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1. Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene

Author

Riccardo Masetti, Salvatore Nicola Bertuccio, Annalisa Astolfi, Francesca Chiarini, Annalisa Lonetti, Valentina Indio, Matilde De Luca, Jessica Bandini, Salvatore Serravalle, Monica Franzoni, Martina Pigazzi, Alberto Maria Martelli, Giuseppe Basso, Franco Locatelli, and Andrea Pession

Subjects
Acute myeloid leukemia, Acute megakaryoblastic leukemia, CBFA2T3-GLIS2, GANT61, Hedgehog pathway, Diseases of the blood and blood-forming organs, RC633-647.5, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background CBFA2T3-GLIS2 is a fusion gene found in 17% of non-Down syndrome acute megakaryoblastic leukemia (non-DS AMKL, FAB M7) and in 8% of pediatric cytogenetically normal acute myeloid leukemia (CN-AML, in association with several French-American-British (FAB) subtypes). Children with AML harboring this aberration have a poor outcome, regardless of the FAB subtype. This fusion gene drives a peculiar expression pattern and leads to overexpression of some of Hedgehog-related genes. GLI-similar protein 2 (GLIS2) is closely related to the GLI family, the final effectors of classic Hedgehog pathway. These observations lend compelling support to the application of GLI inhibitors in the treatment of AML with the aberration CBFA2T3-GLIS2. GANT61 is, nowadays, the most potent inhibitor of GLI family proteins. Methods We exposed to GANT61 AML cell lines and primary cells positive and negative for CBFA2T3-GLIS2 and analyzed the effect on cellular viability, induction of apoptosis, cell cycle, and expression profile. Results As compared to AML cells without GLIS2 fusion, GANT61 exposure resulted in higher sensitivity of both cell lines and primary AML cells carrying CBFA2T3-GLIS2 to undergo apoptosis and G1 cell cycle arrest. Remarkably, gene expression studies demonstrated downregulation of GLIS2-specific signature genes in both treated cell lines and primary cells, in comparison with untreated cells. Moreover, chromatin immunoprecipitation analysis revealed direct regulation by GLIS2 chimeric protein of DNMT1 and DNMT3B, two genes implicated in important epigenetic functions. Conclusions Our findings indicate that the GLI inhibitor GANT61 may be used to specifically target the CBFA2T3-GLIS2 fusion gene in pediatric AML.

Published
2017
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2. HLA-mismatched hematopoietic stem cell tranplantation for pediatric solid tumors

Author

Andrea Pession, Riccardo Masetti, Corinne Di Leo, Monica Franzoni, and Arcangelo Prete

Subjects
Medicine, Pediatrics, RJ1-570
Abstract

Even if the overall survival of children with cancer is significantly improved over these decades, the cure rate of high-risk pediatric solid tumors such as neuroblastoma, Ewing’s sarcoma family tumors or rhabdomiosarcoma remain challenging. Autologous hematopoietic stem cell transplantation (HSCT) allows chemotherapy dose intensification beyond marrow tolerance and has become a fundamental tool in the multimodal therapeutical approach of these patients. Anyway this procedure does not allow to these children an eventfree survival approaching more than 50% at 5 years. New concepts of allogeneic HSCT and in particular HLA-mismatched HSCT for high risk solid tumors do not rely on escalation of chemo therapy intensity and tumor load reduction but rather on a graft-versus-tumor effect. We here report an experimental study design of HLA-mismatched HSCT for the treatment of pediatric solid tumors and the inherent preliminary results.

Published
2011
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3. Supplementary Figure 3 from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Author

Janet Shipley, Andrea Pession, Roberto Corradini, Stefano Fanti, Giorgio Cantelli-Forti, Patrizia Hrelia, Rosangela Marchelli, Brenda Summersgill, Monica Franzoni, Khin Thway, Valentina Ambrosini, Jorge S. Reis-Filho, Serena Formica, Ivo Leuschner, Andrea Faccini, Linda J. Valentijn, Cristina Nanni, Ryan Bishop, Salvatore Serravalle, Kathryn R. Taylor, Annalisa Astolfi, Jane Renshaw, Andrea Tortori, Edoardo Missiaglia, Stefania Purgato, Joanna Selfe, Korinne Di Leo, Zoë S. Walters, Consuelo Camerin, Alan McIntyre, and Roberto Tonelli

Abstract

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Published
2023
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4. Data from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Author

Janet Shipley, Andrea Pession, Roberto Corradini, Stefano Fanti, Giorgio Cantelli-Forti, Patrizia Hrelia, Rosangela Marchelli, Brenda Summersgill, Monica Franzoni, Khin Thway, Valentina Ambrosini, Jorge S. Reis-Filho, Serena Formica, Ivo Leuschner, Andrea Faccini, Linda J. Valentijn, Cristina Nanni, Ryan Bishop, Salvatore Serravalle, Kathryn R. Taylor, Annalisa Astolfi, Jane Renshaw, Andrea Tortori, Edoardo Missiaglia, Stefania Purgato, Joanna Selfe, Korinne Di Leo, Zoë S. Walters, Consuelo Camerin, Alan McIntyre, and Roberto Tonelli

Abstract

Purpose: Rhabdomyosarcomas are a major cause of cancer death in children, described with MYCN amplification and, in the alveolar subtype, transcription driven by the PAX3-FOXO1 fusion protein. Our aim was to determine the prevalence of N-Myc protein expression and the potential therapeutic effects of reducing expression in rhabdomyosarcomas, including use of an antigene strategy that inhibits transcription.Experimental Design: Protein expression was assessed by immunohistochemistry. MYCN expression was reduced in representative cell lines by RNA interference and an antigene peptide nucleic acid (PNA) oligonucleotide conjugated to a nuclear localization signal peptide. Associated gene expression changes, cell viability, and apoptosis were analyzed in vitro. As a paradigm for antigene therapy, the effects of systemic treatment of mice with rhabdomyosarcoma cell line xenografts were determined.Results: High N-Myc levels were significantly associated with genomic amplification, presence of the PAX3/7-FOXO1 fusion genes, and proliferative capacity. Sustained reduction of N-Myc levels in all rhabdomyosarcoma cell lines that express the protein decreased cell proliferation and increased apoptosis. Positive feedback was shown to regulate PAX3-FOXO1 and N-Myc levels in the alveolar subtype that critically decrease PAX3-FOXO1 levels on reducing N-Myc. Pharmacologic systemic administration of the antigene PNA can eliminate alveolar rhabdomyosarcoma xenografts in mice, without relapse or toxicity.Conclusion: N-Myc, with its restricted expression in non-fetal tissues, is a therapeutic target to treat rhabdomyosarcomas, and blocking gene transcription using antigene oligonucleotide strategies has therapeutic potential in the treatment of cancer and other diseases that has not been previously realized in vivo. Clin Cancer Res; 18(3); 796–807. ©2011 AACR.

Published
2023
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5. Supplementary Tables 6-7 from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Author

Janet Shipley, Andrea Pession, Roberto Corradini, Stefano Fanti, Giorgio Cantelli-Forti, Patrizia Hrelia, Rosangela Marchelli, Brenda Summersgill, Monica Franzoni, Khin Thway, Valentina Ambrosini, Jorge S. Reis-Filho, Serena Formica, Ivo Leuschner, Andrea Faccini, Linda J. Valentijn, Cristina Nanni, Ryan Bishop, Salvatore Serravalle, Kathryn R. Taylor, Annalisa Astolfi, Jane Renshaw, Andrea Tortori, Edoardo Missiaglia, Stefania Purgato, Joanna Selfe, Korinne Di Leo, Zoë S. Walters, Consuelo Camerin, Alan McIntyre, and Roberto Tonelli

Abstract

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Published
2023
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6. Supplementary Figure 6 from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Author

Janet Shipley, Andrea Pession, Roberto Corradini, Stefano Fanti, Giorgio Cantelli-Forti, Patrizia Hrelia, Rosangela Marchelli, Brenda Summersgill, Monica Franzoni, Khin Thway, Valentina Ambrosini, Jorge S. Reis-Filho, Serena Formica, Ivo Leuschner, Andrea Faccini, Linda J. Valentijn, Cristina Nanni, Ryan Bishop, Salvatore Serravalle, Kathryn R. Taylor, Annalisa Astolfi, Jane Renshaw, Andrea Tortori, Edoardo Missiaglia, Stefania Purgato, Joanna Selfe, Korinne Di Leo, Zoë S. Walters, Consuelo Camerin, Alan McIntyre, and Roberto Tonelli

Abstract

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Published
2023
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7. Supplementary Figure 1 from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Author

Janet Shipley, Andrea Pession, Roberto Corradini, Stefano Fanti, Giorgio Cantelli-Forti, Patrizia Hrelia, Rosangela Marchelli, Brenda Summersgill, Monica Franzoni, Khin Thway, Valentina Ambrosini, Jorge S. Reis-Filho, Serena Formica, Ivo Leuschner, Andrea Faccini, Linda J. Valentijn, Cristina Nanni, Ryan Bishop, Salvatore Serravalle, Kathryn R. Taylor, Annalisa Astolfi, Jane Renshaw, Andrea Tortori, Edoardo Missiaglia, Stefania Purgato, Joanna Selfe, Korinne Di Leo, Zoë S. Walters, Consuelo Camerin, Alan McIntyre, and Roberto Tonelli

Abstract

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Published
2023
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8. Supplementary Materials and Methods from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Author

Janet Shipley, Andrea Pession, Roberto Corradini, Stefano Fanti, Giorgio Cantelli-Forti, Patrizia Hrelia, Rosangela Marchelli, Brenda Summersgill, Monica Franzoni, Khin Thway, Valentina Ambrosini, Jorge S. Reis-Filho, Serena Formica, Ivo Leuschner, Andrea Faccini, Linda J. Valentijn, Cristina Nanni, Ryan Bishop, Salvatore Serravalle, Kathryn R. Taylor, Annalisa Astolfi, Jane Renshaw, Andrea Tortori, Edoardo Missiaglia, Stefania Purgato, Joanna Selfe, Korinne Di Leo, Zoë S. Walters, Consuelo Camerin, Alan McIntyre, and Roberto Tonelli

Abstract

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Published
2023
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9. CCR Translation for This Article from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Author

Janet Shipley, Andrea Pession, Roberto Corradini, Stefano Fanti, Giorgio Cantelli-Forti, Patrizia Hrelia, Rosangela Marchelli, Brenda Summersgill, Monica Franzoni, Khin Thway, Valentina Ambrosini, Jorge S. Reis-Filho, Serena Formica, Ivo Leuschner, Andrea Faccini, Linda J. Valentijn, Cristina Nanni, Ryan Bishop, Salvatore Serravalle, Kathryn R. Taylor, Annalisa Astolfi, Jane Renshaw, Andrea Tortori, Edoardo Missiaglia, Stefania Purgato, Joanna Selfe, Korinne Di Leo, Zoë S. Walters, Consuelo Camerin, Alan McIntyre, and Roberto Tonelli

Abstract

CCR Translation for This Article from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Published
2023
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10. Supplementary Figure 5 from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Author

Janet Shipley, Andrea Pession, Roberto Corradini, Stefano Fanti, Giorgio Cantelli-Forti, Patrizia Hrelia, Rosangela Marchelli, Brenda Summersgill, Monica Franzoni, Khin Thway, Valentina Ambrosini, Jorge S. Reis-Filho, Serena Formica, Ivo Leuschner, Andrea Faccini, Linda J. Valentijn, Cristina Nanni, Ryan Bishop, Salvatore Serravalle, Kathryn R. Taylor, Annalisa Astolfi, Jane Renshaw, Andrea Tortori, Edoardo Missiaglia, Stefania Purgato, Joanna Selfe, Korinne Di Leo, Zoë S. Walters, Consuelo Camerin, Alan McIntyre, and Roberto Tonelli

Abstract

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Published
2023
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11. Supplementary Tables 1-3 from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Author

Janet Shipley, Andrea Pession, Roberto Corradini, Stefano Fanti, Giorgio Cantelli-Forti, Patrizia Hrelia, Rosangela Marchelli, Brenda Summersgill, Monica Franzoni, Khin Thway, Valentina Ambrosini, Jorge S. Reis-Filho, Serena Formica, Ivo Leuschner, Andrea Faccini, Linda J. Valentijn, Cristina Nanni, Ryan Bishop, Salvatore Serravalle, Kathryn R. Taylor, Annalisa Astolfi, Jane Renshaw, Andrea Tortori, Edoardo Missiaglia, Stefania Purgato, Joanna Selfe, Korinne Di Leo, Zoë S. Walters, Consuelo Camerin, Alan McIntyre, and Roberto Tonelli

Abstract

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Published
2023
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12. Supplementary Figure 2 from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Author

Janet Shipley, Andrea Pession, Roberto Corradini, Stefano Fanti, Giorgio Cantelli-Forti, Patrizia Hrelia, Rosangela Marchelli, Brenda Summersgill, Monica Franzoni, Khin Thway, Valentina Ambrosini, Jorge S. Reis-Filho, Serena Formica, Ivo Leuschner, Andrea Faccini, Linda J. Valentijn, Cristina Nanni, Ryan Bishop, Salvatore Serravalle, Kathryn R. Taylor, Annalisa Astolfi, Jane Renshaw, Andrea Tortori, Edoardo Missiaglia, Stefania Purgato, Joanna Selfe, Korinne Di Leo, Zoë S. Walters, Consuelo Camerin, Alan McIntyre, and Roberto Tonelli

Abstract

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Published
2023
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13. Supplementary Figure 4 from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Author

Janet Shipley, Andrea Pession, Roberto Corradini, Stefano Fanti, Giorgio Cantelli-Forti, Patrizia Hrelia, Rosangela Marchelli, Brenda Summersgill, Monica Franzoni, Khin Thway, Valentina Ambrosini, Jorge S. Reis-Filho, Serena Formica, Ivo Leuschner, Andrea Faccini, Linda J. Valentijn, Cristina Nanni, Ryan Bishop, Salvatore Serravalle, Kathryn R. Taylor, Annalisa Astolfi, Jane Renshaw, Andrea Tortori, Edoardo Missiaglia, Stefania Purgato, Joanna Selfe, Korinne Di Leo, Zoë S. Walters, Consuelo Camerin, Alan McIntyre, and Roberto Tonelli

Abstract

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Published
2023
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14. Supplementary Table 5 from Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Author

Janet Shipley, Andrea Pession, Roberto Corradini, Stefano Fanti, Giorgio Cantelli-Forti, Patrizia Hrelia, Rosangela Marchelli, Brenda Summersgill, Monica Franzoni, Khin Thway, Valentina Ambrosini, Jorge S. Reis-Filho, Serena Formica, Ivo Leuschner, Andrea Faccini, Linda J. Valentijn, Cristina Nanni, Ryan Bishop, Salvatore Serravalle, Kathryn R. Taylor, Annalisa Astolfi, Jane Renshaw, Andrea Tortori, Edoardo Missiaglia, Stefania Purgato, Joanna Selfe, Korinne Di Leo, Zoë S. Walters, Consuelo Camerin, Alan McIntyre, and Roberto Tonelli

Abstract

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Published
2023
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15. Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Author

Stefano Fanti, Ivo Leuschner, Andrea Tortori, Salvatore Serravalle, Zoë S. Walters, Cristina Nanni, Brenda Summersgill, Ryan Bishop, Serena Formica, Joanna Selfe, Stefania Purgato, Monica Franzoni, Patrizia Hrelia, Linda J. Valentijn, Andrea Pession, Consuelo Camerin, Kathryn R. Taylor, Andrea Faccini, Annalisa Astolfi, Valentina Ambrosini, Rosangela Marchelli, Edoardo Missiaglia, Roberto Corradini, Giorgio Cantelli-Forti, Roberto Tonelli, Korinne Di Leo, Alan McIntyre, Jorge S. Reis-Filho, Jane Renshaw, Khin Thway, Janet Shipley, R. Tonelli, A. McIntyre, C. Camerin, Z.S. Walter, K. Di Leo, J. Selfe, S. Purgato, E. Missiaglia, A. Tortori, J. Renshaw, A. Astolfi, K.R. Taylor, S. Serravalle, R. Bishop, C. Nanni, L.J. Valentijn, A. Faccini, I. Leuschner, S. Formica, Jorge S Reis-Filho9, V. Ambrosini, K. Thway, M. Franzoni, B. Summersgill, R. Marchelli, P. Hrelia, G. Cantelli-Forti, S. Fanti, R. Corradini, A. Pession, J. Shipley, Cancer Center Amsterdam, and Oncogenomics

Subjects
Peptide Nucleic Acids, Cancer Research, Oncogene Proteins, Fusion, Transcription, Genetic, Blotting, Western, Gene Dosage, Genes, myc, Mice, Nude, Apoptosis, Electrophoretic Mobility Shift Assay, Biology, Real-Time Polymerase Chain Reaction, N-Myc Proto-Oncogene Protein, Fusion gene, Proto-Oncogene Proteins c-myc, Mice, RNA interference, Cell Line, Tumor, Gene expression, MYCN, medicine, In Situ Nick-End Labeling, Animals, Humans, Paired Box Transcription Factors, neoplasms, RHABDOMYOSARCOMA, Oncogene Proteins, Cell growth, Reverse Transcriptase Polymerase Chain Reaction, Nuclear Proteins, Genetic Therapy, ANTI-MYCN PNA OLIGONUCLEOTIDE, medicine.disease, Molecular biology, Immunohistochemistry, Xenograft Model Antitumor Assays, ANTIGENE THERAPY, Real-time polymerase chain reaction, PAX-FOXO1, Oncology, Alveolar rhabdomyosarcoma, Cancer research, N-Myc
Abstract

Purpose: Rhabdomyosarcomas are a major cause of cancer death in children, described with MYCN amplification and, in the alveolar subtype, transcription driven by the PAX3-FOXO1 fusion protein. Our aim was to determine the prevalence of N-Myc protein expression and the potential therapeutic effects of reducing expression in rhabdomyosarcomas, including use of an antigene strategy that inhibits transcription. Experimental Design: Protein expression was assessed by immunohistochemistry. MYCN expression was reduced in representative cell lines by RNA interference and an antigene peptide nucleic acid (PNA) oligonucleotide conjugated to a nuclear localization signal peptide. Associated gene expression changes, cell viability, and apoptosis were analyzed in vitro. As a paradigm for antigene therapy, the effects of systemic treatment of mice with rhabdomyosarcoma cell line xenografts were determined. Results: High N-Myc levels were significantly associated with genomic amplification, presence of the PAX3/7-FOXO1 fusion genes, and proliferative capacity. Sustained reduction of N-Myc levels in all rhabdomyosarcoma cell lines that express the protein decreased cell proliferation and increased apoptosis. Positive feedback was shown to regulate PAX3-FOXO1 and N-Myc levels in the alveolar subtype that critically decrease PAX3-FOXO1 levels on reducing N-Myc. Pharmacologic systemic administration of the antigene PNA can eliminate alveolar rhabdomyosarcoma xenografts in mice, without relapse or toxicity. Conclusion: N-Myc, with its restricted expression in non-fetal tissues, is a therapeutic target to treat rhabdomyosarcomas, and blocking gene transcription using antigene oligonucleotide strategies has therapeutic potential in the treatment of cancer and other diseases that has not been previously realized in vivo. Translational Relevance Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma. They are a leading cause of cancer death in children with few therapeutic options in highrisk categories. N-Myc is a transcription factor belonging to the MYC protein family that has a highly restricted expression pattern in non-fetal tissues. N-Myc protein expression in patient samples of rhabdomyosarcoma and an apoptotic response to sustained reduction of expression in rhabdomyosarcoma cell lines imply that N-Myc represents a tumor-specific therapeutic target in these tumors. Systemic treatment of mice with rhabdomyosarcoma cell line xenografts using an antigene peptide nucleic acid (PNA) oligonucleotide conjugated to a nuclear localization signal peptide that inhibits transcription of MYCN shows promise by eliminating tumors. This direct antigene approach may have therapeutic potential in the treatment of other cancers and diseases.

Published
2012

16. Pediatric early T-cell precursor leukemia with NF1 deletion and high-sensitivity in vitro to tipifarnib

Author

Andrea Pession, Carlotta Biagi, Francesca Chiarini, Annalisa Astolfi, Fraia Melchionda, Riccardo Masetti, Monica Franzoni, Salvatore Serravalle, Biagi C., Astolfi A., Masetti R., Serravalle S., Franzoni M., Chiarini F., Melchionda F., and Pession A.

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, Cancer Research, medicine.medical_specialty, T cell, ETP-ALL, NF1, tipifarnib, ETP-ALL, NF1, tipifarnib, NO, hemic and lymphatic diseases, Acute lymphocytic leukemia, Internal medicine, Precursor cell, Medicine, neoplasms, Hematology, business.industry, Cancer, medicine.disease, eye diseases, In vitro, nervous system diseases, Leukemia, medicine.anatomical_structure, Oncology, Immunology, Cancer research, Tipifarnib, business, medicine.drug
Abstract

Pediatric early T-cell precursor leukemia with NF1 deletion and high-sensitivity in vitro to tipifarnib

Published
2010

17. G1 cell-cycle arrest and apoptosis by histone deacetylase inhibition in MLL-AF9 acute myeloid leukemia cells is p21 dependent and MLL-AF9 independent

Author

Simona Ferrari, Saverio Minucci, Andriy Khobta, Marco Ballarini, Monica Franzoni, Renato Campanini, Giovanni Capranico, Francesca Freccero, Andrea Pession, Roberto Tonelli, G. Di Cola, Raffaele Fronza, Paolo Paolucci, Maria D'Apolito, Roberta Sartini, Danilo Nicola Dongiovanni, R Tonelli, R Sartini, R Fronza, F Freccero, M Franzoni, D Dongiovanni, M Ballarini, S Ferrari, M D'apolito, G Di Cola, G Capranico, A Khobta, R Campanini, P Paolucci, S Minucci, and A Pession

Subjects
Cancer Research, Programmed cell death, Tumor suppressor gene, medicine.drug_class, Apoptosis, Biology, Histone Deacetylases, hemic and lymphatic diseases, Cell Line, Tumor, medicine, Humans, Enzyme Inhibitors, neoplasms, Histone deacetylase inhibitor, G1 Phase, Myeloid leukemia, Hematology, Cell cycle, Histone Deacetylase Inhibitors, Oncology, Leukemia, Myeloid, Acute Disease, Cancer research, G1 cells, MLL-AF9 cells, p21, myeloid leukemia, Histone deacetylase, G1 phase
Abstract

G1 cell-cycle arrest and apoptosis by histone deacetylase inhibition in MLL-AF9 acute myeloid leukemia cells is p21 dependent and MLL-AF9 independent

Published
2006

18. Anti-gene peptide nucleic acid specifically inhibits MYCN expression in human neuroblastoma cells leading to cell growth inhibition and apoptosis

Author

Andrea Pession, Jason M. Shohet, Andrea Faccini, Raffaele Fronza, Roberto Corradini, Stefano Sforza, Roberto Tonelli, Fabrizio Bologna, Rosangela Marchelli, Simone Alboresi, Stefania Purgato, Consuelo Camerin, Monica Franzoni, TONELLI R, PURGATO S, CAMERIN C, FRONZA R, BOLOGNA F, ALBORESI S, FRANZONI M, CORRADINI R, SFORZA S, FACCINI A, SHOHET JM, MARCHELLI R, and PESSION A.

Subjects
Peptide Nucleic Acids, Cancer Research, Peptide nucleic acid, Cell growth, Apoptosis, Biology, medicine.disease, Molecular biology, Blot, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, chemistry.chemical_compound, Neuroblastoma, Oncology, Antigen, chemistry, Annexin, Transcription (biology), medicine, Tumor Cells, Cultured, Humans, neoplasms
Abstract

We developed an anti-gene peptide nucleic acid (PNA) for selective inhibition of MYCN transcription in neuroblastoma cells, targeted against a unique sequence in the antisense DNA strand of exon 2 of MYCN and linked at its NH2 terminus to a nuclear localization signal peptide. Fluorescence microscopy showed specific nuclear delivery of the PNA in six human neuroblastoma cell lines: GI-LI-N and IMR-32 (MYCN-amplified/overexpressed); SJ-N-KP and NB-100 (MYCN-unamplified/low-expressed); and GI-CA-N and GI-ME-N (MYCN-unamplified/unexpressed). Antiproliferative effects were observable at 24 hours (GI-LI-N, 60%; IMR-32, 70%) and peaked at 72 hours (GI-LI-N, 80%; IMR-32, 90%; SK-N-KP, 60%; NB-100, 50%); no reduction was recorded for GI-CA-N and GI-ME-N (controls). In MYCN-amplified/overexpressed IMR-32 cells and MYCN-unamplified/low-expressed SJ-N-KP cells, inhibition was recorded of MYCN mRNA (by real-time PCR) and N-Myc (Western blotting); these inhibitory effects increased over 3 days after single treatment in IMR-32. Anti-gene PNA induced G1-phase accumulation (39–53%) in IMR-32 and apoptosis (56% annexin V–positive cells at 24 hours in IMR-32 and 22% annexin V–positive cells at 48 hours in SJ-N-KP). Selective activity of the PNA was shown by altering three point mutations, and by the observation that an anti-gene PNA targeted against the noncoding DNA strand did not exert any effect. These findings could encourage research into development of an anti-gene PNA–based tumor-specific agent for neuroblastoma (and other neoplasms) with MYCN expression.

Published
2005

19. MLL-AF9 oncogene expression affects cell growth but not terminal differentiation and is downregulated during monocyte-macrophage maturation in AML-M5 THP-1 cells

Author

Claudia Beltramini, Andrea Pession, Monica Franzoni, Franco Locatelli, Giulia Biserni, Vincenzo Martino, Guido Paolucci, Francesea Freccero, Roberto Tonelli, Luca Montemurro, and Laura Pattacini

Subjects
Cancer Research, Cell division, Oncogene Proteins, Fusion, Cellular differentiation, Down-Regulation, Biology, Monocytes, Cell Line, hemic and lymphatic diseases, Genetics, medicine, Humans, THP1 cell line, neoplasms, Molecular Biology, Oncogene, Cell growth, Monocyte, Macrophages, Cell Differentiation, Oncogenes, Phenotype, medicine.anatomical_structure, Cell culture, Immunology, Cancer research, Cell Division, Myeloid-Lymphoid Leukemia Protein
Abstract

The MLL-AF9 oncogene - one of the most frequent MLL/HRX/ALL-1 rearrangements found in infantile and therapy-related leukaemias - originates from t(9;11)(p22;q23) and is mainly associated with monocytic acute myeloid leukaemia (AML-M5; FAB-classification). Here, we investigated the MLL-AF9 function by means of an antisense phosphorothioate-oligodeoxyribonucleotide (MLL-AF9-PS-ODNas) using the THP-1 AML-M5 cell line carrying t(9;11). Having confirmed that MLL-AF9-PS-ODNas induces strong inhibition of THP-1 cell growth, but only a moderate increase in apoptosis, we found that MLL-AF9-PS-ODNas did not induce morpho-functional terminal differentiation or restore M-CSF-, G-CSF- or GM-CSF-induced differentiation. Moreover, THP-1 cells showed the same phenotype with/without MLL-AF9-PS-ODNas. In THP-1 cells differentiated to mature macrophage-like cells by PMA/TPA or ATRA, MLL-AF9 expression was downregulated. Thus, in the monocytic lineage, MLL-AF9 may be expressed only in early phases and can induce deregulated amplification in both nonmalignant and malignant cells, maintaining the monocytic phenotype without blocking final maturation. Our findings suggest that: (1) as well as directly promoting cell growth, MLL-AF9 may also indirectly determine phenotype; (2) other leukaemogenic mutations associated with MLL-AF9-related leukaemias should be searched for mainly in processes of resistance to apoptosis (where MLL-AF9 may play only a limited role) and differentiation blockage (where MLL-AF9 may play no role).

Published
2003

21. N−3 PUFAs modulate global gene expression profile in cultured rat cardiomyocytes. Implications in cardiac hypertrophy and heart failure

Author

Andrea Pession, Annalisa Astolfi, Pierluigi Biagi, Monica Franzoni, Mattia Di Nunzio, Annalisa Pession, Luca Morandi, Alessandra Bordoni, Francesca Danesi, A. Bordoni, A. Astolfi, L. Morandi, A. Pession, F. Danesi, M. Di Nunzio, M. Franzoni, and P.L. Biagi

Subjects
medicine.medical_specialty, N-3 PUFA, Cardiotonic Agents, Eicosapentaenoic acid, Dermatopontin, Biophysics, Peroxisome proliferator-activated receptor, Inflammation, Cardiomegaly, n−3 PUFA, Biology, Biochemistry, Structural Biology, Internal medicine, Gene expression, Fatty Acids, Omega-3, Genetics, medicine, Extracellular, Animals, Myocytes, Cardiac, STAT3, Molecular Biology, Cells, Cultured, DNA Primers, chemistry.chemical_classification, Heart Failure, Base Sequence, Cell growth, Gene Expression Profiling, Cell Biology, Cultured cardiomyocytes, Rats, Docosahexaenoic acid, Endocrinology, chemistry, biology.protein, Tumor necrosis factor alpha, medicine.symptom
Abstract

In cardiac cells the effects of n−3 PUFAs on the whole genome are still unknown despite their recognized cardioprotective effects and ability to modulate gene expression. We have evaluated the effects of n−3 PUFAs supplementation on the global gene expression profile in cultured neonatal rat cardiomyocytes, detecting many genes related to lipid transport and metabolism among the upregulated ones. Many of the downregulated genes appeared related to inflammation, cell growth, extracellular and cardiac matrix remodelling, calcium movements and ROS generation. Our data allow to speculate that the cardioprotective effect of n−3 PUFAs is related to a direct modulation of genes in cardiac cells.

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