A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes
Abstract Background miRNAs are small non-coding RNAs that regulate gene expression and are linked to cancer development and progression. miRNA profiles are currently studied as new prognostic factors or therapeutic perspectives. Among hematological cancers, myelodysplastic syndromes at higher risk o...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-02-01
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| Series: | Clinical Epigenetics |
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| Online Access: | https://doi.org/10.1186/s13148-023-01441-9 |
| _version_ | 1797864376146853888 |
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| author | Sara Mongiorgi Alessia De Stefano Stefano Ratti Valentina Indio Annalisa Astolfi Irene Casalin Andrea Pellagatti Stefania Paolini Sarah Parisi Michele Cavo Andrea Pession James A. McCubrey Pann-Ghill Suh Lucia Manzoli Jacqueline Boultwood Carlo Finelli Lucio Cocco Matilde Y. Follo |
| author_facet | Sara Mongiorgi Alessia De Stefano Stefano Ratti Valentina Indio Annalisa Astolfi Irene Casalin Andrea Pellagatti Stefania Paolini Sarah Parisi Michele Cavo Andrea Pession James A. McCubrey Pann-Ghill Suh Lucia Manzoli Jacqueline Boultwood Carlo Finelli Lucio Cocco Matilde Y. Follo |
| author_sort | Sara Mongiorgi |
| collection | DOAJ |
| description | Abstract Background miRNAs are small non-coding RNAs that regulate gene expression and are linked to cancer development and progression. miRNA profiles are currently studied as new prognostic factors or therapeutic perspectives. Among hematological cancers, myelodysplastic syndromes at higher risk of evolution into acute myeloid leukemia are treated with hypomethylating agents, like azacitidine, alone or in combination with other drugs, such as lenalidomide. Recent data showed that, during azacitidine and lenalidomide therapy, the concurrent acquisition of specific point mutations affecting inositide signalling pathways is associated with lack or loss of response to therapy. As these molecules are implicated in epigenetic processes, possibly involving miRNA regulation, and in leukemic progression, through the regulation of proliferation, differentiation and apoptosis, here we performed a new miRNA expression analysis of 26 high-risk patients with myelodysplastic syndromes treated with azacitidine and lenalidomide at baseline and during therapy. miRNA array data were processed, and bioinformatic results were correlated with clinical outcome to investigate the translational relevance of selected miRNAs, while the relationship between selected miRNAs and specific molecules was experimentally tested and proven. Results Patients’ overall response rate was 76.9% (20/26 cases): complete remission (5/26, 19.2%), partial remission (1/26, 3.8%), marrow complete remission (2/26, 7.7%), hematologic improvement (6/26, 23.1%), hematologic improvement with marrow complete remission (6/26, 23.1%), whereas 6/26 patients (23.1%) had a stable disease. miRNA paired analysis showed a statistically significant up-regulation of miR-192-5p after 4 cycles of therapy (vs baseline), that was confirmed by real-time PCR analyses, along with an involvement of BCL2, that was proven to be a miR-192-5p target in hematopoietic cells by luciferase assays. Furthermore, Kaplan–Meier analyses showed a significant correlation between high levels of miR-192-5p after 4 cycles of therapy and overall survival or leukemia-free survival, that was stronger in responders, as compared with patients early losing response and non-responders. Conclusions This study shows that high levels of miR-192-5p are associated with higher overall survival and leukemia-free survival in myelodysplastic syndromes responding to azacitidine and lenalidomide. Moreover, miR-192-5p specifically targets and inhibits BCL2, possibly regulating proliferation and apoptosis and leading to the identification of new therapeutic targets. |
| first_indexed | 2024-04-09T22:51:58Z |
| format | Article |
| id | doaj.art-c109ec95839b4454ba98608885f40f32 |
| institution | Directory Open Access Journal |
| issn | 1868-7083 |
| language | English |
| last_indexed | 2024-04-09T22:51:58Z |
| publishDate | 2023-02-01 |
| publisher | BMC |
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| series | Clinical Epigenetics |
| spelling | doaj.art-c109ec95839b4454ba98608885f40f322023-03-22T11:37:39ZengBMCClinical Epigenetics1868-70832023-02-0115111210.1186/s13148-023-01441-9A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromesSara Mongiorgi0Alessia De Stefano1Stefano Ratti2Valentina Indio3Annalisa Astolfi4Irene Casalin5Andrea Pellagatti6Stefania Paolini7Sarah Parisi8Michele Cavo9Andrea Pession10James A. McCubrey11Pann-Ghill Suh12Lucia Manzoli13Jacqueline Boultwood14Carlo Finelli15Lucio Cocco16Matilde Y. Follo17Cellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of BolognaCellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of BolognaCellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of Bologna“Giorgio Prodi” Cancer Research Center, University of BolognaDepartment of Medical and Surgical Sciences, University of BolognaCellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of BolognaBlood Cancer UK Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, and Oxford BRC Haematology ThemeIRCCS - Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology “ L. e A. Seràgnoli”, University of BolognaIRCCS - Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology “ L. e A. Seràgnoli”, University of BolognaIRCCS - Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology “ L. e A. Seràgnoli”, University of BolognaIRCCS Azienda Ospedaliero-Universitaria di Bologna, Division of Pediatrics, University of BolognaDepartment of Microbiology and Immunology, Brody School of Medicine, East Carolina UniversityKorea Brain Research InstituteCellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of BolognaBlood Cancer UK Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, and Oxford BRC Haematology ThemeIRCCS - Azienda Ospedaliero-Universitaria di Bologna, Institute of Hematology “ L. e A. Seràgnoli”, University of BolognaCellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of BolognaCellular Signalling Laboratory, Department of Biomedical and Neuromotor Sciences, University of BolognaAbstract Background miRNAs are small non-coding RNAs that regulate gene expression and are linked to cancer development and progression. miRNA profiles are currently studied as new prognostic factors or therapeutic perspectives. Among hematological cancers, myelodysplastic syndromes at higher risk of evolution into acute myeloid leukemia are treated with hypomethylating agents, like azacitidine, alone or in combination with other drugs, such as lenalidomide. Recent data showed that, during azacitidine and lenalidomide therapy, the concurrent acquisition of specific point mutations affecting inositide signalling pathways is associated with lack or loss of response to therapy. As these molecules are implicated in epigenetic processes, possibly involving miRNA regulation, and in leukemic progression, through the regulation of proliferation, differentiation and apoptosis, here we performed a new miRNA expression analysis of 26 high-risk patients with myelodysplastic syndromes treated with azacitidine and lenalidomide at baseline and during therapy. miRNA array data were processed, and bioinformatic results were correlated with clinical outcome to investigate the translational relevance of selected miRNAs, while the relationship between selected miRNAs and specific molecules was experimentally tested and proven. Results Patients’ overall response rate was 76.9% (20/26 cases): complete remission (5/26, 19.2%), partial remission (1/26, 3.8%), marrow complete remission (2/26, 7.7%), hematologic improvement (6/26, 23.1%), hematologic improvement with marrow complete remission (6/26, 23.1%), whereas 6/26 patients (23.1%) had a stable disease. miRNA paired analysis showed a statistically significant up-regulation of miR-192-5p after 4 cycles of therapy (vs baseline), that was confirmed by real-time PCR analyses, along with an involvement of BCL2, that was proven to be a miR-192-5p target in hematopoietic cells by luciferase assays. Furthermore, Kaplan–Meier analyses showed a significant correlation between high levels of miR-192-5p after 4 cycles of therapy and overall survival or leukemia-free survival, that was stronger in responders, as compared with patients early losing response and non-responders. Conclusions This study shows that high levels of miR-192-5p are associated with higher overall survival and leukemia-free survival in myelodysplastic syndromes responding to azacitidine and lenalidomide. Moreover, miR-192-5p specifically targets and inhibits BCL2, possibly regulating proliferation and apoptosis and leading to the identification of new therapeutic targets.https://doi.org/10.1186/s13148-023-01441-9miRNA profilingMyelodysplastic syndromesBCL2AzacitidineLenalidomide |
| spellingShingle | Sara Mongiorgi Alessia De Stefano Stefano Ratti Valentina Indio Annalisa Astolfi Irene Casalin Andrea Pellagatti Stefania Paolini Sarah Parisi Michele Cavo Andrea Pession James A. McCubrey Pann-Ghill Suh Lucia Manzoli Jacqueline Boultwood Carlo Finelli Lucio Cocco Matilde Y. Follo A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes Clinical Epigenetics miRNA profiling Myelodysplastic syndromes BCL2 Azacitidine Lenalidomide |
| title | A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes |
| title_full | A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes |
| title_fullStr | A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes |
| title_full_unstemmed | A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes |
| title_short | A miRNA screening identifies miR-192-5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes |
| title_sort | mirna screening identifies mir 192 5p as associated with response to azacitidine and lenalidomide therapy in myelodysplastic syndromes |
| topic | miRNA profiling Myelodysplastic syndromes BCL2 Azacitidine Lenalidomide |
| url | https://doi.org/10.1186/s13148-023-01441-9 |
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