JUN is a key transcriptional regulator of the unfolded protein response in acute myeloid leukemia

Zhou, Chun; Martı́nez, Esteban; Marcantonio, Daniela Di; Solanki-Patel, Nehal; Aghayev, Turan; Peri, Suraj; Ferraro, Francesca; Skórski, Tomasz; Scholl, Claudia; Fröhling, Stefan; Balachandran, Siddharth; Wiest, David L.; Sykes, Stephen M.

doi:10.1038/leu.2016.329

Cited by 62 publications

(55 citation statements)

References 61 publications

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“…Intriguingly, shRNA-mediated genetic ablation of XBP1 or ATF4 induced AML cell apoptosis and significantly extended disease latency in vivo in a murine model. Therefore, these findings tied the reduced AML cell survival observed when c-Jun activity was inhibited, to the loss of cytoprotective UPR signaling [106]. Moreover, the results identified the UPR as a promising potential therapeutic target in AML.…”

Section: Upr Involvement In Amlmentioning

confidence: 84%

“…c-Jun has been recently identified as a key transcriptional regulator of the UPR in AML. Indeed, upon ER stress induction, c-Jun is activated via mitogen-activated protein kinase kinase (MEK)/extracellular-regulated kinase (ERK) signaling and binds to the promoters of XBP1 and ATF4, thereby increasing their transcription and allowing leukemic cells to properly negotiate ER stress through cytoprotective UPR [106]. Of note, c-Jun/UPR signaling was activated by conventional chemotherapeutics (cytarabine, doxorubicine) used for AML patient treatment.…”

Section: Upr Involvement In Amlmentioning

confidence: 99%

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The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Martelli

Paganelli

Chiarini

et al. 2020

Cancers

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The unfolded protein response (UPR) is an evolutionarily conserved adaptive response triggered by the stress of the endoplasmic reticulum (ER) due, among other causes, to altered cell protein homeostasis (proteostasis). UPR is mediated by three main sensors, protein kinase RNA-like endoplasmic reticulum kinase (PERK), activating transcription factor 6α (ATF6α), and inositol-requiring enzyme-1α (IRE1α). Given that proteostasis is frequently disregulated in cancer, UPR is emerging as a critical signaling network in controlling the survival, selection, and adaptation of a variety of neoplasias, including breast cancer, prostate cancer, colorectal cancer, and glioblastoma. Indeed, cancer cells can escape from the apoptotic pathways elicited by ER stress by switching UPR into a prosurvival mechanism instead of cell death. Although most of the studies on UPR focused on solid tumors, this intricate network plays a critical role in hematological malignancies, and especially in multiple myeloma (MM), where treatment with proteasome inhibitors induce the accumulation of unfolded proteins that severely perturb proteostasis, thereby leading to ER stress, and, eventually, to apoptosis. However, UPR is emerging as a key player also in acute leukemias, where recent evidence points to the likelihood that targeting UPR-driven prosurvival pathways could represent a novel therapeutic strategy. In this review, we focus on the oncogene-specific regulation of individual UPR signaling arms, and we provide an updated outline of the genetic, biochemical, and preclinical therapeutic findings that support UPR as a relevant, novel target in acute leukemias.

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Section: Upr Involvement In Amlmentioning

confidence: 84%

Section: Upr Involvement In Amlmentioning

confidence: 99%

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Martelli

Paganelli

Chiarini

et al. 2020

Cancers

View full text Add to dashboard Cite

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“…The c-Jun oncogene is a member of the activator protein-1 (AP-1) family of transcription factors that is phosphorylated and activated by the JNK [51]. Previous study suggested that shRNAmediated inhibition of Jun decreased AML cell survival and propagation in vivo [52].…”

Section: Discussionmentioning

confidence: 99%

Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia through inhibiting MSH2

Liu

Wang

et al. 2020

Preprint

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Background: Nuclear factor erythroid 2-related factor 2 (Nrf2, also called NFE2L2) has been shown to play a pivotal role in preventing cancer cells from being affected by chemotherapy. Gene mutation is a crucial reason of chemotherapy-resistance in acute myeloid leukemia (AML). However, the relationship between Nrf2 and tumor mutation burden and its mechanism in regulating chemotherapy-resistance remains unclear. Methods: The whole-exome sequencing analysis were used to measure tumor mutation. RNA sequencing, Oncomine, qRT-PCR, Western blotting and immunocytochemistry were employed to detect differences in genes and proteins. The KEGG pathway enrichment analysis and GeneMANIN were performed pathway analysis. Functional assays, such as annexin V/PI, Hoechst33342 staining and DCFH were performed to examine the apoptosis and reactive oxygen species (ROS) of AML cells in vitro. Subcutaneous xenograft model was established to investigate in vivo growth. Results: Nrf2 expression was associated with tumor mutation burden in AML. Patients with Nrf2 overexpression had higher frequency of gene mutation and drug resistance. Nrf2 overexpression protected the AML cells from apoptosis induced by cytarabine in vitro and increased the risk of gene mutant drug resistance in vivo. Furthermore, Nrf2 overexpression inhibited MSH2 protein expression, which caused DNA mismatch repair (MMR) deficiency. Mechanistically, the inhibition of MSH2 by Nrf2 was in a ROS-independent manner. Further studies showed that an increased activation of JNK/c-Jun signaling in Nrf2 overexpression cells, which inhibited the expression of MSH2 protein. Conclusions: Our findings provided evidence that high Nrf2 expression inhibited MSH2 expression, caused MMR deficiency and increased the tumor mutation burden, which can induce gene instability-dependent drug resistance in AML. This study demonstrates the reason why the high Nrf2 expression leads to the increase of gene mutation frequency in AML, and provides a new strategy for clinical practice.

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“…JUN encodes a virus-like protein, which regulates gene expression in response to cell stimulation by interacting directly with target DNA sequences. Several studies have shown that the transcription factor JUN is essential for neuronal microtubule assembly and apoptosis (Nateri et al 2004) and plays a very key regulatory role in the unfolded protein response in acute myeloid leukemia, which can serve as a promising therapeutic target in this disease (Zhou et al 2017). Recently, PPI analysis of AD and non-alcoholic fatty liver disease (NAFLD) has revealed that JUN is one of the hubbottleneck proteins in the PPI network and is an important target for both AD and NAFLD (Karbalaei et al 2018;Paquet et al 2017).…”

Section: Research Articlementioning

confidence: 99%

Identification of key genes and pathways for Alzheimer’s disease via combined analysis of genome-wide expression profiling in the hippocampus

Fang

Wang

et al. 2019

Biophys Rep

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In this study, combined analysis of expression profiling in the hippocampus of 76 patients with Alzheimer's disease (AD) and 40 healthy controls was performed. The effects of covariates (including age, gender, postmortem interval, and batch effect) were controlled, and differentially expressed genes (DEGs) were identified using a linear mixed-effects model. To explore the biological processes, functional pathway enrichment and protein-protein interaction (PPI) network analyses were performed on the DEGs. The extended genes with PPI to the DEGs were obtained. Finally, the DEGs and the extended genes were ranked using the convergent functional genomics method. Eighty DEGs with q \ 0.1, including 67 downregulated and 13 upregulated genes, were identified. In the pathway enrichment analysis, the 80 DEGs were significantly enriched in one Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, GABAergic synapses, and 22 Gene Ontology terms. These genes were mainly involved in neuron, synaptic signaling and transmission, and vesicle metabolism. These processes are all linked to the pathological features of AD, demonstrating that the GABAergic system, neurons, and synaptic function might be affected in AD. In the PPI network, 180 extended genes were obtained, and the hub gene occupied in the most central position was CDC42. After prioritizing the candidate genes, 12 genes, including five DEGs (ITGB5, RPH3A, GNAS, THY1, and SEPT6) and seven extended genes (JUN, GDI1, GNAI2, NEK6, UBE2D3, CDC42EP4, and ERCC3), were found highly relevant to the progression of AD and recognized as promising biomarkers for its early diagnosis.

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JUN is a key transcriptional regulator of the unfolded protein response in acute myeloid leukemia

Cited by 62 publications

References 61 publications

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

The Unfolded Protein Response: A Novel Therapeutic Target in Acute Leukemias

Nrf2 overexpression increases risk of high tumor mutation burden in acute myeloid leukemia through inhibiting MSH2

Identification of key genes and pathways for Alzheimer’s disease via combined analysis of genome-wide expression profiling in the hippocampus

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