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
Department of Biopathology, University of Tor Vergata, Rome, Italy.
Blood. 2008 Oct 15;112(8):3383-90. doi: 10.1182/blood-2007-10-115600. Epub 2008 Jul 23.
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.
伴有t(15;17)易位的治疗相关急性早幼粒细胞白血病（t-APL）是使用靶向拓扑异构酶II的药物进行癌症治疗时公认的并发症。然而，在米托蒽醌治疗多发性硬化症（MS）后也出现了此类病例。对12例MS患者中与米托蒽醌相关的t-APL病例进行分析发现，与新发APL相比，15号染色体断点的分布有所改变，偏向于PML内含子6内的断裂（12例中的11例，92% 对比1022例中的622例，61%：P = 0.035）。尽管该内含子跨度约1 kb，但5例接受米托蒽醌治疗的患者的断点位于一个8 bp区域（1482 - 9）内，该区域与先前在t-APL中报道的“热点”相对应，这使含米托蒽醌的乳腺癌治疗变得复杂。在分别接受米托蒽醌治疗MS和乳腺癌后出现的2例t-APL病例中，在约17 kb的RARA内含子2内鉴定出了另一个共享断点。对4例病例进行功能分析，包括在14446 - 49处共享的RARA内含子2断点，证实这些断点在米托蒽醌存在的情况下均为拓扑异构酶IIα介导的DNA切割的优先位点。这项研究进一步支持了米托蒽醌在PML和RARA基因中诱导的DNA损伤优先位点的存在，这可能是接触该药物后发生这种白血病亚型倾向的基础。
