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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.
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Submitted October 3, 2007
Accepted July 5, 2008
Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis
Syed Khizer Hasan, Ashley N Mays, Tiziana Ottone, Antonio Ledda, Giorgio La Nasa, Chiara Cattaneo, Erika Borlenghi, Lorella Melillo, Enrico Montefusco, Jose Cervera, Christopher Stephen, Gnanam Satchi, Anne Lennard, Marta Libura, Jo Ann W. Byl, Neil Osheroff, Sergio Amadori, Carolyn A Felix, Maria Teresa Voso, Wolfgang R Sperr, Jordi Esteve, Miguel A Sanz, David Grimwade, and Francesco Lo-Coco*
Department of Biopathology, University of Tor Vergata, Rome, Italy
Department of Medical & Molecular Genetics, King's College London School of Medicine, London, United Kingdom
Ematologia/Centro Trapianti Midollo Osseo, Ospedale "R. Binaghi" Cagliari, Cagliari, Italy
Ematologia, Spedali Civili, Brescia, Italy
Hematology Department, "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Rome, Rome, Italy
Department of Hematology, S. Andrea Hospital, University La Sapienza, Rome, Rome, Italy
Hematology Department, University Hospital La Fe, Valencia, Spain
Department of Haematology, Pilgrim Hospital, Boston, Lincolnshire, United Kingdom
Department of Haematology, Whiston Hospital, Whiston, United Kingdom
Department of Haematology, Royal Victoria Infirmary, Newcastle, United Kingdom
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, United States
Department of Pediatrics, Division of Oncology, University of Pennsylvania School of Medicine, The Children's Hospital of Philadelphia, Philadelphia, United States
Istituto di Ematologia, Universita' Cattolica del Sacro Cuore, Rome, Italy
Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria
Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
* Corresponding author; email: francesco.lo.coco{at}uniroma2.it.
Therapy-related acute promyelocytic leukemia (t-APL) with the t(15;17) translocation is a well-recognized complication of cancer treatment with agents targeting topoisomerase II. However, cases are emerging following 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 compared to de novo APL, biased towards disruption within PML intron 6 (11/12, 92% vs 622/1022, 61%: p=0.035). Despite this intron spanning  1kb, the breakpoint in five mitoxantrone-treated patients fell within an 8bp 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 17kb RARA intron 2 involving two 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 14446-49, 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 particular subtype of leukemia following exposure to this agent.
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