Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis

• Published in: Blood 2008-10, Vol.112 (8), p.3383-3390
• Main Authors: Hasan, Syed Khizer, Mays, Ashley N., Ottone, Tiziana, Ledda, Antonio, La Nasa, Giorgio, Cattaneo, Chiara, Borlenghi, Erika, Melillo, Lorella, Montefusco, Enrico, Cervera, José, Stephen, Christopher, Satchi, Gnanam, Lennard, Anne, Libura, Marta, Byl, Jo Ann W., Osheroff, Neil, Amadori, Sergio, Felix, Carolyn A., Voso, Maria Teresa, Sperr, Wolfgang R., Esteve, Jordi, Sanz, Miguel A., Grimwade, David, Lo-Coco, Francesco
• Format: Article
• Language: English
• Subjects: Adult; Antigens, Neoplasm - metabolism; Biological and medical sciences; Chromosome aberrations; Chromosomes, Human, Pair 15; Chromosomes, Human, Pair 17; DNA - chemistry; DNA Topoisomerases, Type II - metabolism; DNA-Binding Proteins - metabolism; Female; Hematologic and hematopoietic diseases; Humans; Introns; Leukemia, Promyelocytic, Acute - chemically induced; Leukemia, Promyelocytic, Acute - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical genetics; Medical sciences; Middle Aged; Mitoxantrone - adverse effects; Mitoxantrone - pharmacology; Models, Genetic; Multiple Sclerosis - therapy; Neoplasia; Translocation, Genetic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-10-115600

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 IIα-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.