title: Allele-specific loss and transcription of the miR-15a/16-1 cluster in chronic lymphocytic leukemia.
abstract: Deregulation of the miR-15a/16-1 cluster has a key role in the pathogenesis of chronic lymphocytic leukemia (CLL), a clinically heterogeneous disease with indolent and aggressive forms. The miR-15a/16-1 locus is located at 13q14, the most frequently deleted region in CLL. Starting from functional investigations of a rare SNP upstream the miR cluster, we identified a novel allele-specific mechanism that exploits a cryptic activator region to recruit the RNA polymerase III for miR-15a/16-1 transcription. This regulation of the miR-15a/16- locus is independent of the DLEU2 host gene, which is often transcribed monoallellically by RPII. We found that normally one allele of miR-15a/16-1 is transcribed by RNAPII, the other one by RNAPIII. In our subset of CLL patients harboring 13q14 deletions, exclusive RNA polymerase III (RPIII)-driven transcription of the miR-15a/16-1 was the consequence of loss of the RPII-regulated allele and correlated with high expression of the poor prognostic marker ZAP70 (P=0.019). Thus, our findings point to a novel biological process, characterized by double allele-specific transcriptional regulation of the miR-15a/16-1 locus by alternative mechanisms. Differential usage of these mechanisms may distinguish at onset aggressive from indolent forms of CLL. This provides a basis for the clinical heterogeneity of the CLL patients carrying 13q14 deletions.
authors.affiliation: 1] Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy [2] Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Veronese
authors.affiliation: 1] Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy [2] Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Pepe
authors.affiliation: Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Chiacchia
authors.affiliation: 1] Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy [2] Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Pagotto
authors.affiliation: Department of Medicine and Aging Science, University G. d'Annunzio Chieti-Pescara, Chieti, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Lanuti
authors.affiliation: 1] Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy [2] Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Veschi
authors.affiliation: Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Di Marco
authors.affiliation: Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.
authors.forename: A
authors.initials: A
authors.lastname: D'Argenio
authors.affiliation: Department of Hematology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Innocenti
authors.affiliation: Department of Hematology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Vannata
authors.affiliation: Department of Hematology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Autore
authors.affiliation: Department of Medicine and Aging Science, University G. d'Annunzio Chieti-Pescara, Chieti, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Marchisio
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
authors.forename: D
authors.initials: D
authors.lastname: Wernicke
authors.affiliation: Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Verginelli
authors.affiliation: Department of Hematology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Leone
authors.affiliation: 1] Department of Medicine, Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA [2] Chronic Lymphocytic Leukemia Research Consortium, San Diego, CA, USA.
authors.forename: L Z
authors.initials: LZ
authors.lastname: Rassenti
authors.affiliation: 1] Department of Medicine, Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA [2] Chronic Lymphocytic Leukemia Research Consortium, San Diego, CA, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: 1] Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy [2] Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Mariani-Costantini
authors.affiliation: Department of Hematology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Laurenti
authors.affiliation: 1] Department of Molecular Virology, Immunology, and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA [2] Chronic Lymphocytic Leukemia Research Consortium, San Diego, CA, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: 1] Unit of General Pathology, Aging Research Center (Ce.S.I.), G. d'Annunzio University Foundation, Chieti, Italy [2] Department of Medical, Oral and Biotechnological Sciences, G. d'Annunzio University, Chieti, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Visone
mesh_terms: D000483:Alleles; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000235:genetics; D056915:DNA Copy Number Variations; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor; C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D004247:DNA
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