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Palmieri R, Paterno G, Mallegni F, Frenza F, De Bernardis I, Moretti F, Meddi E, Del Principe MI, Maurillo L, Venditti A, Buccisano F. Therapy-related Myeloid Neoplasms: Considerations for Patients' Clinical Evaluation. Mediterr J Hematol Infect Dis 2023; 15:e2023051. [PMID: 37705524 PMCID: PMC10497317 DOI: 10.4084/mjhid.2023.051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 08/11/2023] [Indexed: 09/15/2023] Open
Abstract
Therapy-related myeloid neoplasms (t-MNs) encompass a specific sub-group of myeloid malignancies arising after exposure to radio/cytotoxic agents for the treatment of unrelated diseases. Such malignancies present unique features, including advanced age, high comorbidities burden, and unfavorable genetic profiles. All these features justify the need for a specific diagnostic work-up and dedicated treatment algorithms. However, as new classification systems recognize the unique clinical characteristics exhibited by t-MN patients, how to assess fitness status in this clinical setting is largely unexplored. Optimizing fitness assessment would be crucial in the management of t-MN patients, considering that factors usually contributing to a worse or better outcome (like age, comorbidities, and treatment history) are patient-specific. In the absence of specific tools for fitness assessment in this peculiar category of AML, the aim of this review is to describe all those factors related to patient, treatment, and disease that allow planning treatments with an optimal risk/benefit ratio.
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Affiliation(s)
- Raffaele Palmieri
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle (WA), USA
| | | | - Flavia Mallegni
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Federica Frenza
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Ilenia De Bernardis
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Federico Moretti
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Elisa Meddi
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | | | - Luca Maurillo
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Adriano Venditti
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Francesco Buccisano
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
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Dauda SE, Collins JA, Byl JAW, Lu Y, Yalowich JC, Mitton-Fry MJ, Osheroff N. Actions of a Novel Bacterial Topoisomerase Inhibitor against Neisseria gonorrhoeae Gyrase and Topoisomerase IV: Enhancement of Double-Stranded DNA Breaks. Int J Mol Sci 2023; 24:12107. [PMID: 37569485 PMCID: PMC10419083 DOI: 10.3390/ijms241512107] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/18/2023] [Accepted: 07/25/2023] [Indexed: 08/13/2023] Open
Abstract
Novel bacterial topoisomerase inhibitors (NBTIs) are an emerging class of antibacterials that target gyrase and topoisomerase IV. A hallmark of NBTIs is their ability to induce gyrase/topoisomerase IV-mediated single-stranded DNA breaks and suppress the generation of double-stranded breaks. However, a previous study reported that some dioxane-linked amide NBTIs induced double-stranded DNA breaks mediated by Staphylococcus aureus gyrase. To further explore the ability of this NBTI subclass to increase double-stranded DNA breaks, we examined the effects of OSUAB-185 on DNA cleavage mediated by Neisseria gonorrhoeae gyrase and topoisomerase IV. OSUAB-185 induced single-stranded and suppressed double-stranded DNA breaks mediated by N. gonorrhoeae gyrase. However, the compound stabilized both single- and double-stranded DNA breaks mediated by topoisomerase IV. The induction of double-stranded breaks does not appear to correlate with the binding of a second OSUAB-185 molecule and extends to fluoroquinolone-resistant N. gonorrhoeae topoisomerase IV, as well as type II enzymes from other bacteria and humans. The double-stranded DNA cleavage activity of OSUAB-185 and other dioxane-linked NBTIs represents a paradigm shift in a hallmark characteristic of NBTIs and suggests that some members of this subclass may have alternative binding motifs in the cleavage complex.
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Affiliation(s)
- Soziema E. Dauda
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Jessica A. Collins
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Jo Ann W. Byl
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Yanran Lu
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
| | - Jack C. Yalowich
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 42310, USA
| | - Mark J. Mitton-Fry
- Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
| | - Neil Osheroff
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA
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Vann KR, Oviatt AA, Osheroff N. Topoisomerase II Poisons: Converting Essential Enzymes into Molecular Scissors. Biochemistry 2021; 60:1630-1641. [PMID: 34008964 PMCID: PMC8209676 DOI: 10.1021/acs.biochem.1c00240] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The extensive length, compaction, and interwound nature of DNA, together with its controlled and restricted movement in eukaryotic cells, create a number of topological issues that profoundly affect all of the functions of the genetic material. Topoisomerases are essential enzymes that modulate the topological structure of the double helix, including the regulation of DNA under- and overwinding and the removal of tangles and knots from the genome. Type II topoisomerases alter DNA topology by generating a transient double-stranded break in one DNA segment and allowing another segment to pass through the DNA gate. These enzymes are involved in a number of critical nuclear processes in eukaryotic cells, such as DNA replication, transcription, and recombination, and are required for proper chromosome structure and segregation. However, because type II topoisomerases generate double-stranded breaks in the genetic material, they also are intrinsically dangerous enzymes that have the capacity to fragment the genome. As a result of this dualistic nature, type II topoisomerases are the targets for a number of widely prescribed anticancer drugs. This article will describe the structure and catalytic mechanism of eukaryotic type II topoisomerases and will go on to discuss the actions of topoisomerase II poisons, which are compounds that stabilize DNA breaks generated by the type II enzyme and convert these essential enzymes into "molecular scissors." Topoisomerase II poisons represent a broad range of structural classes and include anticancer drugs, dietary components, and environmental chemicals.
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Affiliation(s)
- Kendra R Vann
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Alexandria A Oviatt
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Neil Osheroff
- Departments of Biochemistry and Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
- VA Tennessee Valley Healthcare System, Nashville, Tennessee 37212, United States
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Hikita K, Yamakage Y, Okunaga H, Motoyama Y, Matsuyama H, Matsuoka K, Murata T, Nakayoshi T, Oda A, Kato K, Tanaka H, Asao N, Dan S, Kaneda N. (S)-Erypoegin K, an isoflavone isolated from Erythrina poeppigiana, is a novel inhibitor of topoisomerase IIα: Induction of G2 phase arrest in human gastric cancer cells. Bioorg Med Chem 2020; 30:115904. [PMID: 33341500 DOI: 10.1016/j.bmc.2020.115904] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/26/2020] [Accepted: 11/27/2020] [Indexed: 10/22/2022]
Abstract
Erypoegin K, an isoflavone isolated from the stem bark of Erythrina poeppigiana, has a single chiral carbon in its structure and exists naturally as a racemic mixture. Our previous study showed (S)-erypoegin K selectively exhibits potent anti-proliferative and apoptosis-inducing activity against human leukemia HL-60 cells. To identify the target molecule of (S)-erypoegin K, we employed the human cancer cell panel analysis (termed JFCR39) coupled with a drug sensitivity database of pharmacologically well-characterized drugs for comparison using the COMPARE algorithm. (S)-erypoegin K exhibited a similar profile to that of etoposide, suggesting the molecular target for erypoegin K may be topoisomerase II (Topo II). Subsequent experiments using purified human Topo IIα established that the (S)-isomer selectively stabilizes the cleavage complex composed of double-stranded plasmid DNA and the enzyme. Moreover, (S)-erypoegin K inhibited decatenation of kinetoplast DNA. Molecular docking studies clearly indicated specific binding of the (S)-isomer to the active site of Topo IIα involving hydrogen bonds that help stabilize the cleavage complex. (S)-erypoegin K displayed potent cytotoxic activity against two human gastric cancer cells GCIY and MKN-1 with IC50 values of 0.270 and 0.327 μM, respectively, and induced enzyme activities of caspase 3 and 9. Cell cycle analysis showed marked cell cycle arrest at G2 phase in both cell lines. (S)-erypoegin K also displayed significant antitumor activity toward GCIY xenografted mice. The present study suggests (S)-erypoegin K acts as a Topo II inhibitor to block the G2/M transition of cancer cells.
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Affiliation(s)
- Kiyomi Hikita
- Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
| | - Yuko Yamakage
- Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
| | - Honoka Okunaga
- Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
| | - Yui Motoyama
- Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
| | - Haruka Matsuyama
- Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
| | - Kenta Matsuoka
- Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
| | - Tomiyasu Murata
- Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
| | - Tomoki Nakayoshi
- Laboratory of Biophysical Chemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
| | - Akifumi Oda
- Laboratory of Biophysical Chemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
| | - Kuniki Kato
- Chubu TLO, Nagoya Industrial Science Research Institute, VBL, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603, Japan
| | - Hitoshi Tanaka
- Laboratory of Natural Product Chemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
| | - Naoki Asao
- Advanced Institute for Materials Research, Tohoku University, 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan; Division of Chemistry and Materials, Graduate School of Science and Technology, Shinshu University, Ueda, Nagano 386-8567, Japan
| | - Shingo Dan
- Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Norio Kaneda
- Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan.
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Tiruneh T, Enawgaw B, Shiferaw E. Genetic Pathway in the Pathogenesis of Therapy-Related Myeloid Neoplasms: A Literature Review. Oncol Ther 2020; 8:45-57. [PMID: 32700075 PMCID: PMC7360004 DOI: 10.1007/s40487-020-00111-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Indexed: 12/20/2022] Open
Abstract
Therapy-related myeloid neoplasms are a life-threatening and often fatal complication, associated with poor prognosis outcomes and with high-risk unfavorable cytogenetic abnormalities including complex karyotype. They occur after the treatment of primary malignancies using chemotherapy and/or radiation therapy. Such therapy is not specific to cancer cells, and also damages the deoxyribonucleic acid (DNA) of normal cells, resulting in unbalanced and balanced translocations. There are eight genetic pathways, whose details are summarized in this review, depending on the cytogenetic abnormalities induced. This abnormality is the major contributor to the development of therapy-related myeloid neoplasms. The etiology of these neoplasms depends on the complex interaction between the nature and dose of the cytotoxic agent, the environment, and the presence of subsequent inherited mutations. This review aims to elaborate upon recent knowledge regarding the etiology, pathogenesis, and genetic pathways of therapy-related myeloid neoplasms. A deeper understanding of their etiology would aid physicians in more careful monitoring of patients during or after cytotoxic therapy for hematological malignancy. Ultimately, this knowledge could influence initial treatment strategies, with the aim of reducing both the incidence and serious complications of neoplasms. Therefore, early detection of DNA lesions is vital. The authors recommend that primary malignancy be treated with targeted therapy.
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Affiliation(s)
- Tegenaw Tiruneh
- Department Hematology and Immunohematology, College of Medicine and Health Sciences, Debre Tabor University, Debre Tabor, Ethiopia. .,School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia.
| | - Bamlaku Enawgaw
- School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Elias Shiferaw
- School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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Infante Lara L, Fenner S, Ratcliffe S, Isidro-Llobet A, Hann M, Bax B, Osheroff N. Coupling the core of the anticancer drug etoposide to an oligonucleotide induces topoisomerase II-mediated cleavage at specific DNA sequences. Nucleic Acids Res 2018; 46:2218-2233. [PMID: 29447373 PMCID: PMC5861436 DOI: 10.1093/nar/gky072] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 01/18/2018] [Accepted: 02/06/2018] [Indexed: 12/13/2022] Open
Abstract
Etoposide and other topoisomerase II-targeted drugs are important anticancer therapeutics. Unfortunately, the safe usage of these agents is limited by their indiscriminate induction of topoisomerase II-mediated DNA cleavage throughout the genome and by a lack of specificity toward cancer cells. Therefore, as a first step toward constraining the distribution of etoposide-induced DNA cleavage sites and developing sequence-specific topoisomerase II-targeted anticancer agents, we covalently coupled the core of etoposide to oligonucleotides centered on a topoisomerase II cleavage site in the PML gene. The initial sequence used for this 'oligonucleotide-linked topoisomerase inhibitor' (OTI) was identified as part of the translocation breakpoint of a patient with acute promyelocytic leukemia (APL). Subsequent OTI sequences were derived from the observed APL breakpoint between PML and RARA. Results indicate that OTIs can be used to direct the sites of etoposide-induced DNA cleavage mediated by topoisomerase IIα and topoisomerase IIβ. OTIs increased levels of enzyme-mediated cleavage by inhibiting DNA ligation, and cleavage complexes induced by OTIs were as stable as those induced by free etoposide. Finally, OTIs directed against the PML-RARA breakpoint displayed cleavage specificity for oligonucleotides with the translocation sequence over those with sequences matching either parental gene. These studies demonstrate the feasibility of using oligonucleotides to direct topoisomerase II-mediated DNA cleavage to specific sites in the genome.
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MESH Headings
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology
- Base Sequence
- DNA Cleavage/drug effects
- DNA Topoisomerases, Type II/metabolism
- Etoposide/chemistry
- Etoposide/pharmacology
- Feasibility Studies
- Humans
- Leukemia, Promyelocytic, Acute/drug therapy
- Leukemia, Promyelocytic, Acute/genetics
- Leukemia, Promyelocytic, Acute/metabolism
- Oligonucleotides/chemistry
- Oligonucleotides/pharmacology
- Oncogene Proteins, Fusion/antagonists & inhibitors
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism
- Topoisomerase II Inhibitors/chemistry
- Topoisomerase II Inhibitors/pharmacology
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Affiliation(s)
- Lorena Infante Lara
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA
| | - Sabine Fenner
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
| | - Steven Ratcliffe
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
| | - Albert Isidro-Llobet
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
| | - Michael Hann
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
| | - Ben Bax
- Platform Technology and Science, GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
- York Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5DD, UK
| | - Neil Osheroff
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA
- Department of Medicine (Hematology/Oncology), Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- VA Tennessee Valley Healthcare System, Nashville, TN 37212, USA
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Kremer B, Tsai DE, Debonera F, Cohen PL, Schuster SJ. Spontaneous remission of acute myeloid leukemia after discontinuation of lenalidomide. Leuk Lymphoma 2017; 59:743-745. [DOI: 10.1080/10428194.2017.1347652] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Brandon Kremer
- Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Donald E. Tsai
- Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Fotini Debonera
- Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Patti L. Cohen
- Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Stephen J. Schuster
- Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
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Bertuccio SN, Serravalle S, Astolfi A, Lonetti A, Indio V, Leszl A, Pession A, Melchionda F. Identification of a cytogenetic and molecular subgroup of acute myeloid leukemias showing sensitivity to L-Asparaginase. Oncotarget 2017; 8:109915-109923. [PMID: 29299118 PMCID: PMC5746353 DOI: 10.18632/oncotarget.18565] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 06/02/2017] [Indexed: 01/11/2023] Open
Abstract
L-Asparaginase (L-Asp) is an enzyme that catalyzes the hydrolysis of L-asparagine to L-aspartic acid, and its depletion induces leukemic cell death. L-Asp is an important component of treatment regimens for Acute Lymphoblastic Leukemia (ALL). Sensitivity to L-Asp is due to the absence of L-Asparagine synthetase (ASNS), the enzyme that catalyzes the biosynthesis of L-asparagine. ASNS gene is located on 7q21.3, and its increased expression in ALLs correlates with L-Asp resistance. Chromosome 7 monosomy (-7) is a recurrent aberration in myeloid disorders, particularly in adverse-risk Acute Myeloid Leukemias (AMLs) and therapy-related myeloid neoplasms (t-MN), that leads to a significant downregulation of the deleted genes, including ASNS. Therefore, we hypothesized that -7 could affect L-Asp sensitivity in AMLs. By treating AML cell lines and primary cells from pediatric patients with L-Asp, we showed that -7 cells were more sensitive than AML cells without -7. Importantly, both ASNS gene and protein expression were significantly lower in -7 AML cell lines, suggesting that haploinsufficiency of ASNS might induce sensitivity to L-Asp in AMLs. To prove the role of ASNS haploinsufficiency in sensitizing AML cells to L-Asp treatment, we performed siRNA-knockdown of ASNS in AML cell lines lacking -7, and observed that ASNS knockdown significantly increased L-Asp cytotoxicity. In conclusion, -7 AMLs showed high sensitivity to L-Asp treatment due to low expression of ASNS. Thus, L-Asp may be considered for treatment of AML pediatric patients carrying -7, in order to improve the outcome of adverse-risk AMLs and t-MN patients.
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Affiliation(s)
- Salvatore Nicola Bertuccio
- Pediatric Hematology and Oncology Unit, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Salvatore Serravalle
- Pediatric Hematology and Oncology Unit, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Annalisa Astolfi
- Pediatric Hematology and Oncology Unit, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.,"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy
| | - Annalisa Lonetti
- Pediatric Hematology and Oncology Unit, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Valentina Indio
- "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy
| | - Anna Leszl
- Department of Woman and Child Health, Laboratory of Hematology-Oncology, University of Padova, Padova, Italy
| | - Andrea Pession
- Pediatric Hematology and Oncology Unit, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.,"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy
| | - Fraia Melchionda
- Pediatric Hematology and Oncology Unit, Department of Pediatrics, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
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Chemical exposure and infant leukaemia: development of an adverse outcome pathway (AOP) for aetiology and risk assessment research. Arch Toxicol 2017; 91:2763-2780. [PMID: 28536863 DOI: 10.1007/s00204-017-1986-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 05/08/2017] [Indexed: 01/06/2023]
Abstract
Infant leukaemia (<1 year old) is a rare disease of an in utero origin at an early phase of foetal development. Rearrangements of the mixed-lineage leukaemia (MLL) gene producing abnormal fusion proteins are the most frequent genetic/molecular findings in infant B cell-acute lymphoblastic leukaemia. In small epidemiological studies, mother/foetus exposures to some chemicals including pesticides have been associated with infant leukaemia; however, the strength of evidence and power of these studies are weak at best. Experimental in vitro or in vivo models do not sufficiently recapitulate the human disease and regulatory toxicology studies are unlikely to capture this kind of hazard. Here, we develop an adverse outcome pathway (AOP) based substantially on an analogous disease-secondary acute leukaemia caused by the topoisomerase II (topo II) poison etoposide-and on cellular and animal models. The hallmark of the AOP is the formation of MLL gene rearrangements via topo II poisoning, leading to fusion genes and ultimately acute leukaemia by global (epi)genetic dysregulation. The AOP condenses molecular, pathological, regulatory and clinical knowledge in a pragmatic, transparent and weight of evidence-based framework. This facilitates the interpretation and integration of epidemiological studies in the process of risk assessment by defining the biologically plausible causative mechanism(s). The AOP identified important gaps in the knowledge relevant to aetiology and risk assessment, including the specific embryonic target cell during the short and spatially restricted period of susceptibility, and the role of (epi)genetic features modifying the initiation and progression of the disease. Furthermore, the suggested AOP informs on a potential Integrated Approach to Testing and Assessment to address the risk caused by environmental chemicals in the future.
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Ewing's Sarcoma as a Second Malignancy in Long-Term Survivors of Childhood Hematologic Malignancies. Sarcoma 2016; 2016:5043640. [PMID: 27524931 PMCID: PMC4976151 DOI: 10.1155/2016/5043640] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2016] [Accepted: 06/19/2016] [Indexed: 12/20/2022] Open
Abstract
Modern multimodal treatment has significantly increased survival for patients affected by hematologic malignancies, especially in childhood. Following remission, however, the risk of developing a further malignancy is an important issue. The long-term estimated risk of developing a sarcoma as a secondary malignancy is increased severalfold in comparison to the general population. Ewing's sarcoma family encompasses a group of highly aggressive, undifferentiated, intra- and extraosseous, mesenchymal tumors, caused by several types of translocations usually involving the EWSR1 gene. Translocation associated sarcomas, such as Ewing sarcoma, are only rarely encountered as therapy associated secondary tumors. We describe the clinical course and management of three patients from a single institution with Ewing's sarcoma that followed successfully treated lymphoblastic T-cell leukemia or non-Hodgkin lymphoma. The literature on secondary Ewing's sarcoma is summarized and possible pathogenic mechanisms are critically discussed.
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11
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Miles MA, Shekhar TM, Hall NE, Hawkins CJ. TRAIL causes deletions at the HPRT and TK1 loci of clonogenically competent cells. Mutat Res 2016; 787:15-31. [PMID: 26943263 DOI: 10.1016/j.mrfmmm.2016.02.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 01/05/2016] [Accepted: 02/02/2016] [Indexed: 12/22/2022]
Abstract
When chemotherapy and radiotherapy are effective, they function by inducing DNA damage in cancerous cells, which respond by undergoing apoptosis. Some adverse effects can result from collateral destruction of non-cancerous cells, via the same mechanism. Therapy-related cancers, a particularly serious adverse effect of anti-cancer treatments, develop due to oncogenic mutations created in non-cancerous cells by the DNA damaging therapies used to eliminate the original cancer. Physiologically achievable concentrations of direct apoptosis inducing anti-cancer drugs that target Bcl-2 and IAP proteins possess negligible mutagenic activity, however death receptor agonists like TRAIL/Apo2L can provoke mutations in surviving cells, probably via caspase-mediated activation of the nuclease CAD. In this study we compared the types of mutations sustained in the HPRT and TK1 loci of clonogenically competent cells following treatment with TRAIL or the alkylating agent ethyl methanesulfonate (EMS). As expected, the loss-of-function mutations in the HPRT or TK1 loci triggered by exposure to EMS were almost all transitions. In contrast, only a minority of the mutations identified in TRAIL-treated clones lacking HPRT or TK1 activity were substitutions. Almost three quarters of the TRAIL-induced mutations were partial or complete deletions of the HPRT or TK1 genes, consistent with sub-lethal TRAIL treatment provoking double strand breaks, which may be mis-repaired by non-homologous end joining (NHEJ). Mis-repair of double-strand breaks following exposure to chemotherapy drugs has been implicated in the pathogenesis of therapy-related cancers. These data suggest that TRAIL too may provoke oncogenic damage to the genomes of surviving cells.
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Affiliation(s)
- Mark A Miles
- Department of Biochemistry and Genetics, La Trobe University, Bundoora, Victoria, Australia; La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia
| | - Tanmay M Shekhar
- Department of Biochemistry and Genetics, La Trobe University, Bundoora, Victoria, Australia; La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia
| | - Nathan E Hall
- La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia; Life Sciences Computation Centre, Victorian Life Sciences Computation Initiative, Melbourne, Victoria, Australia
| | - Christine J Hawkins
- Department of Biochemistry and Genetics, La Trobe University, Bundoora, Victoria, Australia; La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria, Australia.
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12
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Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia. Blood 2015; 126:2676-85. [PMID: 26463423 DOI: 10.1182/blood-2015-09-667378] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Infant B-cell acute lymphoblastic leukemia (B-ALL) accounts for 10% of childhood ALL. The genetic hallmark of most infant B-ALL is chromosomal rearrangements of the mixed-lineage leukemia (MLL) gene. Despite improvement in the clinical management and survival (∼85-90%) of childhood B-ALL, the outcome of infants with MLL-rearranged (MLL-r) B-ALL remains dismal, with overall survival <35%. Among MLL-r infant B-ALL, t(4;11)+ patients harboring the fusion MLL-AF4 (MA4) display a particularly poor prognosis and a pro-B/mixed phenotype. Studies in monozygotic twins and archived blood spots have provided compelling evidence of a single cell of prenatal origin as the target for MA4 fusion, explaining the brief leukemia latency. Despite its aggressiveness and short latency, current progress on its etiology, pathogenesis, and cellular origin is limited as evidenced by the lack of mouse/human models recapitulating the disease phenotype/latency. We propose this is because infant cancer is from an etiologic and pathogenesis standpoint distinct from adult cancer and should be seen as a developmental disease. This is supported by whole-genome sequencing studies suggesting that opposite to the view of cancer as a "multiple-and-sequential-hit" model, t(4;11) alone might be sufficient to spawn leukemia. The stable genome of these patients suggests that, in infant developmental cancer, one "big-hit" might be sufficient for overt disease and supports a key contribution of epigenetics and a prenatal cell of origin during a critical developmental window of stem cell vulnerability in the leukemia pathogenesis. Here, we revisit the biology of t(4;11)+ infant B-ALL with an emphasis on its origin, genetics, and disease models.
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13
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Inhibition of Bcl-2 or IAP proteins does not provoke mutations in surviving cells. Mutat Res 2015; 777:23-32. [PMID: 25916945 DOI: 10.1016/j.mrfmmm.2015.04.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 03/31/2015] [Accepted: 04/07/2015] [Indexed: 11/21/2022]
Abstract
Chemotherapy and radiotherapy can cause permanent damage to the genomes of surviving cells, provoking severe side effects such as second malignancies in some cancer survivors. Drugs that mimic the activity of death ligands, or antagonise pro-survival proteins of the Bcl-2 or IAP families have yielded encouraging results in animal experiments and early phase clinical trials. Because these agents directly engage apoptosis pathways, rather than damaging DNA to indirectly provoke tumour cell death, we reasoned that they may offer another important advantage over conventional therapies: minimisation or elimination of side effects such as second cancers that result from mutation of surviving normal cells. Disappointingly, however, we previously found that concentrations of death receptor agonists like TRAIL that would be present in vivo in clinical settings provoked DNA damage in surviving cells. In this study, we used cell line model systems to investigate the mutagenic capacity of drugs from two other classes of direct apoptosis-inducing agents: the BH3-mimetic ABT-737 and the IAP antagonists LCL161 and AT-406. Encouragingly, our data suggest that IAP antagonists possess negligible genotoxic activity. Doses of ABT-737 that were required to damage DNA stimulated Bax/Bak-independent signalling and exceeded concentrations detected in the plasma of animals treated with this drug. These findings provide hope that cancer patients treated by BH3-mimetics or IAP antagonists may avoid mutation-related illnesses that afflict some cancer survivors treated with conventional DNA-damaging anti-cancer therapies.
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14
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Zhang YC, Zhou YQ, Yan B, Shi J, Xiu LJ, Sun YW, Liu X, Qin ZF, Wei PK, Li YJ. Secondary acute promyelocytic leukemia following chemotherapy for gastric cancer: a case report. World J Gastroenterol 2015; 21:4402-4407. [PMID: 25892894 PMCID: PMC4394105 DOI: 10.3748/wjg.v21.i14.4402] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Revised: 11/29/2014] [Accepted: 01/16/2015] [Indexed: 02/06/2023] Open
Abstract
Therapy-related acute myeloid leukemia (t-AML) refers to a heterogeneous group of myeloid neoplasms that develop in patients following extensive exposure to either cytotoxic agents or radiation. The development of t-AML has been reported following treatment of cancers ranging from hematological malignancies to solid tumors; however, to our knowledge, t-AML has never been reported following treatment of gastric cancer. In this study, we report the development of t-acute promyelocytic leukemia in a cT4N1M0 gastric cancer patient after an approximate 44 mo latency period following treatment with 4 cycles of oxaliplatin (OXP) (85 mg/m(2) on day 1) plus capecitabine (1250 mg/m(2) orally twice daily on days 1-14) in combination with recombinant human granulocyte-colony stimulating factor treatment. Karyotype analysis of the patient revealed 46,XY,t(15;17)(q22;q21)[15]/46,idem,-9,+add(9)(p22)[2]/46,XY[3], which, according to previous studies, includes some "favorable" genetic abnormalities. The patient was then treated with all-trans retinoic acid (ATRA, 25 mg/m(2)/d) plus arsenic trioxide (ATO, 10 mg/d) and attained complete remission. Our case illuminated the role of certain cytotoxic agents in the induction of t-AML following gastric cancer treatment. We recommend instituting a mandatory additional evaluation for patients undergoing these therapies in the future.
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MESH Headings
- Aged
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Biomarkers, Tumor/genetics
- Biopsy
- Capecitabine/adverse effects
- Granulocyte Colony-Stimulating Factor/adverse effects
- Humans
- Karyotyping
- Leukemia, Promyelocytic, Acute/chemically induced
- Leukemia, Promyelocytic, Acute/diagnosis
- Leukemia, Promyelocytic, Acute/drug therapy
- Leukemia, Promyelocytic, Acute/genetics
- Male
- Organoplatinum Compounds/adverse effects
- Oxaliplatin
- Predictive Value of Tests
- Remission Induction
- Risk Factors
- Stomach Neoplasms/drug therapy
- Tomography, X-Ray Computed
- Treatment Outcome
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15
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Singh ZN, Jethava Y, Post GR, Alapat D, Sawyer J, Waheed S, Nair B, Usmani SZ, Bailey C, Petty N, Van Rhee F, Barlogie B. Fulminant onset of acute leukemia from normal hematopoiesis within 3 months of follow up for multiple myeloma treated with total therapy protocols. Clin Case Rep 2015; 3:183-92. [PMID: 25838910 PMCID: PMC4377252 DOI: 10.1002/ccr3.180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 10/02/2014] [Accepted: 10/25/2014] [Indexed: 01/12/2023] Open
Abstract
Assiduous surveillance for genetic aberrations is necessary in patients on cytotoxic therapies to detect therapy-related myeloid neoplasms (t-MN). Current modalities include metaphase cytogenetics and FISH. Since t-MN may develop abruptly in cytogenetically normal patients, a discussion exploring additional methods such as SNP-array and targeted-deep-sequencing to detect subchromosomal abnormalities is needed.
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Affiliation(s)
- Zeba N Singh
- Department of Pathology, University of Arkansas for Medical Sciences 4301 W. Markham Street Slot 502, Little Rock, Arkansas, 72205
| | - Yogesh Jethava
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences 4301 West Markham Slot 816, Little Rock, Arkansas, 72205
| | - Ginell R Post
- Department of Pathology, University of Arkansas for Medical Sciences 4301 W. Markham Street Slot 502, Little Rock, Arkansas, 72205
| | - Daisy Alapat
- Department of Pathology, University of Arkansas for Medical Sciences 4301 W. Markham Street Slot 502, Little Rock, Arkansas, 72205
| | - Jeffrey Sawyer
- Department of Pathology, University of Arkansas for Medical Sciences 4301 W. Markham Street Slot 502, Little Rock, Arkansas, 72205
| | - Sarah Waheed
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences 4301 West Markham Slot 816, Little Rock, Arkansas, 72205
| | - Bijay Nair
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences 4301 West Markham Slot 816, Little Rock, Arkansas, 72205
| | - Saad Z Usmani
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences 4301 West Markham Slot 816, Little Rock, Arkansas, 72205
| | - Clyde Bailey
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences 4301 West Markham Slot 816, Little Rock, Arkansas, 72205
| | - Nathan Petty
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences 4301 West Markham Slot 816, Little Rock, Arkansas, 72205
| | - Frits Van Rhee
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences 4301 West Markham Slot 816, Little Rock, Arkansas, 72205
| | - Bart Barlogie
- Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences 4301 West Markham Slot 816, Little Rock, Arkansas, 72205
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16
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Smith NA, Byl JAW, Mercer SL, Deweese JE, Osheroff N. Etoposide quinone is a covalent poison of human topoisomerase IIβ. Biochemistry 2014; 53:3229-36. [PMID: 24766193 PMCID: PMC4033626 DOI: 10.1021/bi500421q] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
![]()
Etoposide is a topoisomerase II poison
that is utilized to treat
a broad spectrum of human cancers. Despite its wide clinical use,
2–3% of patients treated with etoposide eventually develop
treatment-related acute myeloid leukemias (t-AMLs) characterized by
rearrangements of the MLL gene. The molecular basis
underlying the development of these t-AMLs is not well understood;
however, previous studies have implicated etoposide metabolites (i.e.,
etoposide quinone) and topoisomerase IIβ in the leukemogenic
process. Although interactions between etoposide quinone and topoisomerase
IIα have been characterized, the effects of the drug metabolite
on the activity of human topoisomerase IIβ have not been reported.
Thus, we examined the ability of etoposide quinone to poison human
topoisomerase IIβ. The quinone induced ∼4 times more
enzyme-mediated DNA cleavage than did the parent drug. Furthermore,
the potency of etoposide quinone was ∼2 times greater against
topoisomerase IIβ than it was against topoisomerase IIα,
and the drug reacted ∼2–4 times faster with the β
isoform. Etoposide quinone induced a higher ratio of double- to single-stranded
breaks than etoposide, and its activity was less dependent on ATP.
Whereas etoposide acts as an interfacial topoisomerase II poison,
etoposide quinone displayed all of the hallmarks of a covalent poison:
the activity of the metabolite was abolished by reducing agents, and
the compound inactivated topoisomerase IIβ when it was incubated
with the enzyme prior to the addition of DNA. These results are consistent
with the hypothesis that etoposide quinone contributes to etoposide-related
leukemogenesis through an interaction with topoisomerase IIβ.
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Affiliation(s)
- Nicholas A Smith
- Departments of †Biochemistry, ‡Medicine (Hematology/Oncology), and §Pharmacology, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-0146, United States
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17
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Lo-Coco F, Hasan SK. Understanding the molecular pathogenesis of acute promyelocytic leukemia. Best Pract Res Clin Haematol 2014; 27:3-9. [DOI: 10.1016/j.beha.2014.04.006] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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18
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Ketron AC, Osheroff N. Phytochemicals as Anticancer and Chemopreventive Topoisomerase II Poisons. PHYTOCHEMISTRY REVIEWS : PROCEEDINGS OF THE PHYTOCHEMICAL SOCIETY OF EUROPE 2014; 13:19-35. [PMID: 24678287 PMCID: PMC3963363 DOI: 10.1007/s11101-013-9291-7] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Phytochemicals are a rich source of anticancer drugs and chemopreventive agents. Several of these chemicals appear to exert at least some of their effects through interactions with topoisomerase II, an essential enzyme that regulates DNA supercoiling and removes knots and tangles from the genome. Topoisomerase II-active phytochemicals function by stabilizing covalent protein-cleaved DNA complexes that are intermediates in the catalytic cycle of the enzyme. As a result, these compounds convert topoisomerase II to a cellular toxin that fragments the genome. Because of their mode of action, they are referred to as topoisomerase II poisons as opposed to catalytic inhibitors. The first sections of this article discuss DNA topology, the catalytic cycle of topoisomerase II, and the two mechanisms (interfacial vs. covalent) by which different classes of topoisomerase II poisons alter enzyme activity. Subsequent sections discuss the effects of several phytochemicals on the type II enzyme, including demethyl-epipodophyllotoxins (semisynthetic anticancer drugs) as well as flavones, flavonols, isoflavones, catechins, isothiocyanates, and curcumin (dietary chemopreventive agents). Finally, the leukemogenic potential of topoisomerase II-targeted phytochemicals is described.
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Affiliation(s)
- Adam C. Ketron
- Department of Biochemistry and the Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 USA
| | - Neil Osheroff
- Departments of Biochemistry and Medicine (Hematology/Oncology) and the Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 USA
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19
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Pendleton M, Lindsey RH, Felix CA, Grimwade D, Osheroff N. Topoisomerase II and leukemia. Ann N Y Acad Sci 2014; 1310:98-110. [PMID: 24495080 DOI: 10.1111/nyas.12358] [Citation(s) in RCA: 149] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Type II topoisomerases are essential enzymes that modulate DNA under- and overwinding, knotting, and tangling. Beyond their critical physiological functions, these enzymes are the targets for some of the most widely prescribed anticancer drugs (topoisomerase II poisons) in clinical use. Topoisomerase II poisons kill cells by increasing levels of covalent enzyme-cleaved DNA complexes that are normal reaction intermediates. Drugs such as etoposide, doxorubicin, and mitoxantrone are frontline therapies for a variety of solid tumors and hematological malignancies. Unfortunately, their use also is associated with the development of specific leukemias. Regimens that include etoposide or doxorubicin are linked to the occurrence of acute myeloid leukemias that feature rearrangements at chromosomal band 11q23. Similar rearrangements are seen in infant leukemias and are associated with gestational diets that are high in naturally occurring topoisomerase II-active compounds. Finally, regimens that include mitoxantrone and epirubicin are linked to acute promyelocytic leukemias that feature t(15;17) rearrangements. The first part of this article will focus on type II topoisomerases and describe the mechanism of enzyme and drug action. The second part will discuss how topoisomerase II poisons trigger chromosomal breaks that lead to leukemia and potential approaches for dissociating the actions of drugs from their leukemogenic potential.
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Affiliation(s)
- Maryjean Pendleton
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee
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20
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Schittenhelm MM, Illing B, Ahmut F, Rasp KH, Blumenstock G, Döhner K, Lopez CD, Kampa-Schittenhelm KM. Attenuated expression of apoptosis stimulating protein of p53-2 (ASPP2) in human acute leukemia is associated with therapy failure. PLoS One 2013; 8:e80193. [PMID: 24312201 PMCID: PMC3842400 DOI: 10.1371/journal.pone.0080193] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Accepted: 09/10/2013] [Indexed: 12/31/2022] Open
Abstract
Inactivation of the p53 pathway is a universal event in human cancers and promotes tumorigenesis and resistance to chemotherapy. Inactivating p53 mutations are uncommon in non-complex karyotype leukemias, thus the p53-pathway must be inactivated by other mechanisms. The Apoptosis Stimulating Protein of p53-2 (ASPP2) is a damage-inducible p53-binding protein that enhances apoptosis at least in part through a p53-mediated pathway. We have previously shown, that ASPP2 is an independent haploinsufficient tumor suppressor in vivo. Now, we reveal that ASPP2 expression is significantly attenuated in acute myeloid and lymphoid leukemia – especially in patients with an unfavorable prognostic risk profile and patients who fail induction chemotherapy. In line, knock down of ASPP2 in expressing leukemia cell lines and native leukemic blasts attenuates damage-induced apoptosis. Furthermore, cultured blasts derived from high-risk leukemias fail to induce ASPP2 expression upon anthracycline treatment. The mechanisms of ASPP2 dysregulation are unknown. We provide evidence that attenuation of ASPP2 is caused by hypermethylation of the promoter and 5′UTR regions in native leukemia blasts. Together, our results suggest that ASPP2 contributes to the biology of leukemia and expression should be further explored as a potential prognostic and/or predictive biomarker to monitor therapy responses in acute leukemia.
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MESH Headings
- Adult
- Aged
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Apoptosis/drug effects
- Apoptosis/genetics
- Apoptosis Regulatory Proteins/genetics
- Apoptosis Regulatory Proteins/metabolism
- Cell Line, Tumor
- Female
- Gene Expression Regulation, Leukemic
- Gene Knockdown Techniques
- Humans
- Leukemia, Myeloid, Acute/drug therapy
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/pathology
- Male
- Middle Aged
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Treatment Failure
- Treatment Outcome
- Young Adult
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Affiliation(s)
- Marcus M. Schittenhelm
- University Hospital Tübingen, Department of Hematology, Oncology, Rheumatology, Immunology and Pulmology, Tübingen, Germany
| | - Barbara Illing
- University Hospital Tübingen, Department of Hematology, Oncology, Rheumatology, Immunology and Pulmology, Tübingen, Germany
| | - Figen Ahmut
- University Hospital Tübingen, Department of Hematology, Oncology, Rheumatology, Immunology and Pulmology, Tübingen, Germany
| | - Katharina Henriette Rasp
- University Hospital Tübingen, Department of Hematology, Oncology, Rheumatology, Immunology and Pulmology, Tübingen, Germany
| | - Gunnar Blumenstock
- Department of Clinical Epidemiology and Applied Biometry, Eberhard Karls University Tübingen, Germany
| | - Konstanze Döhner
- University Hospital Ulm, Department of Internal Medicine III, Ulm, Germany
| | - Charles D. Lopez
- Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health & Science University and The OHSU Knight Cancer Institute, Portland, Oregon, United States of America
| | - Kerstin M. Kampa-Schittenhelm
- University Hospital Tübingen, Department of Hematology, Oncology, Rheumatology, Immunology and Pulmology, Tübingen, Germany
- * E-mail:
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21
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Glukhov SI, Rubtsov MA, Alexeyevsky DA, Alexeevski AV, Razin SV, Iarovaia OV. The broken MLL gene is frequently located outside the inherent chromosome territory in human lymphoid cells treated with DNA topoisomerase II poison etoposide. PLoS One 2013; 8:e75871. [PMID: 24086652 PMCID: PMC3783379 DOI: 10.1371/journal.pone.0075871] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Accepted: 08/19/2013] [Indexed: 12/31/2022] Open
Abstract
The mixed lineage leukaemia (MLL) gene is frequently rearranged in secondary leukaemias, in which it could fuse to a variety of different partners. Breakage in the MLL gene preferentially occurs within a ~8 kb region that possesses a strong DNA topoisomerase II cleavage site. It has been proposed that DNA topoisomerase II-mediated DNA cleavage within this and other regions triggers translocations that occur due to incorrect joining of broken DNA ends. To further clarify a possible mechanism for MLL rearrangements, we analysed the frequency of MLL cleavage in cells exposed to etoposide, a DNA topoisomerase II poison commonly used as an anticancer drug, and positioning of the broken 3'-end of the MLL gene in respect to inherent chromosomal territories. It was demonstrated that exposure of human Jurkat cells to etoposide resulted in frequent cleavage of MLL genes. Using MLL-specific break-apart probes we visualised cleaved MLL genes in ~17% of nuclei. Using confocal microscopy and 3D modelling, we demonstrated that in cells treated with etoposide and cultivated for 1 h under normal conditions, ~9% of the broken MLL alleles were present outside the chromosome 11 territory, whereas in both control cells and cells inspected immediately after etoposide treatment, virtually all MLL alleles were present within the chromosomal territory. The data are discussed in the framework of the "breakage first" model of juxtaposing translocation partners. We propose that in the course of repairing DNA topoisomerase II-mediated DNA lesions (removal of stalled DNA topoisomerase II complexes and non-homologous end joining), DNA ends acquire additional mobility, which allows the meeting and incorrect joining of translocation partners.
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Affiliation(s)
- Sergey I. Glukhov
- Department of Molecular Biology, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Mikhail A. Rubtsov
- Department of Molecular Biology, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Daniil A. Alexeyevsky
- Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia
| | - Andrei V. Alexeevski
- A.N. Belozersky Institute for Physical and Chemical Biology, Lomonosov Moscow State University, Moscow, Russia
- Department of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia
- Scientific Research Institute for System Studies (NIISI RAN), Moscow, Russia
| | - Sergey V. Razin
- Department of Molecular Biology, Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
- Institute of Gene Biology RAS, Moscow, Russia
- LIA 1066 French-Russian Joint Cancer Research Laboratory, Villejuif, France–Moscow, Russia
- * E-mail:
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22
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Bailly C. Contemporary challenges in the design of topoisomerase II inhibitors for cancer chemotherapy. Chem Rev 2012; 112:3611-40. [PMID: 22397403 DOI: 10.1021/cr200325f] [Citation(s) in RCA: 218] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Christian Bailly
- Centre de Recherche et Développement, Institut de Recherche Pierre Fabre, Toulouse, France.
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23
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Gostissa M, Alt FW, Chiarle R. Mechanisms that promote and suppress chromosomal translocations in lymphocytes. Annu Rev Immunol 2011; 29:319-50. [PMID: 21219174 DOI: 10.1146/annurev-immunol-031210-101329] [Citation(s) in RCA: 118] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Recurrent chromosomal translocations are characteristic features of many types of cancers, especially lymphomas and leukemias. Several basic mechanistic factors are required for the generation of most translocations. First, DNA double-strand breaks (DSBs) must be present simultaneously at the two participating loci. Second, the two broken loci must either be in proximity or be moved into proximity to be joined. Finally, cellular DNA repair pathways must be available to join the two broken loci to complete the translocation. These mechanistic factors can vary in different normal and mutant cells and, as a result, substantially influence the frequency at which particular translocations are generated in a given cell type. Ultimately, however, appearance of recurrent oncogenic translocations in tumors is, in most cases, strongly influenced by selection for the translocated oncogene during the tumorigenesis process. In this review, we discuss in depth the factors and pathways that contribute to the generation of translocations in lymphocytes and other cell types. We also discuss recent findings regarding mechanisms that underlie the appearance of recurrent translocations in tumors.
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Affiliation(s)
- Monica Gostissa
- Howard Hughes Medical Institute, Immune Disease Institute, Program in Cellular and Molecular Medicine, Children's Hospital Boston, Massachusetts 02115, USA
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24
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Myelodysplastic syndromes with deletions of chromosome 11q lack cryptic MLL rearrangement and exhibit characteristic clinicopathologic features. Leuk Res 2011; 35:351-7. [PMID: 20691474 DOI: 10.1016/j.leukres.2010.07.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2010] [Revised: 06/24/2010] [Accepted: 07/12/2010] [Indexed: 02/03/2023]
Abstract
Deletions of chromosome 11q[del(11q)] as part of a non-complex karyotype are infrequent in myelodysplastic syndromes (MDS), leaving the clinicopathologic and genetic features largely undefined. From three large medical centers over a 10-year period, we identified 32 MDS cases where del(11q) was present either as a sole (n=23) or associated with another abnormality (n=9), showing an overall 0.6% frequency in MDS. These patients included 15 men and 17 women, with a median age of 68 years. Three were therapy-related, and 29 were primary MDS. These cases were characterized by transfusion-dependent anemia (65%); frequent ring sideroblasts (RS) (59%); bone marrow hypocellularity (22%), and less severe thrombocytopenia. With a median follow-up of 32 months, 9/24 (38%) cases progressed to acute myeloid leukemia (AML), and the overall survival (OS) was 35 months (3-105). Fluorescence in situ hybridization (FISH) showed MLL deletion in 6/10 cases, but no cryptic MLL translocations in all 15 MDS cases tested. In contrast, FISH performed in AML with del(11q) showed MLL rearrangement in 3/17 (18%) cases. In summary, del(11)q occurring in a non-complex karyotype is predominantly associated with primary MDS, lack of cryptic MLL rearrangements, and shows characteristic clinicopathological features. These clinicopathological features are likely attributed to commonly deleted regions of 11q and their involved genes.
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25
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Sill H, Olipitz W, Zebisch A, Schulz E, Wölfler A. Therapy-related myeloid neoplasms: pathobiology and clinical characteristics. Br J Pharmacol 2011; 162:792-805. [PMID: 21039422 PMCID: PMC3042191 DOI: 10.1111/j.1476-5381.2010.01100.x] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2010] [Revised: 10/21/2010] [Accepted: 10/22/2010] [Indexed: 12/21/2022] Open
Abstract
Therapy-related myeloid neoplasms (t-MNs) are serious long-term consequences of cytotoxic treatments for an antecedent disorder. t-MNs are observed after ionizing radiation as well as conventional chemotherapy including alkylating agents, topoisomerase-II-inhibitors and antimetabolites. In addition, adjuvant use of recombinant human granulocyte-colony stimulating factor may also increase the risk of t-MNs. There is clinical and biological overlap between t-MNs and high-risk de novo myelodysplastic syndromes and acute myeloid leukaemia suggesting similar mechanisms of leukaemogenesis. Human studies and animal models point to a prominent role of genetic susceptibilty in the pathogenesis of t-MNs. Common genetic variants have been identified that modulate t-MN risk, and t-MNs have been observed in some cancer predisposition syndromes. In either case, establishing a leukaemic phenotype requires acquisition of somatic mutations - most likely induced by the cytotoxic treatment. Knowledge of the specific nature of the initiating exposure has allowed the identification of crucial pathogenetic mechanisms and for these to be modelled in vitro and in vivo. Prognosis of patients with t-MNs is dismal and at present, the only curative approach for the majority of these individuals is haematopoietic stem cell transplantation, which is characterized by high transplant-related mortality rates. Novel transplantation strategies using reduced intensity conditioning regimens as well as novel drugs - demethylating agents and targeted therapies - await clinical testing and may improve outcome. Ultimately, individual assessment of genetic risk factors may translate into tailored therapies and establish a strategy for reducing t-MN incidences without jeopardizing therapeutic success rates for the primary disorders.
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MESH Headings
- Animals
- Antineoplastic Agents/adverse effects
- Genetic Predisposition to Disease
- Hematopoietic Stem Cell Transplantation
- Humans
- Leukemia, Myeloid, Acute/chemically induced
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/physiopathology
- Leukemia, Myeloid, Acute/therapy
- Myelodysplastic Syndromes/chemically induced
- Myelodysplastic Syndromes/genetics
- Myelodysplastic Syndromes/physiopathology
- Myelodysplastic Syndromes/therapy
- Neoplasms, Second Primary/chemically induced
- Neoplasms, Second Primary/genetics
- Neoplasms, Second Primary/physiopathology
- Neoplasms, Second Primary/therapy
- Prognosis
- Radiotherapy/adverse effects
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Affiliation(s)
- H Sill
- Department of Internal Medicine, Division of Haematology, Medical University of Graz, Graz, Austria.
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