A Novel miRNA Restores the Chemosensitivity of AML Cells Through Targeting FosB

Wang, Huiwen; Zhan, Huien; Xinya, Jiang; Jin, Li-Lian; Zhao, Tianming; Xie, Shurong; Liu, Wei; Jia, Yan; Liang, Hui; Zeng, Hui

doi:10.3389/fmed.2020.582923

Cited by 7 publications

(6 citation statements)

References 20 publications

(20 reference statements)

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“…Therefore, small molecule inhibitors targeting UPR components are promising candidates for overcoming drug resistance. A growing number of studies have proven that miRNAs can act as tumor promoters or suppressors, and their dysregulation promotes tumor metastasis and therapeutic resistance by facilitating the activation of oncogenic signaling pathways [162][163][164]. For instance, miR-410 as a carcinogenic miRNA contributes to tumorigenesis and increases cell resistance to cisplatin in lung cell lines [165].…”

Section: Therapeutic Strategies Based On Ncrnas and The Upr In Cancermentioning

confidence: 99%

Interplay between endoplasmic reticulum stress and non-coding RNAs in cancer

Zhao

Zeng

2020

J Hematol Oncol

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To survive, cancer cells are subjected to various internal and external adverse factors, including genetic mutations, hypoxia, nutritional deficiencies, and drug toxicity. All of these factors result in the accumulation of unfolded proteins in the endoplasmic reticulum, which leads to a condition termed endoplasmic reticulum stress (ER stress) and triggers the unfolded protein response (UPR). UPR downstream components strictly control transcription and translation reprogramming to ensure selective gene expression, including that of non-coding RNA (ncRNAs), to adapt to adverse environments. NcRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play important roles in regulating target gene expression and protein translation, and their aberrant expression is related to tumor development. Dysregulation of ncRNAs is involved in the regulation of various cellular characteristics of cancer cells, including growth, apoptosis, metastasis, angiogenesis, drug sensitivity, and tumor stem cell properties. Notably, ncRNAs and ER stress can regulate each other and collaborate to determine the fate of tumor cells. Therefore, investigating the interaction between ER stress and ncRNAs is crucial for developing effective cancer treatment and prevention strategies. In this review, we summarize the ER stress-triggered UPR signaling pathways involved in carcinogenesis followed by the mutual regulation of ER stress and ncRNAs in cancer, which provide further insights into the understanding of tumorigenesis and therapeutic strategies.

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Section: Therapeutic Strategies Based On Ncrnas and The Upr In Cancermentioning

confidence: 99%

Interplay between endoplasmic reticulum stress and non-coding RNAs in cancer

Zhao

Zeng

2020

J Hematol Oncol

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“…Among AP‐1 inhibitors, T‐5224 is a lead compound that specifically inhibits the binding of AP‐1 to regulatory regions of target genes, such as inflammation‐related genes, 36,37 and is currently under phase II clinical trials for patients with rheumatoid arthritis and other inflammatory diseases after the absence of serious side effects was confirmed in phase I trials (JapicCTI‐101359) 38 . The clinical relevance of AP‐1 inhibitors is supported by a recent report that T‐5224 was able to restore the sensitivity of acute myeloid leukaemia cells to cytosine arabinoside 48 . The spectrum of clinical applications of AP‐1 inhibitors might be expanded to MM in combination with lenalidomide in the future.…”

Section: Discussionmentioning

confidence: 91%

c‐FOS is an integral component of the IKZF1 transactivator complex and mediates lenalidomide resistance in multiple myeloma

Osada

Kikuchi

Iha

et al. 2023

Clinical & Translational Med

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BackgroundThe immunomodulatory drug lenalidomide, which is now widely used for the treatment of multiple myeloma (MM), exerts pharmacological action through the ubiquitin‐dependent degradation of IKZF1 and subsequent down‐regulation of interferon regulatory factor 4 (IRF4), a critical factor for the survival of MM cells. IKZF1 acts principally as a tumour suppressor via transcriptional repression of oncogenes in normal lymphoid lineages. In contrast, IKZF1 activates IRF4 and other oncogenes in MM cells, suggesting the involvement of unknown co‐factors in switching the IKZF1 complex from a transcriptional repressor to an activator. The transactivating components of the IKZF1 complex might promote lenalidomide resistance by residing on regulatory regions of the IRF4 gene to maintain its transcription after IKZF1 degradation.MethodsTo identify unknown components of the IKZF1 complex, we analyzed the genome‐wide binding of IKZF1 in MM cells using chromatin immunoprecipitation‐sequencing (ChIP‐seq) and screened for the co‐occupancy of IKZF1 with other DNA‐binding factors on the myeloma genome using the ChIP‐Atlas platform.ResultsWe found that c‐FOS, a member of the activator protein‐1 (AP‐1) family, is an integral component of the IKZF1 complex and is primarily responsible for the activator function of the complex in MM cells. The genome‐wide screening revealed the co‐occupancy of c‐FOS with IKZF1 on the regulatory regions of IKZF1‐target genes, including IRF4 and SLAMF7, in MM cells but not normal bone marrow progenitors, pre‐B cells or mature T‐lymphocytes. c‐FOS and IKZF1 bound to the same consensus sequence as the IKZF1 complex through direct protein‐protein interactions. The complex also includes c‐JUN and IKZF3 but not IRF4. Treatment of MM cells with short‐hairpin RNA against FOS or a selective AP‐1 inhibitor significantly enhanced the anti‐MM activity of lenalidomide in vitro and in two murine MM models. Furthermore, an AP‐1 inhibitor mitigated the lenalidomide resistance of MM cells.ConclusionsC‐FOS determines lenalidomide sensitivity and mediates drug resistance in MM cells as a co‐factor of IKZF1 and thus, could be a novel therapeutic target for further improvement of the prognosis of MM patients.

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“…3E ). The B/My MPAL B-lymphoid lineage demonstrated significant enrichment of FOSB pathways, which has been associated with poor outcomes in AML (45). The TNFA signaling pathway via NF-κB was also found to be specifically enriched in a progenitor lineage that is known to promote leukemia cell survival in AML ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The upregulation of these pathways in B/My MPAL T cells suggests that there may be activity related to immunosuppression, T cell proliferation, and T cell activation present. Enrichment of the FOSB pathways in B/My MPAL B cells and the TNFA signaling pathway via NF-κB in progenitor cells have been associated with poor leukemia outcomes (45). For T/My MPAL, B-lymphoid cells showed enrichment of multiple pathways including IL-10 signaling, the CSK pathway, and IFN-γ signaling.…”

Section: Discussionmentioning

confidence: 99%

Single Cell RNA Sequencing Driven Characterization of Pediatric Mixed Phenotype Acute Leukemia

Mumme

Raikar

Bhasin

et al. 2022

Preprint

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BackgroundMixed phenotype acute leukemia (MPAL) is a rare subgroup of leukemia characterized by blast cells that display both myeloid and lymphoid lineage features, making this cancer difficult to diagnose and treat. A deeper characterization of MPAL at the molecular level is essential to better understand similarities/differences to the more common and better-studied leukemias, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Therefore, we performed single-cell RNA sequencing (scRNAseq) on MPAL bone marrow (BM) samples in an attempt to develop a more granular map of the MPAL microenvironment landscape.MethodsWe analyzed ∼16,000 cells from five pediatric MPAL BM samples collected at diagnosis to generate a single-cell transcriptomic landscape of B/Myeloid (B/My) and T/Myeloid (T/My) MPAL blasts and associated microenvironment cells. Cell clusters were identified using principal component analysis and uniform manifold approximation and projection (UMAP). Unsupervised analysis was performed to determine the overall relationship among B/My MPAL, T/My MPAL, and other acute leukemias – B-ALL, T-ALL, and AML. Supervised differentially expressed gene (DEG) analysis was performed to identify B/My and T/My MPAL blast-specific signatures. MPAL sample transcriptome profiles were compared with normal BM stem and immune cells to identify MPAL-specific dysregulation. Gene set enrichment analysis (GSEA) was performed, and significantly enriched pathways were compared in MPAL subtypes. Comparative analysis was performed on diagnostic samples based on their future minimal residual disease (MRD) and relapse status.ResultsB/My MPAL and T/My MPAL blasts displayed distinct subtype-specific blast signatures. UMAP analysis revealed that B/My MPAL samples had greater overlap with B-ALL samples, while T/My MPAL samples clustered separately from other acute leukemia subtypes. Genes overexpressed in both MPAL subtypes’ blasts compared to other leukemias and healthy controls included PLIN2, CD81, and UBE2S. B/My MPAL blast-specific genes included IRS2, SMIM3, and HBEGF, whereas T/My MPAL blast-overexpressed genes included IER5, BOD1L1, and HPGD. Sirtuin signaling, p38 MPAK signaling, and PI3K signaling pathways were upregulated in B/My MPAL blasts while oxidative phosphorylation and Rho family GTPases signaling pathways were upregulated in T/My MPAL blasts. Transcriptomic, pathways, and cell communication level differences were observed in the MPAL samples based on future MRD and clinical outcome status.ConclusionsWe have for the first time described the single-cell landscape of pediatric MPAL and demonstrate that B/My and T/My MPAL have unique scRNAseq profiles distinct from each other as well as from ALL and AML.

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A Novel miRNA Restores the Chemosensitivity of AML Cells Through Targeting FosB

Cited by 7 publications

References 20 publications

Interplay between endoplasmic reticulum stress and non-coding RNAs in cancer

Interplay between endoplasmic reticulum stress and non-coding RNAs in cancer

c‐FOS is an integral component of the IKZF1 transactivator complex and mediates lenalidomide resistance in multiple myeloma

Single Cell RNA Sequencing Driven Characterization of Pediatric Mixed Phenotype Acute Leukemia

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