title: Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis.
abstract: 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 IIalpha-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.
authors.affiliation: Department of Biopathology, University of Tor Vergata, Rome, Italy.
authors.forename: Syed Khizer
authors.initials: SK
authors.lastname: Hasan
authors.forename: Ashley N
authors.initials: AN
authors.lastname: Mays
authors.forename: Tiziana
authors.initials: T
authors.lastname: Ottone
authors.forename: Antonio
authors.initials: A
authors.lastname: Ledda
authors.forename: Giorgio
authors.initials: G
authors.lastname: La Nasa
authors.forename: Chiara
authors.initials: C
authors.lastname: Cattaneo
authors.forename: Erika
authors.initials: E
authors.lastname: Borlenghi
authors.forename: Lorella
authors.initials: L
authors.lastname: Melillo
authors.forename: Enrico
authors.initials: E
authors.lastname: Montefusco
authors.forename: José
authors.initials: J
authors.lastname: Cervera
authors.forename: Christopher
authors.initials: C
authors.lastname: Stephen
authors.forename: Gnanam
authors.initials: G
authors.lastname: Satchi
authors.forename: Anne
authors.initials: A
authors.lastname: Lennard
authors.forename: Marta
authors.initials: M
authors.lastname: Libura
authors.forename: Jo Ann W
authors.initials: JA
authors.lastname: Byl
authors.forename: Neil
authors.initials: N
authors.lastname: Osheroff
authors.forename: Sergio
authors.initials: S
authors.lastname: Amadori
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Felix
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Voso
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Sperr
authors.forename: Jordi
authors.initials: J
authors.lastname: Esteve
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Sanz
authors.forename: David
authors.initials: D
authors.lastname: Grimwade
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo-Coco
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000378:metabolism; D002884:Chromosomes, Human, Pair 15; D002886:Chromosomes, Human, Pair 17; D004247:DNA / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D007438:Introns; D015473:Leukemia, Promyelocytic, Acute / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000009:adverse effects / Q000494:pharmacology; D008957:Models, Genetic; D009103:Multiple Sclerosis / Q000628:therapy*; D014178:Translocation, Genetic
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D004247:DNA; D008942:Mitoxantrone; D004250:DNA Topoisomerases, Type II