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Blood, 15 October 2008, Vol. 112, No. 8, pp. 3383-3390. Prepublished online as a Blood First Edition Paper on July 23, 2008; DOI 10.1182/blood-2007-10-115600. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-10-115600v1 112/8/3383    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hasan, S. K. Articles by Lo-Coco, F. Search for Related Content PubMed PubMed Citation Articles by Hasan, S. K. Articles by Lo-Coco, F. Related Collections Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis Syed Khizer Hasan1,*, Ashley N. Mays2,*, Tiziana Ottone1, Antonio Ledda3, Giorgio La Nasa3, Chiara Cattaneo4, Erika Borlenghi4, Lorella Melillo5, Enrico Montefusco6, José Cervera7, Christopher Stephen8, Gnanam Satchi9, Anne Lennard10, Marta Libura2, Jo Ann W. Byl11, Neil Osheroff11, Sergio Amadori1, Carolyn A. Felix12, Maria Teresa Voso13, Wolfgang R. Sperr14, Jordi Esteve15, Miguel A. Sanz7, David Grimwade2, and Francesco Lo-Coco1 1 Department of Biopathology, University of Tor Vergata, Rome, Italy; 2 Department of Medical & Molecular Genetics, King's College London School of Medicine, London, United Kingdom; 3 Ematologia/Centro Trapianti Midollo Osseo, Ospedale R. Binaghi, Cagliari, Italy; 4 Ematologia, Spedali Civili, Brescia, Italy; 5 Hematology Department, Casa Sollievo della Sofferenza Hospital, S. Giovanni Rotondo, Italy; 6 Department of Hematology, S. Andrea Hospital, University La Sapienza, Rome, Italy; 7 Hematology Department, University Hospital La Fe, Valencia, Spain; 8 Department of Haematology, Pilgrim Hospital, Boston, United Kingdom; 9 Department of Haematology, Whiston Hospital, Prescot, United Kingdom; 10 Department of Haematology, Royal Victoria Infirmary, Newcastle, United Kingdom; 11 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN; 12 Department of Pediatrics, University of Pennsylvania School of Medicine, Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA; 13 Istituto di Ematologia, Universita' Cattolica del Sacro Cuore, Rome, Italy; 14 Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical, University of Vienna, Vienna, Austria; and 15 Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain Therapy-related acute promyelocytic leukemia (t-APL) with t(15;17) translocation is a well-recognized complication of cancer treatment with agents targeting topoisomerase II. However, cases are emerging after mitoxantrone therapy for multiple sclerosis (MS). Analysis of 12 cases of mitoxantrone-related t-APL in MS patients revealed an altered distribution of chromosome 15 breakpoints versus de novo APL, biased toward disruption within PML intron 6 (11 of 12, 92% vs 622 of 1022, 61%: P = .035). Despite this intron spanning approximately 1 kb, breakpoints in 5 mitoxantrone-treated patients fell within an 8-bp region (1482-9) corresponding to the "hotspot" previously reported in t-APL, complicating mitoxantrone-containing breast cancer therapy. Another shared breakpoint was identified within the approximately 17-kb RARA intron 2 involving 2 t-APL cases arising after mitoxantrone treatment for MS and breast cancer, respectively. Analysis of PML and RARA genomic breakpoints in functional assays in 4 cases, including the shared RARA intron 2 breakpoint at 14 446-49, confirmed each to be preferential sites of topoisomerase II-mediated DNA cleavage in the presence of mitoxantrone. This study further supports the presence of preferential sites of DNA damage induced by mitoxantrone in PML and RARA genes that may underlie the propensity to develop this subtype of leukemia after exposure to this agent. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. E. Deweese and N. Osheroff The DNA cleavage reaction of topoisomerase II: wolf in sheep's clothing Nucleic Acids Res., February 1, 2009; 37(3): 738 - 748. [Abstract] [Full Text] [PDF]

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