignancy of B cells of unknown etiology. Deletions of the chromosomal region 13q14 are commonly associated with CLL, with monoclonal B cell lymphocytosis (MBL), which occasionally precedes CLL, and with aggressive lymphoma, suggesting that this region contains a tumor-suppressor gene. Here, we demonstrate that deletion in mice of the 13q14-minimal deleted region (MDR), which encodes the DLEU2/miR-15a/16-1 cluster, causes development of indolent B cell-autonomous, clonal lymphoproliferative disorders, recapitulating the spectrum of CLL-associated phenotypes observed in humans. miR-15a/16-1-deletion accelerates the proliferation of both human and mouse B cells by modulating the expression of genes controlling cell-cycle progression. These results define the role of 13q14 deletions in the pathogenesis of CLL.

The molecular mechanism involved in the process of antigen-driven somatic hypermutation of Ig genes is unknown, but it is commonly believed that this mechanism is restricted to the Ig loci. B cell lymphomas commonly display multiple somatic mutations clustering in the 5 -regulatory region of BCL-6, a proto-oncogene encoding for a POZ͞Zinc finger transcriptional repressor expressed in germinal center (GC) B cells and required for GC formation. To determine whether BCL-6 mutations represent a tumor-associated phenomenon or ref lect a physiologic mechanism, we screened single human tonsillar GC B cells for mutations occurring in the BCL-6 5 -noncoding region and in the Ig variable heavy chain sequences. Thirty percent of GC B cells, but not naive B cells, displayed mutations in the 742 bp region analyzed within the first intron of BCL-6 (overall frequency: 5 ؋ 10 ؊4 ͞bp). Accordingly, an expanded survey in lymphoid malignancies showed that BCL-6 mutations are restricted to B cell tumors displaying GC or post-GC phenotype and carrying mutated Ig variable heavy chain sequences. These results indicate that the somatic hypermutation mechanism active in GC B cells physiologically targets non-Ig sequences.Somatic hypermutation is one of the mechanisms by which Ig genes are modified in B cells to generate a large repertoire of B lymphocytes, each expressing a unique antibody molecule (1). This process is activated in germinal center (GC) B cells (2-4), where it introduces mutations in the variable region of Ig genes (IgV) at a frequency of 2-8 ϫ 10 Ϫ2 in humans (5). The mechanism involved in IgV hypermutation is not known, although experimental evidence suggests that it requires transcription of the target sequences and the presence of the Ig enhancer but not a specific promoter (6-8).It is generally assumed that the process of somatic hypermutation is restricted to the Ig loci including heavy and light chain variable region genes (1). However, B cell lymphomas were shown to display somatic hypermutation of the 5Ј-noncoding region of BCL-6 (9, 10), a proto-oncogene encoding a POZ͞Zinc finger transcriptional repressor normally expressed within GC B cells and required for GC formation (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). In 30% of diffuse large cell lymphoma (DLCL) and 5-10% of follicular lymphoma (FL), the BCL-6 gene is altered structurally by chromosomal translocations (11). In addition, mutations of its 5Ј-noncoding region were frequently found in DLCL and FL even in the absence of translocations involving this locus (9, 10). In most tumor cases, mutations were multiple, often biallelic, and clustered in the 5Ј regulatory sequences at frequencies (7 ϫ 10 Ϫ4 through 1.6 ϫ 10 Ϫ2 ͞bp) comparable with that of IgV genes in B cells (9). These findings raised the question of whether BCL-6 mutations represent a tumor associated misfunction or the effect of the IgV hypermutation process acting on non-Ig genes.To address this issue, we have investigated the presence of BCL-6 mutations in normal GC and naive B cells by...