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Inactivation of mismatch repair (MMR) is the cause of the common cancer predisposition disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), as well as 10-40% of sporadic colorectal, endometrial, ovarian, gastric, and urothelial cancers. Elevated mutation rates (mutator phenotype), including simple repeat instability [microsatellite instability (MSI)] are a signature of MMR defects. MicroRNAs (miRs) have been implicated in the control of critical cellular pathways involved in development and cancer. Here we show that overexpression of miR-155 significantly down-regulates the core MMR proteins, hMSH2, hMSH6, and hMLH1, inducing a mutator phenotype and MSI. An inverse correlation between the expression of miR-155 and the expression of MLH1 or MSH2 proteins was found in human colorectal cancer. Finally, a number of MSI tumors with unknown cause of MMR inactivation displayed miR-155 overexpression. These data provide support for miR-155 modulation of MMR as a mechanism of cancer pathogenesis.colorectal cancer | DNA repair | microRNA

Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic stem cell transplant (alloHSCT), underscoring the need to further elucidate its mechanisms and develop novel treatments. Based on recent observations that microRNA-155 (miR-155) is up-regulated during T-cell activation, we hypothesized that miR-155 is involved in the modulation of aGVHD.Here we show that miR-155 expression was up-regulated in T cells from mice developing aGVHD after alloHSCT. Mice receiving miR-155-deficient donor lymphocytes had markedly reduced lethal aGVHD, whereas lethal aGVHD developed rapidly in mice recipients of miR-155 overexpressing T cells. Blocking miR-155 expression using a synthetic antimiR-155 after alloHSCT decreased aGVHD severity and prolonged survival in mice. Finally, miR-155 up-regulation was shown in specimens from patients with pathologic evidence of intestinal aGVHD. Altogether, our data indicate a role for miR-155 in the regulation of GVHD and point to miR-155 as a novel target for therapeutic intervention in this disease.

Multiple studies have established that microRNAs (miRNAs) are involved in the initiation and progression of cancer. Notably, miR-155 is one of the most overexpressed miRNAs in several solid and hematological malignancies. Ectopic miR-155 expression in mice B cells (Eμ-miR-155 transgenic mice) has been shown to induce pre-B-cell proliferation followed by high-grade lymphoma/leukemia. Loss of miR-155 in mice resulted in impaired immunity due to defective T-cell-mediated immune response. Here we provide a mechanistic insight into miR-155-induced leukemogenesis in the Eμ-miR-155 mouse model through genome-wide transcriptome analysis of naïve B cells and target studies. We found that a key transcriptional repressor and proto-oncogene, Bcl6 is significantly down-regulated in Eμ-miR-155 mice. The reduction of Bcl6 subsequently leads to de-repression of some of the known Bcl6 targets like inhibitor of differentiation (Id2), interleukin-6 (IL6), cMyc, Cyclin D1, and Mip1α/ccl3, all of which promote cell survival and proliferation. We show that Bcl6 is indirectly regulated by miR-155 through Mxd1/Mad1 up-regulation. Interestingly, we found that miR-155 directly targets HDAC4, a corepressor partner of BCL6. Furthermore, ectopic expression of HDAC4 in human-activated B-cell-type diffuse large B-cell lymphoma (DLBCL) cells results in reduced miR-155-induced proliferation, clonogenic potential, and increased apoptosis. Meta-analysis of the diffuse large B-cell lymphoma patient microarray data showed that miR-155 expression is inversely correlated with Bcl6 and Hdac4. Hence this study provides a better understanding of how miR-155 causes disruption of the BCL6 transcriptional machinery that leads to up-regulation of the survival and proliferation genes in miR-155-induced leukemias.NfκB | Ingenuity Pathway Analysis M icroRNAs (miRNAs) are 18-24-nucleotide-long noncoding RNA molecules that regulate gene expression in many cellular processes including proliferation, differentiation, and development. Recent studies have established that expression of miRNAs is widely altered in a variety of cancers and miR-155 is one of the most frequently overexpressed miRNAs in various solid and hematological malignancies (1). miR-155 is highly upregulated in Hodgkin, primary mediastinal, and diffuse large B-cell lymphomas (DLBCL) (2, 3) and is almost absent or significantly down-regulated in primary cases of Burkitt lymphoma (4). Overexpression of bic, host mRNA of miR-155, caused increased incidence of leukemia and a decrease in latency of lymphoma development in chickens with elevated levels of MYC (5). Overexpression of miR-155 in mice B cells (Eμ-miR-155) has been shown to cause pre-B-cell leukemia/high-grade lymphoma (6), whereas deletion of bic/miR-155 in mice has been attributed to immunodeficiency and impaired T-cell-dependent antibody response (7,8). Additionally, sustained miR-155 expression in stem cell progenitors induced a myeloproliferative disease in transplanted mice (9). Despite the availability of multiple animal models and a ...

miR-17∼92 is a polycistronic microRNA (miR) cluster (consisting of miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a) which frequently is overexpressed in several solid and lymphoid malignancies. Loss-and gain-of-function studies have revealed the role of miR-17∼92 in heart, lung, and B-cell development and in Mycinduced B-cell lymphomas, respectively. Recent studies indicate that overexpression of this locus leads to lymphoproliferation, but no experimental proof that dysregulation of this cluster causes B-cell lymphomas or leukemias is available. To determine whether miR-17∼92-overexpression induces lymphomagenesis/leukemogenesis, we generated a B-cell-specific transgenic mouse model with targeted overexpression of this cluster in B cells. The miR-17∼92 overexpression was driven by the Eμ-enhancer and Ig heavy-chain promoter, and a 3′ GFP tag was added to the transgene to track the miR expression. Expression analysis using Northern Blot and quantitative RT-PCR confirmed 2.5-to 25-fold overexpression of all six miRs in the transgenic mice spleens as compared with spleens from wild-type mice. Eμ-miR-17∼92 mice developed B-cell malignancy by the age of 12-18 mo with a penetrance of ∼80% (49% splenic B-cell lymphoproliferative disease, 28% lymphoma). At this stage mice exhibited severe splenomegaly with abnormal B-cell-derived white pulp expansion and enlarged lymph nodes. Interestingly, we found three classes of B-cell lymphomas/leukemias at varying grades of differentiation. These included expansion of CD19 + and CD5 + double-positive B cells similar to the aggressive form of human B-cell chronic lymphocytic leukemia, B220 + CD43 + B1-cell proliferation, and a CD19 + aggressive diffuse large B-cell lymphoma-like disease, as assessed by flow cytometry and histopathological analysis. miR-17∼92 cluster | animal model | SLC/ABC transporters M icroRNAs (miRs) are 21-to 22-nucleotide-long noncoding RNA molecules that regulate the expression of multiple cellular genes, and their dysregulation is involved in many human diseases including cancer. The MiR-17∼92 cluster frequently is up-regulated in several different malignancies including diffuse large B-cell lymphoma (DLBCL) (1) and lung cancer (2, 3). The MiR-17∼92 cluster is encoded by the chromosome 13q31 locus in humans and the 14qE4 locus in mice. This genomic region is amplified in DLBCLs and several other tumors (reviewed in ref. 4). The cluster consists of six miRs (miR-17, 18a, 19a, 20a, 19b-1, and 92a-1) and has two paralogs in the genome, miR-106a∼363 and miR-106b∼25, proposed to have arisen through series of duplication and deletion events during vertebrate evolution (5).The first suggestion for its possible role in oncogenesis came from the study in Eμ-Myc mice in which enforced expression of miR-17∼92 was shown to accelerate B-cell tumor development (6). An additional study that investigated the role of miR-17∼92 in mice by driving its overexpression under the human CD2 promoter in both B and T cells found that mice overexpressing the miR-17∼92 clust...