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miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eµ-miR-155 transgenic mouse model

Author:
Sandhu, Sukhinder K., Volinia, Stefano, Costinean, Stefan, Galasso, Marco, Neinast, Reid, Santhanam, Ramasamy, Parthun, Mark R., Perrotti, Danilo, Marcucci, Guido, Garzon, Ramiro, Croce, Carlo M.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.49 pp. 20047-20052
ISSN:
0027-8424
Subject:
B-lymphocytes, animal models, apoptosis, cell viability, cyclins, gene expression regulation, histone deacetylase, immune response, interleukin-6, leukemia, lymphoma, meta-analysis, mice, microRNA, microarray technology, patients, proto-oncogenes, repressor proteins, transcription (genetics), transcriptomics, transgenic animals
Abstract:
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.
Agid:
1735521