Molecular analysis of t(15;17) genomic breakpoints in secondary acute promyelocytic leukemia arising after treatment of multiple sclerosis.
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.
Hasan
Syed Khizer
SK
Department of Biopathology, University of Tor Vergata, Rome, Italy.
Mays
Ashley N
AN
Ottone
Tiziana
T
Ledda
Antonio
A
La Nasa
Giorgio
G
Cattaneo
Chiara
C
Borlenghi
Erika
E
Melillo
Lorella
L
Montefusco
Enrico
E
Cervera
José
J
Stephen
Christopher
C
Satchi
Gnanam
G
Lennard
Anne
A
Libura
Marta
M
Byl
Jo Ann W
JA
Osheroff
Neil
N
Amadori
Sergio
S
Felix
Carolyn A
CA
Voso
Maria Teresa
MT
Sperr
Wolfgang R
WR
Esteve
Jordi
J
Sanz
Miguel A
MA
Grimwade
David
D
Lo-Coco
Francesco
F
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
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D004247:DNA; D008942:Mitoxantrone; D004250:DNA Topoisomerases, Type II