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Human Molecular Genetics Advance Access published online on February 1, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl010
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received December 6, 2005
Revised January 27, 2006
Accepted January 27, 2006

Article

MYC-containing double minutes in hematologic malignancies: evidence in favor of the episome model and exclusion of MYC as the target gene

Clelia Tiziana Storlazzi 1, Thoas Fioretos 2, Cecilia Surace 1, Angelo Lonoce 1, Angela Mastrorilli 1, Bodil Strömbeck 2, Pietro D'Addabbo 1, Francesco Iacovelli 1, Crescenzio Minervini 1, Anna Aventin 3, Nicole Dastugue 4, Christa Fonatsch 5, Anne Hagemeijer 6, Martine Jotterand 7, Dominique Mühlematter 8, Marina Lafage-Pochitaloff 8, Florence Nguyen-Khac 9, Claudia Schoch 10, Marilyn L. Slovak 11, Arabella Smith 12, Francesc Solè 13, Nadine Van Roy 14, Bertil Johansson 2, and Mariano Rocchi 15 *

1 Department of Genetics and Microbiology, University of Bari, Italy
2 Department of Clinical Genetics, University Hospital, Lund, Sweden
3 Department of Hematology, Hospital Sant Pau, Barcelona, Spain
4 Génétique des hemopathies, hopital Purpan, Toulouse, France
5 Institut für Medizinische Biologie, Universitat Wien, Austria
6 Center for Human Genetics, University of Leuven, Leuven, Belgium
7 Unité de cytogénétique du cancer, CHUV, Lausanne, Switzerland
8 Departement de Biopathologie, Institut Paoli-Calmettes, INSERM UMR 599, Université de la Méditerranée, Marseille, France
9 Service d'Hematologie Biologique, Groupe Hospitalier Pitie-Salpetriere, Paris, France
10 Kliniukum Grosshadern, LFL, München, Germany
11 Division of Pathology, City of Hope National Medical Center, Duarte, California, USA
12 Department of Cytogenetics, Children's Hospital at Westmead, Westmead, Australia
13 Laboratori de Citogenètica i Biologia Molecular, Servei de Patologia, Hospital del Mar, Barcelona, Spain
14 Department of Medical Genetics, Ghent University Hospital, Ghent, Belgium
15 Department of Genetics and Microbiology, University of Bari, Via Amendola 165/A, 70126, Bari, Italy

* To whom correspondence should be addressed.
Mariano Rocchi, E-mail: rocchi{at}biologia.uniba.it


  Abstract

Double minutes (dmin) - circular, extrachromosomal 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 approximately 1% of the cases. Most of them consist of an amplified segment from chromosome band 8q24, always including the MYC gene. Besides that, little is known about their internal structure. We have characterized in detail the genomic organization of 32 AML and 2 MDS cases with MYC-containing dmin. The minimally amplified region was shown to be 4.26 Mb in size, harboring 5 known genes, with the proximal and the distal amplicon breakpoints clustering in two regions of approximately 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 overexpressed in only a subset of the AML/MDS cases, while 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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