Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Antibiotics, Antineoplastic / administration & dosage
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Antibiotics, Antineoplastic / adverse effects*
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism
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Chromosomes, Human, Pair 15 / genetics*
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Chromosomes, Human, Pair 15 / metabolism
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Chromosomes, Human, Pair 17 / genetics*
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Chromosomes, Human, Pair 17 / metabolism
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DNA Damage / drug effects
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DNA Damage / genetics
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DNA Topoisomerases, Type II / genetics
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DNA Topoisomerases, Type II / metabolism
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Epirubicin / administration & dosage
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Epirubicin / adverse effects*
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Female
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Humans
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Introns / genetics
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Leukemia, Promyelocytic, Acute / chemically induced
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Leukemia, Promyelocytic, Acute / genetics*
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Leukemia, Promyelocytic, Acute / metabolism
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Middle Aged
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Mitoxantrone / pharmacology
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Neoplasms, Second Primary / chemically induced
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Neoplasms, Second Primary / genetics*
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Neoplasms, Second Primary / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Promyelocytic Leukemia Protein
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Quantitative Trait Loci
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / metabolism
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Retinoic Acid Receptor alpha
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Topoisomerase II Inhibitors
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Translocation, Genetic / drug effects*
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
Substances
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Antibiotics, Antineoplastic
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Nuclear Proteins
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Promyelocytic Leukemia Protein
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RARA protein, human
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Receptors, Retinoic Acid
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Retinoic Acid Receptor alpha
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Topoisomerase II Inhibitors
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Transcription Factors
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Tumor Suppressor Proteins
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PML protein, human
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Epirubicin
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Mitoxantrone
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DNA Topoisomerases, Type II