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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-trans retinoic acid (ATRA) an...

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Autores principales: Albanesi, Jacopo, Noguera, Nelida Ines, Banella, Cristina, Colangelo, Tommaso, De Marinis, Elisabetta, Leone, Stefano, Palumbo, Orazio, Voso, Maria Teresa, Ascenzi, Paolo, Nervi, Clara, Bianchi, Fabrizio, di Masi, Alessandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716236/
https://www.ncbi.nlm.nih.gov/pubmed/33167477
http://dx.doi.org/10.3390/cells9112423
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author Albanesi, Jacopo
Noguera, Nelida Ines
Banella, Cristina
Colangelo, Tommaso
De Marinis, Elisabetta
Leone, Stefano
Palumbo, Orazio
Voso, Maria Teresa
Ascenzi, Paolo
Nervi, Clara
Bianchi, Fabrizio
di Masi, Alessandra
author_facet Albanesi, Jacopo
Noguera, Nelida Ines
Banella, Cristina
Colangelo, Tommaso
De Marinis, Elisabetta
Leone, Stefano
Palumbo, Orazio
Voso, Maria Teresa
Ascenzi, Paolo
Nervi, Clara
Bianchi, Fabrizio
di Masi, Alessandra
author_sort Albanesi, Jacopo
collection PubMed
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-trans 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.
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spelling pubmed-77162362020-12-05 Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells Albanesi, Jacopo Noguera, Nelida Ines Banella, Cristina Colangelo, Tommaso De Marinis, Elisabetta Leone, Stefano Palumbo, Orazio Voso, Maria Teresa Ascenzi, Paolo Nervi, Clara Bianchi, Fabrizio di Masi, Alessandra Cells Article 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-trans 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. MDPI 2020-11-05 /pmc/articles/PMC7716236/ /pubmed/33167477 http://dx.doi.org/10.3390/cells9112423 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Albanesi, Jacopo
Noguera, Nelida Ines
Banella, Cristina
Colangelo, Tommaso
De Marinis, Elisabetta
Leone, Stefano
Palumbo, Orazio
Voso, Maria Teresa
Ascenzi, Paolo
Nervi, Clara
Bianchi, Fabrizio
di Masi, Alessandra
Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716236/
https://www.ncbi.nlm.nih.gov/pubmed/33167477
http://dx.doi.org/10.3390/cells9112423
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