Original Article
DNA Topoisomerase II in Therapy-Related Acute Promyelocytic Leukemia
N Engl J Med 2005; 352:1529-1538April 14, 2005
- Abstract
Background
Chromosomal translocations leading to chimeric oncoproteins are important in leukemogenesis, but how they form is unclear. We studied acute promyelocytic leukemia (APL) with the t(15;17) translocation that developed after treatment of breast or laryngeal cancer with chemotherapeutic agents that poison topoisomerase II.
Methods
We used long-range polymerase chain reaction and sequence analysis to characterize t(15;17) genomic breakpoints in therapy-related APL. To determine whether topoisomerase II was directly involved in mediating breaks of double-stranded DNA at the observed translocation breakpoints, we used a functional in vitro assay to examine topoisomerase II–mediated cleavage in the normal homologues of the PML and RARA breakpoints.
Results
Translocation breakpoints in APL that developed after exposure to mitoxantrone, a topoisomerase II poison, were tightly clustered in an 8-bp region within PML intron 6. In functional assays, this “hot spot” and the corresponding RARA breakpoints were common sites of mitoxantrone-induced cleavage by topoisomerase II. Etoposide and doxorubicin also induced cleavage by topoisomerase II at the translocation breakpoints in APL arising after exposure to these agents. Short, homologous sequences in PML and RARA suggested the occurrence of DNA repair by means of the nonhomologous end-joining pathway.
Conclusions
Drug-induced cleavage of DNA by topoisomerase II mediates the formation of chromosomal translocation breakpoints in mitoxantrone-related APL and in APL that occurs after therapy with other topoisomerase II poisons.
Media in This Article
Figure 1
Identification of a Breakpoint Hot Spot in PML Intron 6 in Mitoxantrone-Related APL.Figure 2
Genomic Breakpoint Junction Sequences in APL Arising after Exposure to Mitoxantrone.Article Activity
- Article
Acute myeloid leukemia (AML) is commonly associated with reciprocal balanced chromosomal translocations that underlie the formation of chimeric proteins that have key roles in the development of leukemia.1,2 The most frequent translocation, t(15;17)(q22;q21), occurs in 10 to 15 percent of cases of AML1 and is the hallmark of acute promyelocytic leukemia (APL). This translocation creates the PML-RARA and RARA-PML fusion genes.3 The resultant PML-RARα fusion protein determines not only the phenotype of APL but also the response of APL to all-trans-retinoic acid and arsenic trioxide treatment.3,4
The transforming function of leukemia-associated fusion proteins has been widely studied, but little is known about the mechanisms that cause the underlying translocations. Insights can be gained from investigations of therapy-related leukemias, all of which have counterparts in primary leukemias. Exposure to drugs that poison topoisomerase II — the anthracyclines daunorubicin, doxorubicin, and epirubicin; the anthracenedione mitoxantrone; and epipodophyllotoxins such as etoposide — predisposes patients to secondary leukemias with balanced chromosomal rearrangements, including MLL translocations involving band 11q23, t(8;21), inv(16), t(15;17), t(9;22), and NUP98 translocations involving band 11p15.5-7 The association of such chromosomal rearrangements with exposure to drugs that affect topoisomerase II suggests a role for topoisomerase II–mediated cleavage of DNA in forming translocations, but how this occurs remains to be established.
Topoisomerase II relaxes supercoiled DNA by cleaving and religating both strands of the double helix through the formation of a transient covalent cleavage intermediate.8 Chemotherapeutic drugs termed “topoisomerase II poisons” convert topoisomerase II into a DNA-damaging enzyme. They disrupt the cleavage–religation equilibrium and thereby increase the concentration of topoisomerase II–mediated cleavage complexes.8 Although the enzyme does not have a known DNA recognition sequence that it is most likely to target, genomic sequencing studies have suggested possible binding sites for the enzyme at translocation breakpoints in primary and treatment-related leukemias with MLL, AML1-ETO, PML-RARA, and NUP98 rearrangements.9-15
In early studies, less than 5 percent of APL cases were a consequence of chemotherapy,16,17 but more recently, the European APL group reported that therapy-related APL accounted for 22 percent of all cases.17 The rising incidence of therapy-related APL parallels the increased use of topoisomerase II poisons, particularly in the treatment of breast cancer. APL with t(15;17) is one of the most frequent secondary cancers that arise after the treatment of breast cancer17-20; mitoxantrone has been implicated in almost half these cases.17,19,20 In the present study, we examined genomic breakpoint regions in patients with APL after exposure to topoisomerase II poisons, particularly mitoxantrone, and used functional assays to gain further insight into mechanisms underlying the formation of the t(15;17) chromosomal translocation.
Methods
Patients and Samples
Genomic breakpoint locations in PML and RARA genes were studied in six patients with therapy-related APL, which arose after mitoxantrone treatment for breast carcinoma (in five) or multiple sclerosis (in one). To determine whether breakpoint clustering in PML intron 6 detected in mitoxantrone-related APL was statistically significant, a comparison was made with breakpoint locations in 7 patients with secondary APL arising after other types of exposure, mostly radiotherapy, and in 35 patients with primary APL. Chromosomal breakpoint mechanisms were subsequently investigated with the use of functional topoisomerase II cleavage assays in four of the patients with mitoxantrone-related cases (Patients 1 through 4) and an additional patient (Patient 5) with secondary APL that developed after exposure to doxorubicin and etoposide (Table 1Table 1
Characteristics of Five Patients with APL Arising after Exposure to Topoisomerase II Poisons.). All patients gave written informed consent, in accordance with the Declaration of Helsinki.Characterization of Genomic Breakpoints
Three breakpoint regions have been identified within the PML locus in APL: intron 3 (bcr3), exon 6 (bcr2), and intron 6 (bcr1); virtually all breakpoints in RARA occur in intron 2.21 The breakpoint pattern in PML was determined by nested reverse-transcriptase polymerase chain reaction (RT-PCR)22; appropriate primers were used to amplify the sequences of genomic breakpoint junctions by long-range or “bubble” PCR, and the PCR products were sequenced.21 Breakpoint junction sequences obtained in this way were confirmed by a patient-specific breakpoint PCR with the use of a fresh aliquot of genomic DNA as template.
In Vitro Topoisomerase II Cleavage Assays
We examined DNA fragments of the normal homologues of PML (GenBank accession numbers S51489 and S57791) and RARA (GenBank accession numbers AF088889 and AJ297538) that encompassed the relevant translocation breakpoints using an in vitro topoisomerase II cleavage assay.23 Substrate DNA was incubated with human topoisomerase IIα in the presence of ATP and exposed to drugs that target topoisomerase II. Final concentrations of etoposide, etoposide catechol, etoposide quinone, and mitoxantrone were 20 μM24; we selected a final concentration of doxorubicin of 25 nM on the basis of a titration using concentrations between 1 nM and 200 nM (data not shown). Cleavage complexes were irreversibly trapped on the addition of sodium dodecyl sulfate, and cleavage products were resolved in a gel containing 8 percent polyacrylamide and 7.0 M urea alongside a DNA-sequencing ladder. This procedure allowed us to map cleavage sites precisely at the sequence level and to analyze the positions of the cleavage sites with respect to translocation breakpoint sites. Cleavage products were visualized by means of autoradiography and quantified with the use of a Phosphorimager and IMAGEQUANT software (Molecular Dynamics).
Statistical Analysis
The significance of the putative mitoxantrone cluster in cases of therapy-related APL or primary plus therapy-related APL was assessed with the use of scan statistics,25 which have been used widely for the assessment of spatial and temporal clustering of events.26 Generally, they are based on the maximal number of events occurring in a prescribed region or interval. This statistic is then referenced against a uniform (null) distribution (over the entire region or period) reflecting the absence of clustering. In the case of translocation breakpoint clustering, the event is the occurrence of a breakpoint, the interval is the number of base pairs spanning the putative cluster, and the reference interval is the relevant intron length.25 Because the distribution of the scan statistic is exceedingly complex, a number of approximations have been developed. Here, we used the accurate, end-point–corrected, large-deviation approximation to the one-dimensional scan statistic.27
Results
Identification of a Translocation Breakpoint Hot Spot in Mitoxantrone-Related APL
Genomic breakpoint junction sequences on the derivative (der) chromosomes 15 and 17 were characterized in APL that arose after mitoxantrone-based treatment for breast cancer in five patients and mitoxantrone treatment for multiple sclerosis in one patient. Remarkably, the der(15) and der(17) PML breakpoints in four of these patients (Patients 1, 2, 3, and 4) (Table 1) were tightly clustered in an 8-bp region (positions 1482 to 1489; GenBank accession number S57791) in PML intron 6 (Figure 1Figure 1
Identification of a Breakpoint Hot Spot in PML Intron 6 in Mitoxantrone-Related APL. and Figure 2Figure 2Genomic Breakpoint Junction Sequences in APL Arising after Exposure to Mitoxantrone.), a result consistent with the presence of a hot spot of DNA damage. Scan statistics indicated that the clustered breakpoints within an intron longer than 1 kb were unlikely to have arisen by chance (P<0.001 for the comparison with 7 cases of APL related to other therapy, P<0.05 for the comparison with the 7 other therapy-related cases plus 35 cases of primary APL, and P<0.05 for the comparison with the 35 cases of primary APL alone).In contrast to the clustering of the PML breakpoints in cases of mitoxantrone-related APL, the RARA breakpoints were dispersed (Table 1 and Figure 2). Study of the der(15) and der(17) sequences in the four patients with mitoxantrone-related cases associated with the hot spot indicated that the breakpoint junctions were formed without the gain or loss of any bases relative to the native PML and RARA sequences (Figure 2). The short sequence homologies between PML and RARA (underlined in Figure 2) are characteristic of DNA repair by the nonhomologous end-joining pathway (NHEJ),28 which requires minimal overlapping sequences between nonhomologous chromosomes to repair breaks in double-stranded DNA.
Site of Functional Topoisomerase II–Mediated Cleavage at the PML Intron 6 Translocation Breakpoint Hot Spot
We evaluated topoisomerase II–mediated cleavage of the normal homologue of the PML translocation breakpoint hot spot in vitro using a 268-bp double-stranded DNA substrate encompassing the 8-bp hot spot in the presence of mitoxantrone, etoposide or its catechol, or quinone metabolites and in the absence of these agents.24 Few cleavage sites were observed in the absence of drug (Figure 3AFigure 3
Functional Topoisomerase II Cleavage Sites at Mitoxantrone-Associated Translocation Breakpoints.). Bands of various sizes and intensities showed where cleavage sites were enhanced by the different agents (Figure 3A).The 8-bp translocation breakpoint hot spot at positions 1482 to 1489 corresponded to a topoisomerase II–mediated cleavage site at position 1484, where the position indicates the base immediately 5' to the cleavage (–1 position). Cleavage at position 1484 was detected in the absence of drug, but it was markedly enhanced by etoposide, both etoposide metabolites, and mitoxantrone. Position 1484 was a preferred site of cleavage by topoisomerase II in the presence of mitoxantrone, as evidenced by the intensity of the cleavage band (Figure 3A). Mitoxantrone-induced cleavage was enhanced by a factor of 8.9 and 2.5, respectively, relative to cleavage at this site without drug or in the presence of etoposide. Cleavage at many sites decreased substantially or was eliminated after heating (Figure 3A). By contrast, the mitoxantrone-induced cleavage at position 1484 remained detectable after heating (Figure 3A), indicating stability of the cleavage complexes. These results show that the PML intron 6 translocation breakpoint hot spot in mitoxantrone-related APL is a preferred and stable mitoxantrone-induced site of cleavage by topoisomerase II.
RARA Translocation Breakpoints in Mitoxantrone-Related APL
We performed in vitro topoisomerase II cleavage assays on double-stranded DNA substrates spanning the normal homologues of the RARA translocation breakpoints in Patients 1, 2, 3, and 4 to determine whether topoisomerase II also mediated the breakage at the RARA locus (Figure 3B and Table 1). In Patient 1 (Figure 3B), topoisomerase II–mediated cleavage was observed at position 2695 of the RARA intron 2 proximal to the der(15) and der(17) RARA translocation breakpoints and was heat-stable (Figure 3B). The RARA breakpoints on both derivative chromosomes in specimens from Patients 2, 3, and 4 were also at, or proximal to, sites of functional mitoxantrone-induced cleavage by topoisomerase II (Table 1). Assays on all substrates were repeated, and the repeated assays confirmed these results.
Sites of Mitoxantrone-Induced Cleavage by Topoisomerase II and t(15;17) Breakpoint Junctions
We used the functional sites of topoisomerase II–mediated cleavage of DNA at the translocation breakpoints to generate a model for the formation of the t(15;17), incorporating known repair mechanisms of breaks in double-stranded DNA. Figure 4Figure 4
Model of the Formation of der(15) and der(17) Breakpoint Junctions in APL in Patient 1. shows how recombination of mitoxantrone-enhanced cleavage sites at PML position 1484 and RARA position 2695 would form the der(15) and der(17) genomic breakpoint junctions identified in the APL in Patient 1. The sites of topoisomerase II–mediated cleavage of each DNA strand are four bases apart, thereby creating 5' overhangs,8 as shown in Figure 4. In the model, repair of the overhangs in PML and RARA entails exonucleolytic digestion, pairing of complementary bases, and joining of the DNA free ends by means of the NHEJ pathway, with template-directed polymerization to fill in any gaps. Models were also generated showing that mitoxantrone-induced cleavage by topoisomerase II formed the der(15) and der(17) breakpoint junctions in the leukemias in Patients 2, 3, and 4 (data not shown).PML and RARA Translocation Breakpoints in Etoposide- and Doxorubicin-Related APL
A fifth patient (Patient 5) received a diagnosis of APL after being treated with etoposide and doxorubicin for laryngeal cancer (Table 1). Study of the breakpoint junction sequences indicated that the translocation occurred with the loss of a single G nucleotide from RARA (position 16089) (Figure 1A in the Supplementary Appendix, available with the full text of this article at www.nejm.org). Short sequence homologies were observed in PML and RARA characteristic of DNA repair by the NHEJ pathway. In the in vitro assay, etoposide, its catechol and quinone metabolites, and doxorubicin induced topoisomerase II–mediated cleavage at the PML and RARA translocation breakpoints. Cleavage was shown to be heat-stable with each of these drugs at the PML breakpoint (Figure 1B in the Supplementary Appendix) and with etoposide quinone at the RARA breakpoint (Figure 1C in the Supplementary Appendix). A model (Figure 1D in the Supplementary Appendix) indicated how recombination of cleavage sites at PML position 1239 and RARA position 16089 would form the der(15) and der(17) genomic breakpoint junctions in this case of APL.
Discussion
Leukemia characterized by balanced translocations, including t(15;17), can be a complication of treatment with anticancer drugs that poison topoisomerase II.29,30 The mechanism by which these drugs predispose patients to leukemia remains in dispute. Some evidence supports a direct role for topoisomerase II in causing the DNA damage that leads to chromosomal rearrangements.6,23,24,31 An indirect mechanism involving the induction of apoptosis-inducing nucleases has also been proposed.32-35
Few genomic breakpoint junctions have been characterized in therapy-related APL.36 Our study of the der(15) and der(17) genomic breakpoint junctions in APL arising after mitoxantrone treatment revealed clustering of breakpoints in the PML gene within an 8-bp region in intron 6, a result consistent with the existence of a translocation breakpoint hot spot. The PML-RARA rearrangements occurred without the gain or loss of any bases relative to the native genes, indicating that the translocation breakpoints in intron 6 were the sites of DNA damage.24 Interestingly, one patient (Patient 3) received only 15 mg of mitoxantrone. This finding is consistent with the absence of a dose–response effect in the development of leukemia that follows epipodophyllotoxin treatment37 and the detection of a leukemia-associated MLL translocation after a low total dose of doxorubicin.38
The mitoxantrone-related PML translocation breakpoint hot spot corresponded with a preferred site of topoisomerase II–mediated cleavage that was not religated after heating. In vitro, mitoxantrone stimulated cleavage at the translocation breakpoint hot spot that was nine times that observed in the absence of the drug. The RARA translocation breakpoints in each of the four patients with mitoxantrone-related APL investigated by functional assays were also found to correspond to mitoxantrone-induced sites of cleavage of DNA by topoisomerase II. Models were devised in which recombination of broken DNA at sites of topoisomerase II–mediated cleavage formed the der(15) and der(17) breakpoint junctions. These studies indicate that mitoxantrone induces cleavage of PML and RARA by topoisomerase II and that this cleavage resulted in the observed translocation breakpoint junctions in mitoxantrone-related APL.
To determine whether topoisomerase II–mediated cleavage is relevant to other drugs in therapy-related APL, we evaluated a patient in whom APL developed after exposure to etoposide and doxorubicin. Etoposide and its metabolites and doxorubicin induced topoisomerase II to cleave DNA at the PML and RARA translocation breakpoints. The cleavage sites could recombine to form the der(15) and der(17) breakpoint junctions observed in this patient. These results suggest that topoisomerase II–mediated cleavage is a general mechanism causing DNA damage in APL that develops after treatment with various agents that target topoisomerase II.
Recent reports of treatment-related APL indicate that epirubicin and mitoxantrone are the most common antecedent drugs and that a substantial proportion of the patients had breast cancer.17-19 Although etoposide is implicated in some cases of treatment-related APL,17-19,36 this drug is more often associated with MLL translocations that disrupt band 11q23.30,39 These observations suggest that different chemotherapeutic agents predispose patients to different translocations. A key question is how such specificity is conferred. Our in vitro assays show that mitoxantrone and etoposide or its metabolites stimulate topoisomerase II to cleave different sites in PML and RARA, implying the existence of different genomic hot spots for topoisomerase II–mediated cleavage in the presence of the different drugs. It is likely that such hot spots occur throughout the genome but that only translocations that confer a proliferative or survival advantage in an appropriate hematopoietic progenitor lead to leukemia. The identification of this translocation mechanism has important implications for the chemotherapy of cancer.
Dr. Mistry was supported by a Medical Research Council studentship and the Generation Trust, Department of Medical and Molecular Genetics, Guy's, King's, and St. Thomas' School of Medicine, and a travel award from the British Society for Haematology. Dr. Felix and Dr. Blair were supported by a grant from the National Institutes of Health (R01 CA77683). Dr. Felix was supported by grants (R01 CA80175, R0185469) from the National Institutes of Health, a Leukemia and Lymphoma Society Translational Research Award, a Leukemia and Lymphoma Society Specialized Center of Research grant, the Joshua Kahan Foundation, and the Friends of the Joseph Claffey Fund. Dr. Felix was also supported in part by a grant from the Pennsylvania Department of Health. The views expressed in this article are those of the authors and do not necessarily represent the views of the Pennsylvania Department of Health. Drs. Grimwade, Cross, and Mason were supported by the Leukaemia Research Fund of Great Britain. Dr. Reiter and Mr. Walz were supported by the Forschungsfonds der Fakultät für Klinische Medizin Mannheim der Universität Heidelberg and the German Bundesminister für Bildung und Forschung through the Kompetenznetz “Akute und chronische Leukämien” (Förderkennzeichen: 01GI0270). Dr. Wiemels is a Scholar of the Leukemia and Lymphoma Society, and Drs. Wiemels and Segal were supported by a grant (CA89032) from the National Institutes of Health. Dr. Osheroff was supported by a grant (GM33944) from the National Institutes of Health.
We are indebted to Jo Ann Byl for preparing the human topoisomerase IIα used in this study.
Source Information
From the Department of Medical and Molecular Genetics, Guy's, King's, and St. Thomas' School of Medicine, London (A.R.M., A.M., E.S., D.G.); the Division of Oncology, Children's Hospital of Philadelphia, Philadelphia (C.A.F., R.J.W.); the Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia (C.A.F.); Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany (A.R., C.W.); Unité de Biologie Cellulaire, Service de Médecine Nucléaire, Hôpital St. Louis, Paris (B.C., A.P., C.C.); the Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco (J.L.W., M.R.S.); Hôpital Avicenne–Paris 13 Université, Bobigny, France (L.A., P.F.); the Center for Cancer Pharmacology, University of Pennsylvania, Philadelphia (I.A.B.); the Departments of Biochemistry and Medicine, Vanderbilt University School of Medicine, Nashville (N.O.); the Department of Haematology, John Radcliffe Hospital, Oxford, United Kingdom (A.J.P.); Institut Paoli-Calmettes, INSERM UMR 599, and Université de la Méditerranée, Marseille, France (M.L.-P.); Wessex Regional Genetics Laboratory, Salisbury, United Kingdom (N.C.P.C.); and the Department of Haematology, University College London Hospitals, London (D.G.).
Address reprint requests to Dr. Grimwade at the Cancer Genetics Laboratory, Department of Medical and Molecular Genetics, 8th Fl., Guy's Tower, Guy's Hospital, London SE1 9RT, United Kingdom, or at david.grimwade@genetics.kcl.ac.uk.
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