title: Burkitt lymphoma beyond MYC translocation: N-MYC and DNA methyltransferases dysregulation.
abstract: BACKGROUND
  The oncogenic transcription factor MYC is pathologically activated in many human malignancies. A paradigm for MYC dysregulation is offered by Burkitt lymphoma, where chromosomal translocations leading to Immunoglobulin gene-MYC fusion are the crucial initiating oncogenic events. However, Burkitt lymphoma cases with no detectable MYC rearrangement but maintaining MYC expression have been identified and alternative mechanisms can be involved in MYC dysregulation in these cases.
  
  
  METHODS
  We studied the microRNA profile of MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases in order to uncover possible differences at the molecular level. Data was validated at the mRNA and protein level by quantitative Real-Time polymerase chain reaction and immunohistochemistry, respectively.
  
  
  RESULTS
  We identified four microRNAs differentially expressed between the two groups. The impact of these microRNAs on the expression of selected genes was then investigated. Interestingly, in MYC translocation-negative cases we found over-expression of DNA-methyl transferase family members, consistent to hypo-expression of the hsa-miR-29 family. This finding suggests an alternative way for the activation of lymphomagenesis in these cases, based on global changes in methylation landscape, aberrant DNA hypermethylation, lack of epigenetic control on transcription of targeted genes, and increase of genomic instability. In addition, we observed an over-expression of another MYC family gene member, MYCN that may therefore represent a cooperating mechanism of MYC in driving the malignant transformation in those cases lacking an identifiable MYC translocation but expressing the gene at the mRNA and protein levels.
  
  
  CONCLUSIONS
  Collectively, our results showed that MYC translocation-positive and MYC translocation-negative Burkitt lymphoma cases are slightly different in terms of microRNA and gene expression. MYC translocation-negative Burkitt lymphoma, similarly to other aggressive B-cell non Hodgkin's lymphomas, may represent a model to understand the intricate molecular pathway responsible for MYC dysregulation in cancer.
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Italy - Via delle Scotte, 6 - 53100, Siena, Italy. defalco@unisi.it.|School of Biological and Chemical Sciences, Queen Mary University of London, London, UK. defalco@unisi.it.
authors.forename: Giulia
authors.initials: G
authors.lastname: De Falco
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Italy - Via delle Scotte, 6 - 53100, Siena, Italy. maradot@libero.it.
authors.forename: Maria Raffaella
authors.initials: MR
authors.lastname: Ambrosio
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Via Zamboni, 33, 40126, Bologna, Italy. fabio.fuligni2@unibo.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Fuligni
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Italy - Via delle Scotte, 6 - 53100, Siena, Italy. onnis2@unisi.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Onnis
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Italy - Via delle Scotte, 6 - 53100, Siena, Italy. bellan@unisi.it.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Bellan
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Italy - Via delle Scotte, 6 - 53100, Siena, Italy. brunojim@libero.it.
authors.forename: Bruno Jim
authors.initials: BJ
authors.lastname: Rocca
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Via Zamboni, 33, 40126, Bologna, Italy. navari@unisi.it.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Navari
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Via Zamboni, 33, 40126, Bologna, Italy. etebary@unibo.it.
authors.forename: Maryam
authors.initials: M
authors.lastname: Etebari
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Italy - Via delle Scotte, 6 - 53100, Siena, Italy. mundol@hotmail.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Mundo
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Italy - Via delle Scotte, 6 - 53100, Siena, Italy. sara.gazaneo@gmail.com.
authors.forename: Sara
authors.initials: S
authors.lastname: Gazaneo
authors.affiliation: Unit of Pathology, Brescia University, Piazza del Mercato, 15, Brescia, Italy. facchett@med.unibs.it.
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Via Zamboni, 33, 40126, Bologna, Italy. stefano.pileri@unibo.it.
authors.forename: Stefano A
authors.initials: SA
authors.lastname: Pileri
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Italy - Via delle Scotte, 6 - 53100, Siena, Italy. leoncinil@unisi.it.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Leoncini
authors.affiliation: Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Via Zamboni, 33, 40126, Bologna, Italy. pierpaolo.piccaluga@unibo.it.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Piccaluga
mesh_terms: D002051:Burkitt Lymphoma / Q000235:genetics* / Q000378:metabolism; D016000:Cluster Analysis; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D005810:Multigene Family; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D059467:Transcriptome; D014178:Translocation, Genetic
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D015254:DNA Modification Methylases