Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells
Acute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all-<i>trans</i> reti...
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MDPI AG
2020-11-01
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| Online Access: | https://www.mdpi.com/2073-4409/9/11/2423 |
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| author | Jacopo Albanesi Nelida Ines Noguera Cristina Banella Tommaso Colangelo Elisabetta De Marinis Stefano Leone Orazio Palumbo Maria Teresa Voso Paolo Ascenzi Clara Nervi Fabrizio Bianchi Alessandra di Masi |
| author_facet | Jacopo Albanesi Nelida Ines Noguera Cristina Banella Tommaso Colangelo Elisabetta De Marinis Stefano Leone Orazio Palumbo Maria Teresa Voso Paolo Ascenzi Clara Nervi Fabrizio Bianchi Alessandra di Masi |
| author_sort | Jacopo Albanesi |
| collection | DOAJ |
| description | Acute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all-<i>trans</i> retinoic acid (ATRA) and arsenic trioxide (ATO). However, therapy resistance, differentiation syndrome, and relapses require the development of new low-toxicity therapies based on the induction of blasts differentiation. In keeping with this, we reasoned that a better understanding of the molecular mechanisms pivotal for ATRA-driven differentiation could definitely bolster the identification of new therapeutic strategies in APL patients. We thus performed an in-depth high-throughput transcriptional profile analysis and metabolic characterization of a well-established APL experimental model based on NB4 cells that represent an unevaluable tool to dissect the complex mechanism associated with ATRA-induced granulocytic differentiation. Pathway-reconstruction analysis using genome-wide transcriptional data has allowed us to identify the activation/inhibition of several cancer signaling pathways (e.g., inflammation, immune cell response, DNA repair, and cell proliferation) and master regulators (e.g., transcription factors, epigenetic regulators, and ligand-dependent nuclear receptors). Furthermore, we provide evidence of the regulation of a considerable set of metabolic genes involved in cancer metabolic reprogramming. Consistently, we found that ATRA treatment of NB4 cells drives the activation of aerobic glycolysis pathway and the reduction of OXPHOS-dependent ATP production. Overall, this study represents an important resource in understanding the molecular “portfolio” pivotal for APL differentiation, which can be explored for developing new therapeutic strategies. |
| first_indexed | 2024-03-09T06:03:54Z |
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| language | English |
| last_indexed | 2024-03-09T06:03:54Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-0442c3793c73473e9c1fbc19d467ffbd2023-12-03T12:05:26ZengMDPI AGCells2073-44092020-11-01911242310.3390/cells9112423Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia CellsJacopo Albanesi0Nelida Ines Noguera1Cristina Banella2Tommaso Colangelo3Elisabetta De Marinis4Stefano Leone5Orazio Palumbo6Maria Teresa Voso7Paolo Ascenzi8Clara Nervi9Fabrizio Bianchi10Alessandra di Masi11Dipartimento di Scienze, Sezione di Scienze e Tecnologie Biomediche, Università Roma Tre, 00146 Roma, ItalyDipartimento di Biomedicina e Prevenzione, Università di Tor Vergata, 00133 Roma, ItalyDipartimento di Biomedicina e Prevenzione, Università di Tor Vergata, 00133 Roma, ItalyFondazione IRCCS Casa Sollievo della Sofferenza, Cancer Biomarkers Unit, 71013 San Giovanni Rotondo (FG), ItalyDepartment of Medico-Surgical Sciences and Biotechnologies, University of Roma “La Sapienza”, 04100 Latina, ItalyDipartimento di Scienze, Sezione di Scienze e Tecnologie Biomediche, Università Roma Tre, 00146 Roma, ItalyFondazione IRCCS Casa Sollievo della Sofferenza, Division of Medical Genetics, 71013 San Giovanni Rotondo (FG), ItalyDipartimento di Biomedicina e Prevenzione, Università di Tor Vergata, 00133 Roma, ItalyDipartimento di Scienze, Sezione di Scienze e Tecnologie Biomediche, Università Roma Tre, 00146 Roma, ItalyDepartment of Medico-Surgical Sciences and Biotechnologies, University of Roma “La Sapienza”, 04100 Latina, ItalyFondazione IRCCS Casa Sollievo della Sofferenza, Cancer Biomarkers Unit, 71013 San Giovanni Rotondo (FG), ItalyDipartimento di Scienze, Sezione di Scienze e Tecnologie Biomediche, Università Roma Tre, 00146 Roma, ItalyAcute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all-<i>trans</i> retinoic acid (ATRA) and arsenic trioxide (ATO). However, therapy resistance, differentiation syndrome, and relapses require the development of new low-toxicity therapies based on the induction of blasts differentiation. In keeping with this, we reasoned that a better understanding of the molecular mechanisms pivotal for ATRA-driven differentiation could definitely bolster the identification of new therapeutic strategies in APL patients. We thus performed an in-depth high-throughput transcriptional profile analysis and metabolic characterization of a well-established APL experimental model based on NB4 cells that represent an unevaluable tool to dissect the complex mechanism associated with ATRA-induced granulocytic differentiation. Pathway-reconstruction analysis using genome-wide transcriptional data has allowed us to identify the activation/inhibition of several cancer signaling pathways (e.g., inflammation, immune cell response, DNA repair, and cell proliferation) and master regulators (e.g., transcription factors, epigenetic regulators, and ligand-dependent nuclear receptors). Furthermore, we provide evidence of the regulation of a considerable set of metabolic genes involved in cancer metabolic reprogramming. Consistently, we found that ATRA treatment of NB4 cells drives the activation of aerobic glycolysis pathway and the reduction of OXPHOS-dependent ATP production. Overall, this study represents an important resource in understanding the molecular “portfolio” pivotal for APL differentiation, which can be explored for developing new therapeutic strategies.https://www.mdpi.com/2073-4409/9/11/2423acute promyelocytic leukemiaaerobic glycolysisall-trans-retinoic acidDNA repairepigenetic regulatorsimmune cell response |
| spellingShingle | Jacopo Albanesi Nelida Ines Noguera Cristina Banella Tommaso Colangelo Elisabetta De Marinis Stefano Leone Orazio Palumbo Maria Teresa Voso Paolo Ascenzi Clara Nervi Fabrizio Bianchi Alessandra di Masi Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells Cells acute promyelocytic leukemia aerobic glycolysis all-trans-retinoic acid DNA repair epigenetic regulators immune cell response |
| title | Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells |
| title_full | Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells |
| title_fullStr | Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells |
| title_full_unstemmed | Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells |
| title_short | Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells |
| title_sort | transcriptional and metabolic dissection of atra induced granulocytic differentiation in nb4 acute promyelocytic leukemia cells |
| topic | acute promyelocytic leukemia aerobic glycolysis all-trans-retinoic acid DNA repair epigenetic regulators immune cell response |
| url | https://www.mdpi.com/2073-4409/9/11/2423 |
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