Human Molecular Genetics Advance Access originally published online on February 1, 2006
Human Molecular Genetics 2006 15(6):933-942; doi:10.1093/hmg/ddl010
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MYC-containing double minutes in hematologic malignancies: evidence in favor of the episome model and exclusion of MYC as the target gene
1Department of Genetics and Microbiology, University of Bari, Via Amendola 165/A, 70126 Bari, Italy, 2Department of Clinical Genetics, University Hospital, Lund, Sweden, 3Department of Hematology, Hospital Sant Pau, Barcelona, Spain, 4Génétique des hemopathies, hopital Purpan, Toulouse, France, 5Institut für Medizinische Biologie, Universitat Wien, Austria, 6Center for Human Genetics, University of Leuven, Leuven, Belgium, 7Unité de cytogénétique du cancer, CHUV, Lausanne, Switzerland, 8Departement de Biopathologie, Institut Paoli-Calmettes, INSERM UMR 599, Université de la Méditerranée, Marseille, France, 9Service d'Hematologie Biologique, Groupe Hospitalier Pitie-Salpetriere, Paris, France, 10Kliniukum Grosshadern, LFL, München, Germany, 11Division of Pathology, City of Hope National Medical Center, Duarte, CA, USA, 12Department of Cytogenetics, Children's Hospital at Westmead, Westmead, Australia, 13Laboratori de Citogenètica i Biologia Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain and 14Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium
* To whom correspondence should be addressed. Tel: +39 (0) 805443371; Fax: +39 (0) 805443386; Email: rocchi{at}biologia.uniba.it
Received December 6, 2005; Revised January 19, 2006; Accepted January 27, 2006
Double minutes (dmin)—circular, extra-chromosomal amplifications of specific acentric DNA fragments—are relatively frequent in malignant disorders, particularly in solid tumors. In acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), dmin are observed in 
1% of the cases. Most of them consist of an amplified segment from chromosome band 8q24, always including the MYC gene. Besides this information, little is known about their internal structure. We have characterized in detail the genomic organization of 32 AML and two MDS cases with MYC-containing dmin. The minimally amplified region was shown to be 4.26 Mb in size, harboring five known genes, with the proximal and the distal amplicon breakpoints clustering in two regions of 500 and 600 kb, respectively. Interestingly, in 23 (68%) of the studied cases, the amplified region was deleted in one of the chromosome 8 homologs at 8q24, suggesting excision of a DNA segment from the original chromosomal location according to the ‘episome model’. In one case, sequencing of both the dmin and del(8q) junctions was achieved and provided definitive evidence in favor of the episome model for the formation of dmin. Expression status of the TRIB1 and MYC genes, encompassed by the minimally amplified region, was assessed by northern blot analysis. The TRIB1 gene was found over-expressed in only a subset of the AML/MDS cases, whereas MYC, contrary to expectations, was always silent. The present study, therefore, strongly suggests that MYC is not the target gene of the 8q24 amplifications.
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