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Articles by M Fabbri
Total Records ( 3 ) for M Fabbri
  R Garzon , S Liu , M Fabbri , Z Liu , C. E.A Heaphy , E Callegari , S Schwind , J Pang , J Yu , N Muthusamy , V Havelange , S Volinia , W Blum , L. J Rush , D Perrotti , M Andreeff , C. D Bloomfield , J. C Byrd , K Chan , L. C Wu , C. M Croce and G. Marcucci
 

Aberrant DNA hypermethylation contributes to myeloid leukemogenesis by silencing structurally normal genes involved in hematopoiesis. MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression by targeting protein-coding mRNAs. Recently, miRNAs have been shown to play a role as both targets and effectors in gene hypermethylation and silencing in malignant cells. In the current study, we showed that enforced expression of miR-29b in acute myeloid leukemia cells resulted in marked reduction of the expression of DNA methyltransferases DNMT1, DNMT3A, and DNMT3B at both RNA and protein levels. This in turn led to decrease in global DNA methylation and reexpression of p15INK4b and ESR1 via promoter DNA hypomethylation. Although down-regulation of DNMT3A and DNMT3B was the result of a direct interaction of miR-29b with the 3' untranslated regions of these genes, no predicted miR-29b interaction sites were found in the DNMT1 3' untranslated regions. Further experiments revealed that miR-29b down-regulates DNMT1 indirectly by targeting Sp1, a transactivator of the DNMT1 gene. Altogether, these data provide novel functional links between miRNAs and aberrant DNA hypermethylation in acute myeloid leukemia and suggest a potentially therapeutic use of synthetic miR-29b oligonucleotides as effective hypomethylating compounds.

  M Fabbri , N Valeri and G. A. Calin
 

MicroRNAs (miRNAs) are small non-coding RNAs with regulatory functions. MiRNAs are aberrantly expressed in almost all human cancers, leading to abnormal levels of target genes. Recently, an increasing number of studies have addressed whether genomic variations including germ line or somatic mutations and single-nucleotide polymorphisms can count for miRNA abnormal expression by altering their biogenesis and/or affect the ability of miRNAs to bind to target messenger RNAs. Here, we provide an extensive review of the studies that have investigated variations occurring both in miRNA genes and in target genes and we discuss the possible clinical implications of these findings. Furthermore, we propose that sequence variations in miRNAs or interactor sites located in mRNAs can be involved in cancer predisposition.

  S Volinia , M Galasso , S Costinean , L Tagliavini , G Gamberoni , A Drusco , J Marchesini , N Mascellani , M. E Sana , R Abu Jarour , C Desponts , M Teitell , R Baffa , R Aqeilan , M. V Iorio , C Taccioli , R Garzon , G Di Leva , M Fabbri , M Catozzi , M Previati , S Ambs , T Palumbo , M Garofalo , A Veronese , A Bottoni , P Gasparini , C. C Harris , R Visone , Y Pekarsky , A de la Chapelle , M Bloomston , M Dillhoff , L. Z Rassenti , T. J Kipps , K Huebner , F Pichiorri , D Lenze , S Cairo , M. A Buendia , P Pineau , A Dejean , N Zanesi , S Rossi , G. A Calin , C. G Liu , J Palatini , M Negrini , A Vecchione , A Rosenberg and C. M. Croce
 

We studied miRNA profiles in 4419 human samples (3312 neoplastic, 1107 nonmalignant), corresponding to 50 normal tissues and 51 cancer types. The complexity of our database enabled us to perform a detailed analysis of microRNA (miRNA) activities. We inferred genetic networks from miRNA expression in normal tissues and cancer. We also built, for the first time, specialized miRNA networks for solid tumors and leukemias. Nonmalignant tissues and cancer networks displayed a change in hubs, the most connected miRNAs. hsa-miR-103/106 were downgraded in cancer, whereas hsa-miR-30 became most prominent. Cancer networks appeared as built from disjointed subnetworks, as opposed to normal tissues. A comparison of these nets allowed us to identify key miRNA cliques in cancer. We also investigated miRNA copy number alterations in 744 cancer samples, at a resolution of 150 kb. Members of miRNA families should be similarly deleted or amplified, since they repress the same cellular targets and are thus expected to have similar impacts on oncogenesis. We correctly identified hsa-miR-17/92 family as amplified and the hsa-miR-143/145 cluster as deleted. Other miRNAs, such as hsa-miR-30 and hsa-miR-204, were found to be physically altered at the DNA copy number level as well. By combining differential expression, genetic networks, and DNA copy number alterations, we confirmed, or discovered, miRNAs with comprehensive roles in cancer. Finally, we experimentally validated the miRNA network with acute lymphocytic leukemia originated in Mir155 transgenic mice. Most of miRNAs deregulated in these transgenic mice were located close to hsa-miR-155 in the cancer network.

 
 
 
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