scholarly journals A circular RNA derived from PLXNB2 as a valuable predictor of the prognosis of patients with acute myeloid leukaemia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Leilei Lin ◽  
Yu Wang ◽  
Sicheng Bian ◽  
Lili Sun ◽  
Zhibo Guo ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Regulatory Networks ◽  
Clinical Samples ◽  
Circular Rnas ◽  
Qrt Pcr ◽  
Rna Fish ◽  
Acute Myeloid

Abstract Background As a common haematological malignancy, acute myeloid leukaemia (AML), particularly with extramedullary infiltration (EMI), often results in a high mortality rate and poor prognosis. Circular RNAs (circRNAs) regulate biological and pathogenic processes, suggesting a potential role in AML. We have previously described the overall alterations in circRNAs and their regulatory networks between patients with AML presenting with and without EMI. This study aims to find new prognostic and therapeutic targets potentially associated with AML. Methods qRT-PCR was performed on samples from 40 patients with AML and 15 healthy controls. The possibility of using circPLXNB2 (circRNA derived from PLXNB2) as a diagnostic and prognostic biomarker for AML was analysed with multiple statistical methods. In vitro, the function of circPLXNB2 was studied by lentivirus transfection, CCK-8 assays, flow cytometry, and Transwell experiments. Western blotting and qRT-PCR were performed to detect the expression of related proteins and genes. The distribution of circPLXNB2 in cells was observed using RNA fluorescence in situ hybridization (RNA-FISH). We also investigated the role of circPLXNB2 by establishing AML xenograft models in NOD/SCID mice. Results By analysing the results of qRT-PCR detection of clinical samples, the expression of the circPLXNB2 and PLXNB2 mRNAs were significantly increased in patients with AML, more specifically in patients with AML presenting with EMI. High circPLXNB2 expression was associated with an obviously shorter overall survival and leukaemia-free survival of patients with AML. The circPLXNB2 expression was positively correlated with PLXNB2 mRNA expression, as evidenced by Pearson’s correlation analysis. RNA-FISH revealed that circPLXNB2 is mainly located in the nucleus. In vitro and in vivo, circPLXNB2 promoted cell proliferation and migration and inhibited apoptosis. Notably, circPLXNB2 also increased the expression of PLXNB2, BCL2 and cyclin D1, and reduced the expression of BAX. Conclusion In summary, we validated the high expression of circPLXNB2 and PLXNB2 in patients with AML. Elevated circPLXNB2 levels were associated with poor clinical outcomes in patients with AML. Importantly, circPLXNB2 accelerated tumour growth and progression, possibly by regulating PLXNB2 expression. Our study highlights the potential of circPLXNB2 as a new prognostic predictor and therapeutic target for AML in the future.

scholarly journals Pre-clinical activity of combined LSD1 and mTORC1 inhibition in MLL-translocated acute myeloid leukaemia

Leukemia ◽  
2019 ◽  
Vol 34 (5) ◽  
pp. 1266-1277 ◽  
Author(s):  
Gauri Deb ◽  
Bettina Wingelhofer ◽  
Fabio M. R. Amaral ◽  
Alba Maiques-Diaz ◽  
John A. Chadwick ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Residual Disease ◽  
Molecular Subtype ◽  
Clinical Activity ◽  
Lineage Differentiation ◽  
A Genome ◽  
Acute Myeloid

AbstractThe histone demethylase lysine-specific demethylase 1 (LSD1 or KDM1A) has emerged as a candidate therapeutic target in acute myeloid leukaemia (AML); tranylcypromine-derivative inhibitors induce loss of clonogenic activity and promote differentiation, in particular in the MLL-translocated molecular subtype of AML. In AML, the use of drugs in combination often delivers superior clinical activity. To identify genes and cellular pathways that collaborate with LSD1 to maintain the leukaemic phenotype, and which could be targeted by combination therapies, we performed a genome-wide CRISPR-Cas9 dropout screen. We identified multiple components of the amino acid sensing arm of mTORC1 signalling—RRAGA, MLST8, WDR24 and LAMTOR2—as cellular sensitizers to LSD1 inhibition. Knockdown of mTORC1 components, or mTORC1 pharmacologic inhibition, in combination with LSD1 inhibition enhanced differentiation in both cell line and primary cell settings, in vitro and in vivo, and substantially reduced the frequency of clonogenic primary human AML cells in a modelled minimal residual disease setting. Synergistic upregulation of a set of transcription factor genes associated with terminal monocytic lineage differentiation was observed. Thus, dual mTORC1 and LSD1 inhibition represents a candidate combination approach for enhanced differentiation in MLL-translocated AML which could be evaluated in early phase clinical trials.

Low-dose cytarabine for acute myeloid leukaemia and myelodysplastic syndromes: in vivo and in vitro cytotoxicity

1991 ◽  
Vol 27 (7) ◽  
pp. 842-845 ◽  
Author(s):  
Gerrit J. Ossenkoppele ◽  
Pierre W. Wijermans ◽  
J.J.P. Nauta ◽  
Peter C. Huijgens ◽  
Mart M.A.C. Langenhuijsen
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Myelodysplastic Syndromes ◽  
Low Dose ◽  
In Vitro Cytotoxicity ◽  
Low Dose Cytarabine ◽  
Acute Myeloid

scholarly journals Luks-pv Induces Apoptosis Through Methyltransferase Set8 in Human Acute Myeloid Leukaemia Cells

2020 ◽  
Author(s):  
Liangfei Xu ◽  
Lan Shi ◽  
Pengsheng Ding ◽  
Fan Ma ◽  
Yangyan Wang ◽  
...  
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Cell Apoptosis ◽  
Target Genes ◽  
Chip Sequencing ◽  
Reverse Transcription Pcr ◽  
Induced Apoptosis ◽  
Acute Myeloid

Abstract Background We previously reported that LukS-PV induces apoptosis in human acute myeloid leukaemia (AML) cells. Furthermore, SET8 is a member of the SET domain-containing methyltransferase family and overexpressed in numerous tumours, including AML and indicated a poor prognosis. However, it is unclear whether LukS-PV induce apoptosis via SET8. In current study, we aimed to investigate the regulatory mechanisms of SET8 and effects on AML cells under the LukS-PV.Methods Flow cytometry was performed to detect apoptosis in AML primary blasts/cell lines treated with LukS-PV and invasion of AML cells in vivo. The expression of SET8 was quantified through reverse-transcription PCR and western blotting. Chromatin-immunoprecipitation (ChIP) sequencing and bioinformatic methods was performed to explore transcriptional target genes which regulated by SET8-H4K20me1 axis. All experiments were performed in triplicate, and all statistical analyses were conducted using SPSS 16.0.Results In this research, we found that LukS-PV induce cell apoptosis in vitro and inhibit cell invasion in vivo. Our results further confirmed SET8 and H4K20me1 were downregulated in LukS-PV-treated AML cells. Furthermore, we confirmed that LukS-PV induced apoptosis via downregulating SET8/H4K20me1. Finally, Genome-wide analysis identified PIK3CB is the target gene for cell apoptosis mediated by SET8/H4K20me1. In a nutshell, LukS-PV induces apoptosis via the PIK3CB/PI3K/AKT/FOXO1 signal pathway by targeting SET8.Conclusions The present results indicate that LukS-PV induces apoptosis in AML cells by downregulating SET8 and regulating downstream molecular targets, suggesting that SET8 is a potential target for AML therapy using LukS-PV for anti-leukaemia treatment.

scholarly journals Circ_0030998 Promotes Tumor Proliferation and Angiogenesis by Sponging miR-567 to Regulate VEGFA in Colorectal Cancer

2020 ◽  
Author(s):  
Longyang Jin ◽  
Chao Han ◽  
Tianyu Zhai ◽  
Xiaoyu Zhang ◽  
Chun Chen ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Circular Rnas ◽  
Potential Therapeutic Target ◽  
Bioinformatic Tools ◽  
Qrt Pcr ◽  
In Vivo Assays ◽  
Rna Fish ◽  
Expression Of Genes

Abstract BackgroundColorectal cancer (CRC) is one of the most common malignancies worldwide. Accumulating studies have demonstrated that circular RNAs (circRNAs), a novel class of noncoding RNAs, are involved in pathological processes, especially in the development of cancers. But the roles of circRNAs in CRC are largely unknown.MethodsThe microarray data GSE138589 was analyzed and qRT-PCR was performed to screen out the circRNA with the highest upregulated level in CRC. QRT-PCR was used to determine the expression of genes in different tissues or cells. RNA-FISH was conducted to identify the subcellular localization of Circ_0030998. In vitro and in vivo assays were performed to determine the effect of Circ_0030998 on the CRC cells proliferation and angiogenesis. The relationships of Circ_0030998, miR-567 and VEGFA were predicted and validated using bioinformatic tools, RIP and luciferase assays.ResultsWe identified a novel circRNA, Circ_0030998, was upregulated in CRC tissues and cells, and its upregulation was related with poor prognosis in CRC patients. Circ_0030998 promoted CRC cells proliferation and angiogenesis. RNA-FISH showed that Circ_0030998 was mainly localized in the cytoplasm of CRC cells. Mechanistic studies demonstrated that Circ_0030998 acted as a miR-567 sponge to relieve its inhibitory effect on VEGFA. Rescue assays validated that Circ_0030998 functioned in CRC cells proliferation and angiogenesis relying on VEGFA.ConclusionsThe present study clarified the Circ_0030998/miR-567/VEGFA regulation axis and indicated that Circ_0030998 could be a potential therapeutic target for CRC.

scholarly journals Novel Identified Circular Transcript of RCAN2, circ-RCAN2, Shows Deviated Expression Pattern in Pig Reperfused Infarcted Myocardium and Hypoxic Porcine Cardiac Progenitor Cells In Vitro

2021 ◽  
Vol 22 (3) ◽  
pp. 1390
Author(s):  
Julia Mester-Tonczar ◽  
Patrick Einzinger ◽  
Johannes Winkler ◽  
Nina Kastner ◽  
Andreas Spannbauer ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Progenitor Cells ◽  
Regulatory Networks ◽  
Circular Rnas ◽  
Cardiac Progenitor Cells ◽  
Tissue Samples ◽  
Healthy Myocardium ◽  
Acute Mi

Circular RNAs (circRNAs) are crucial in gene regulatory networks and disease development, yet circRNA expression in myocardial infarction (MI) is poorly understood. Here, we harvested myocardium samples from domestic pigs 3 days after closed-chest reperfused MI or sham surgery. Cardiac circRNAs were identified by RNA-sequencing of rRNA-depleted RNA from infarcted and healthy myocardium tissue samples. Bioinformatics analysis was performed using the CIRIfull and KNIFE algorithms, and circRNAs identified with both algorithms were subjected to differential expression (DE) analysis and validation by qPCR. Circ-RCAN2 and circ-C12orf29 expressions were significantly downregulated in infarcted tissue compared to healthy pig heart. Sanger sequencing was performed to identify the backsplice junctions of circular transcripts. Finally, we compared the expressions of circ-C12orf29 and circ-RCAN2 between porcine cardiac progenitor cells (pCPCs) that were incubated in a hypoxia chamber for different time periods versus normoxic pCPCs. Circ-C12orf29 did not show significant DE in vitro, whereas circ-RCAN2 exhibited significant ischemia-time-dependent upregulation in hypoxic pCPCs. Overall, our results revealed novel cardiac circRNAs with DE patterns in pCPCs, and in infarcted and healthy myocardium. Circ-RCAN2 exhibited differential regulation by myocardial infarction in vivo and by hypoxia in vitro. These results will improve our understanding of circRNA regulation during acute MI.

scholarly journals Macrophages in Acute Myeloid Leukaemia: Significant Players in Therapy Resistance and Patient Outcomes

2021 ◽  
Vol 9 ◽  
Author(s):  
Katerina E. Miari ◽  
Monica L. Guzman ◽  
Helen Wheadon ◽  
Mark T. S. Williams
Keyword(s):  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Clinical Outcomes ◽  
Patient Outcomes ◽  
Therapy Resistance ◽  
Research Field ◽  
Cell Death Pathways ◽  
Leukaemic Cells ◽  
Acute Myeloid

Acute Myeloid Leukaemia (AML) is a commonly occurring severe haematological malignancy, with most patients exhibiting sub-optimal clinical outcomes. Therapy resistance significantly contributes towards failure of traditional and targeted treatments, disease relapse and mortality in AML patients. The mechanisms driving therapy resistance in AML are not fully understood, and approaches to overcome therapy resistance are important for curative therapies. To date, most studies have focused on therapy resistant mechanisms inherent to leukaemic cells (e.g., TP53 mutations), overlooking to some extent, acquired mechanisms of resistance through extrinsic processes. In the bone marrow microenvironment (BMME), leukaemic cells interact with the surrounding bone resident cells, driving acquired therapy resistance in AML. Growing evidence suggests that macrophages, highly plastic immune cells present in the BMME, play a role in the pathophysiology of AML. Leukaemia-supporting macrophage subsets (CD163+CD206+) are elevated in preclinical in vivo models of AML and AML patients. However, the relationship between macrophages and therapy resistance in AML warrants further investigation. In this review, we correlate the potential links between macrophages, the development of therapy resistance, and patient outcomes in AML. We specifically focus on macrophage reprogramming by AML cells, macrophage-driven activation of anti-cell death pathways in AML cells, and the association between macrophage phenotypes and clinical outcomes in AML, including their potential prognostic value. Lastly, we discuss therapeutic targeting of macrophages, as a strategy to circumvent therapy resistance in AML, and discuss how emerging genomic and proteomic-based approaches can be utilised to address existing challenges in this research field.

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