Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
JournalCells
Volume9
Issue number11
DOIs
Publication statusPublished - Nov 5 2020

Keywords

  • acute promyelocytic leukemia
  • aerobic glycolysis
  • all-trans-retinoic acid
  • DNA repair
  • epigenetic regulators
  • immune cell response
  • inflammation
  • metabolism
  • NB4 cell line
  • transcriptomic profile

ASJC Scopus subject areas

  • Medicine(all)

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