Evidence for direct involvement of epirubicin in the formation of chromosomal translocations in t(15;17) therapy-related acute promyelocytic leukemia.
Therapy-related acute promyelocytic leukemia (t-APL) with t(15;17)(q22;q21) involving the PML and RARA genes is associated with exposure to agents targeting topoisomerase II (topoII), particularly mitoxantrone and epirubicin. We previously have shown that mitoxantrone preferentially induces topoII-mediated DNA damage in a "hotspot region" within PML intron 6. To investigate mechanisms underlying epirubicin-associated t-APL, t(15;17) genomic breakpoints were characterized in 6 cases with prior breast cancer. Significant breakpoint clustering was observed in PML and RARA loci (P = .009 and P = .017, respectively), with PML breakpoints lying outside the mitoxantrone-associated hotspot region. Recurrent breakpoints identified in the PML and RARA loci in epirubicin-related t-APL were shown to be preferential sites of topoII-induced DNA damage, enhanced by epirubicin. Although site preferences for DNA damage differed between mitoxantrone and epirubicin, the observation that particular regions of the PML and RARA loci are susceptible to these agents may underlie their respective propensities to induce t-APL.
Mays
Ashley N
AN
Department of Medical & Molecular Genetics, King's College London School of Medicine, London, United Kingdom.
Osheroff
Neil
N
Xiao
Yuanyuan
Y
Wiemels
Joseph L
JL
Felix
Carolyn A
CA
Byl
Jo Ann W
JA
Saravanamuttu
Kandeepan
K
Peniket
Andrew
A
Corser
Robert
R
Chang
Cherry
C
Hoyle
Christine
C
Parker
Anne N
AN
Hasan
Syed K
SK
Lo-Coco
Francesco
F
Solomon
Ellen
E
Grimwade
David
D
D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics* / Q000378:metabolism; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics; D015473:Leukemia, Promyelocytic, Acute / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D008942:Mitoxantrone / Q000494:pharmacology; D016609:Neoplasms, Second Primary / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D040641:Quantitative Trait Loci; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic / Q000187:drug effects*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D059005:Topoisomerase II Inhibitors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D015251:Epirubicin; D008942:Mitoxantrone; D004250:DNA Topoisomerases, Type II