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

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.

Role of cardiolipins, mitochondria, and autophagy in the differentiation process activated by all-trans retinoic acid in acute promyelocytic leukemia

“…Subsequently, we determined the time-frame of the perturbations caused by ATRA on CRLS1/LPGAT1/LPCAT1/LPCAT2/LPCAT4/LCLAT1 and PGS1. Thus, we compared our RNA-seq data with the publicly available transcriptomic results obtained in NB4 cells exposed to ATRA for 4, 12, 24, 72, and 120 h [ 34 , 35 ] (Fig. 4D ).…”

Integrated bioinformatics analysis of differentially expressed genes and immune cell infiltration characteristics in Esophageal Squamous cell carcinoma

“…The mechanical properties and configuration of the ECM have been demonstrated to play important roles in sustaining proliferation, evading growth suppression, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion, avoiding immune destruction, deregulating cellular energetics, and facilitating genomic instability and tumor-promoting chronic inflammation 17 . Numerous interactions between esophageal cancer cells and the ECM seem to be intricate 18 . Many studies have demonstrated that different ECM molecules play a regulatory role in the development and metastasis of ESCC 19 – 21 .…”

Cancer Metabolism as a New Real Target in Tumor Therapy

“…Conversely, Albanesi and colleagues [20] found that ATRA treatment, a differentiation therapy, in the acute promyelocytic leukemia cell line NB4, correlates with the activation of aerobic glycolysis and the reduction in OXPHOS-dependent ATP production, proposing that granulocytic differentiation and patient therapy could be favored by OXPHOS inhibition. A tight association between current cancer therapies and metabolic rewiring was also proposed by Verma and colleagues [21].…”