Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells.
Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells.
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NB4急性早幼粒细胞白血病细胞中ATRA诱导粒细胞分化的转录和代谢解剖。
DOI：
10.3390/cells9112423
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发表时间：
2020-11-05
期刊：
影响因子：
6
通讯作者：
di Masi A
中科院分区：
文献类型：
--
作者：
Albanesi J;Noguera NI;Banella C;Colangelo T;De Marinis E;Leone S;Palumbo O;Voso MT;Ascenzi P;Nervi C;Bianchi F;di Masi A
急性早幼粒细胞白血病（APL）是一种以平衡的相互易位为特征的血液病，其导致致癌融合蛋白PML-RARα的合成。APL主要通过基于全反式维甲酸（ATRA）和三氧化二砷（ATO）给药的分化治疗来管理。然而，治疗抗性、分化综合征和复发需要开发基于诱导原始细胞分化的新的低毒性疗法。与此相一致，我们推断，更好地理解ATRA驱动分化的关键分子机制肯定会支持APL患者新治疗策略的确定。因此，我们进行了深入的高通量转录谱分析和代谢表征的一个完善的APL实验模型的基础上NB 4细胞，代表一个不可评估的工具，解剖与ATRA诱导粒细胞分化的复杂机制。使用全基因组转录数据的途径重建分析使我们能够鉴定几种癌症信号传导途径的激活/抑制（例如，炎症、免疫细胞应答、DNA修复和细胞增殖）和主调节因子（例如，转录因子、表观遗传调节因子和配体依赖性核受体）。此外，我们提供了证据的调节相当一组代谢基因参与癌症代谢重编程。因此，我们发现ATRA处理NB 4细胞后，可激活有氧糖酵解途径，减少OXPHOS依赖的ATP生成。总体而言，这项研究代表了一个重要的资源，在理解的分子“投资组合”的APL分化的关键，可以探索开发新的治疗策略。
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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影响因子：
8
作者：
Fazi, F;Travaglini, L;Nervi, C
通讯作者：
Nervi, C
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