scholarly journals Revealing Key LncRNAs in Cytogenetically Normal Acute Myeloid Leukemia by Reconstruction of the LncRNA–miRNA–mRNA Network Based on the Competitive Endogenous RNA Theory

2021 ◽  
Author(s):  
Tao Sun ◽  
Lin Dong ◽  
Yan Guo ◽  
Hai Zhao ◽  
Manzhi Wang
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Expression Omnibus ◽  
Prognostic Indicators ◽  
Functional Assay ◽  
Protein Coding ◽  
Therapy Targets ◽  
Non Coding Rnas ◽  
Competitive Endogenous Rna ◽  
Acute Myeloid

Abstract Background Cytogenetically normal acute myeloid leukemia(CN-AML) is a heterogeneous disease with different prognosis.Researches on prognostic indicators and therapy targets of CN-AML are still ongoing.Instead of protein-coding genes,more and more researches were focused on the non-coding RNAs especially long non-coding RNAs(lncRNAs) which may play an important role in the development and prognosis of AML.Although a large number of lncRNAs had been found, our knowledge of their function and pathological significance is still in its infancy.The purpose of this research is to identify the key lncRNAs and explore their function in CN-AML by reconstructing the lncRNA–miRNA–mRNA network based on the competitive endogenous RNA(ceRNA) theory. Results We reconstructed a global triple network based on the ceRNA theory using the data from National Center for Biotechnology Information Gene Expression Omnibus and published literature. According to the topological algorithm,we identified the key lncRNAs which had both the higher node degrees and the higher number of lncRNA–miRNA and miRNA–mRNA pairs in the ceRNA network. Meanwhile, Gene Ontology (GO) and pathway analysis were performed using databases such as DAVID,KOBAS and Cytoscape plug-in ClueGO respectively.The lncRNA–miRNA–mRNA network was composed of 90 lncRNAs,33mRNAs,26 miRNAs and 259 edges in the lncRNA upregulated group,and 18 lncRNAs,11 mRNAs,6 miRNAs and 45 edges in the lncRNA downregulated group.The functional assay showed that 53 pathways and 108 GO terms were enriched. Three lncRNAs(XIST,GABPB1-AS1,TUG1)could possibly be selected as key lncRNAs wihch may play an important role in the development of CN-AML.Particularly,GABPB1-AS1 was highly expressed in CN-AML by both bioinformatics analysis and experimental verification in AML cell line(THP-1) by quantitative real-time polymerase chain reaction.In addition, GABPB1-AS1 was also negatively correlated with overall survival of AML patients. Conclusion The lncRNA–miRNA–mRNA network revealed key lncRNAs and their functions in CN-AML.Particularly,lncRNA GABPB1-AS1 was firstly proposed in AML.We believe that GABPB1-AS1 is expected to become a candidate diagnostic biomarker or potential therapeutic target.

scholarly journals Revealing key lncRNAs in cytogenetically normal acute myeloid leukemia by reconstruction of the lncRNA–miRNA–mRNA network based on the competitive endogenous RNA theory

2021 ◽  
Author(s):  
Tao Sun ◽  
Lin Dong ◽  
Yan Guo ◽  
Hai Zhao ◽  
Manzhi Wang
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Expression Omnibus ◽  
Prognostic Indicators ◽  
Functional Assay ◽  
Protein Coding ◽  
Therapy Targets ◽  
Non Coding Rnas ◽  
Competitive Endogenous Rna ◽  
Acute Myeloid

Abstract Background: Cytogenetically normal acute myeloid leukemia(CN-AML) is a heterogeneous disease with different prognosis.Researches on prognostic indicators and therapy targets of CN-AML are still ongoing.Instead of protein-coding genes,more and more researches were focused on the non-coding RNAs especially long non-coding RNAs(lncRNAs) which may play an important role in the development and prognosis of AML.Although a large number of lncRNAs had been found, our knowledge of their function and pathological significance is still in its infancy.The purpose of this research is to identify the key lncRNAs and explore their function in CN-AML by reconstructing the lncRNA–miRNA–mRNA network based on the competitive endogenous RNA(ceRNA) theory. Results: We reconstructed a global triple network based on the ceRNA theory using the data from National Center for Biotechnology Information Gene Expression Omnibus and published literature. According to the topological algorithm,we identified the key lncRNAs which had both the higher node degrees and the higher number of lncRNA–miRNA and miRNA–mRNA pairs in the ceRNA network. Meanwhile, Gene Ontology (GO) and pathway analysis were performed using databases such as DAVID,KOBAS and Cytoscape plug-in ClueGO respectively.The lncRNA–miRNA–mRNA network was composed of 90 lncRNAs,33mRNAs,26 miRNAs and 259 edges in the lncRNA upregulated group,and 18 lncRNAs,11 mRNAs,6 miRNAs and 45 edges in the lncRNA downregulated group.The functional assay showed that 53 pathways and 108 GO terms were enriched. Three lncRNAs(XIST,GABPB1-AS1,TUG1)could possibly be selected as key lncRNAs wihch may play an important role in the development of CN-AML.Particularly,GABPB1-AS1 was highly expressed in CN-AML by both bioinformatics analysis and experimental verification in AML cell line(THP-1) by quantitative real‐time polymerase chain reaction.In addition, GABPB1-AS1 was also negatively correlated with overall survival of AML patients. Conclusion: The lncRNA–miRNA–mRNA network revealed key lncRNAs and their functions in CN-AML.Particularly,lncRNA GABPB1-AS1 was firstly proposed in AML.We believe that GABPB1-AS1 is expected to become a candidate diagnostic biomarker or potential therapeutic target.

scholarly journals The characteristics of circRNA as competing endogenous RNA in pathogenesis of acute myeloid leukemia

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Siyuan Zhang
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Gene Expression Omnibus ◽  
The Novel ◽  
Competing Endogenous Rna ◽  
Regulatory Modules ◽  
Cerna Network ◽  
Regulatory Module ◽  
Acute Myeloid

Abstract Background As one of the novel molecules, circRNA has been identified closely involved in the pathogenesis of many diseases. However, the function of circRNA in acute myeloid leukemia (AML) still remains unknown. Methods In the current study, the RNA expression profiles were obtained from Gene Expression Omnibus (GEO) datasets. The differentially expressed RNAs were identified using R software and the competing endogenous RNA (ceRNA) network was constructed using Cytoscape. Functional and pathway enrichment analyses were performed to identify the candidate circRNA-mediated aberrant signaling pathways. The hub genes were identified by MCODE and CytoHubba plugins of Cytoscape, and then a subnetwork regulatory module was established. Results A total of 27 circRNA-miRNA pairs and 208 miRNA-mRNA pairs, including 12 circRNAs, 24 miRNAs and 112 mRNAs were included in the ceRNA network. Subsequently, a subnetwork, including 4 circRNAs, 5 miRNAs and 6 mRNAs, was established based on related circRNA-miRNA-mRNA regulatory modules. Conclusions In summary, this work analyzes the characteristics of circRNA as competing endogenous RNA in AML pathogenesis, which would provide hints for developing novel prognostic, diagnostic and therapeutic strategy for AML.

New Molecular Therapy Targets in Acute Myeloid Leukemia

2007 ◽  
pp. 243-262 ◽  
Author(s):  
Utz Krug ◽  
Hubert Serve ◽  
Carsten Müller-Tidow ◽  
Rolf M. Mesters ◽  
Björn Steffen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Therapy ◽  
Therapy Targets ◽  
Acute Myeloid

Clinical and Functional Relevance of Interactions Between the Bone Marrow Stormal Microenvironment and Primary Human Acute Myeloid Leukemia (AML) Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2756-2756
Author(s):  
Soumit K. Basu ◽  
Sylvia Chien ◽  
Xin Zhao ◽  
Kenneth J. Kopecky ◽  
Frederick R. Appelbaum ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
T Test ◽  
Laminin Receptor ◽  
Functional Assay ◽  
Adhesion Receptors ◽  
Adhesion Receptor ◽  
Acute Myeloid ◽  
E Cadherin

Abstract Abstract 2756 Objectives: Adhesion of acute myeloid leukemia (AML) blasts in the bone marrow (BM) microenvironment confers protection from chemotherapy cytotoxicity. We sought to extend our knowledge of the molecular mechanisms by which the BM stroma support AML by identifying all functionally relevant adhesion receptors that were associated with clinical outcomes, identifying new functional AML-stromal interactions, and examining for aberrant cytokine production by stroma derived from patient AML BM. Methods: We prospectively analyzed by multicolor flow cytometry the expression of 17 different adhesion receptors by AML blasts derived from peripheral blood or BM of 42 adult patients, ages 19–80. Analyses included percent expression, mean fluorescence intensity (MFI), and in 7 patients, the adhesion receptors expressed by the CD34+CD38−CD123+ putative leukemia stem cell (LSC) population. We correlated percent expression and MFI with the likelihood of complete remission (CR) using Wilcoxon two-sample testing with Monte Carlo estimation of the exact p value. Guided by data from the AML blast adhesion receptor analyses, we designed a functional screen to assay primary AML blast adhesion to a normal BM stromal cell line (HS27a). For 10 patients, we assessed the capacity of function blocking monoclonal antibodies directed against a panel of 11 adhesion molecules to inhibit adhesion of purified primary AML blasts to HS27a, allowing functional identification of previously undescribed AML-stromal adhesion determinants not only on AML cells but also on BM stroma. Lastly, we successfully grew primary BM stroma from 5 AML patients, assessed production of 10 cytokines important for normal hematopoiesis, and measured the same cytokines directly in plasma of AML patient BM aspirate specimens. Results: Adhesion receptor analysis demonstrates that the mean expression by all AML patients was >90% for CD11a, β1, PECAM-1, CD44, α4, and α5. Comparison of the adhesion receptor profile of the LSC population to the blast population from which they derived showed a 23.1% +/− 7.7% (mean ± standard error) increase in the expression of α6, and a decrease by 0.4% ± 2.5% for CD34+ blasts compared with all blasts (p = 0.04, Student t-test). We found that in our sample of 18 pretreatment BM samples the 15 patients having CR had a higher MFI for αL (p = 0.021), a higher % blasts expressing α4 (p = 0.039) and PECAM1 (p = 0.012), and a lower MFI for α2 (p = 0.029), α6 (p = 0.028), and CXCR4 (p = 0.005). The data for α4 and CXCR4 agree with prior publications demonstrating improved outcomes for high α4β1 expression and poorer outcomes with high CXCR4 expression (Blood 2009; 113:866–74, J Clin Oncol 2010; 28:2831–8, Blood 2007; 109:786–91). Analyzing the functional importance of adhesion receptors for AML-stromal interactions, we found that function blocking antibodies to β1 (p = 0.0003, Student two-sided t-test), CXCR4 (p < 0.0001), and E-cadherin (p < 0.00002) most strongly inhibited AML blast adhesion to HS27a, with mean inhibitions of 71%, 67%, and 63% respectively (Fig 1). While β1 and CXCR4 represent known factors in AML-stromal adhesion, we propose a novel role for E-cadherin in AML as a potentially novel therapeutic target whose known biology in other malignancies spans cell-cell adhesion and canonical β-catenin/Wnt signaling. The magnitude of the β1 blocking effect proved consistent with its partnering role with multiple adhesion receptors (e.g. α2, α4, α5, and α6). Analyzing the microenvironment cytokine milieu we found normal BM produced G-CSF, SDF-1, and SCF (6, 3001, and 4857 pg/mL respectively) as expected while some AML specimens produced undetectable levels of G-CSF (4/5 plasmas, 4/5 stromas), SCF (4/5 plasmas), or SDF-1 (2/5 plasmas, 3/5 stromas). Conclusions: Among the 6 receptors correlated with response to induction chemotherapy, high α6 (VLA6 laminin receptor) and CXCR4 MFI correlated with poor outcome. The putative LSC subpopulation showed significantly more α6 expression compared with the entire AML blast population. Antibodies against β1, CXCR4, and E-cadherin exhibited the highest function blocking (60–75% range) of AML-stromal adhesion and our AML-stroma functional assay offers a tool to screen for more novel interactions. Cytokine profiling of the AML microenvironment showed deficiencies in cytokines necessary for normal hematopoiesis which may contribute to the clinical cytopenias in AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Noncoding RNAs in Acute Myeloid Leukemia: From Key Regulators to Clinical Players

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Alessandro Fatica
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Suppressor Genes ◽  
Myeloid Leukemia ◽  
Hematological Malignancies ◽  
Aberrant Expression ◽  
Genetic Abnormalities ◽  
Non Coding Rnas ◽  
Recent Demonstration ◽  
Acute Myeloid

Recent analyses have shown that human cells transcribe almost their entire genomes, implying the existence of a huge mass of ncRNAs. At the present, microRNAs are the most investigated regulative non-coding RNAs. Several studies have demonstrated that microRNAs play a crucial role in hematopoietic differentiation and hematological malignancies, including acute myeloid leukemia (AML). Aberrant expression of microRNAs has been associated with specific genetic abnormalities and clinical outcome of patients with AML. In addition, since microRNAs can function as either oncogenes or tumor suppressor genes, the potential of using these molecules as therapeutic targets opens up new opportunities in the future of AML therapy. The recent demonstration that other regulatory ncRNAs, in addition to microRNAs, are involved in hematopoietic cell differentiation and diseases, suggests that they may also have a biological relevance in AML. This paper will describe the role of ncRNAs in AML and discuss the expectations for the use of ncRNAs in diagnosis, prognosis, and therapy of AML.

scholarly journals Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia

Haematologica ◽  
2021 ◽  
Author(s):  
Dimitrios Papaioannou ◽  
Hatice G. Ozer ◽  
Deedra Nicolet ◽  
Amog P. Urs ◽  
Tobias Herold ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Rna Sequencing ◽  
Clinical Significance ◽  
Genetic Variants ◽  
Myeloid Leukemia ◽  
Sequencing Data ◽  
Younger Adults ◽  
Non Coding Rnas ◽  
Acute Myeloid

Expression levels of long non-coding RNAs (lncRNAs) have been shown to associate with clinical outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the frequency and clinical significance of genetic variants in the nucleotide sequences of lncRNAs in AML patients is unknown. Herein, we analyzed total RNA sequencing data of 377 younger adults (aged

scholarly journals SPOP accelerates acute myeloid leukemia initiation and development through miR-183-mediated METAP2 inhibition

2020 ◽  
Author(s):  
Jifeng Yu ◽  
Yingmei Li ◽  
Ling Sun ◽  
Lijie Han ◽  
Yu Liu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Nuclear Translocation ◽  
In Silico Analysis ◽  
Prognostic Indicators ◽  
Proliferation And Apoptosis ◽  
Functional Relevance ◽  
Acute Myeloid

Abstract Background: Recent miRNA profiling studies have implicated the potential use of miRNAs as as diagnostic and prognostic indicators in acute myeloid leukemia (AML), which has been reportedly implicated in the interplay with certain mRNAs. Herein this study, we intend to characterize the functional relevance of SPOP/miR-183/METAP2 axis in AML in vivo and in vitro. Methods: Differentially expressed mRNAs and downstream regulatory miRNA were predicted by in silico analysis. We induced SPOP/miR-183/METAP2 overexpression or inhibition to examine their effects on AML cell proliferation and apoptosis in vitro and tumor growth in vivo , along with their interaction with β-catenin. Results: SPOP and miR-183 were highly expressed, while METAP2 was poorly expressed in patient peripheral blood samples and cell lines of AML. SPOP accelerated the proliferation of AML cells and repressed apoptosis. Mechanistically, SPOP enhanced β-catenin protein stability and nuclear translocation leading to upregulated expression of miR-183. MiR-183 facilitated proliferation and inhibited apoptosis of AML cells by targeting METAP2. Furthermore, miR-183 inhibition and METAP2 overexpression reversed SPOP-induced AML cell malignancy. Besides, in vitro findings were reproduced by in vivo findings. Conclusion: SPOP stimulated AML malignant progression by inducing β-catenin stability and miR-183/METAP2 axis activation, highlighting a potential therapeutic target against AML recurrence and metastasis.

scholarly journals Identification of TFE3/TFEB and its Related Genes as Prognostic Biomarkers in Acute Myeloid Leukemia

2021 ◽  
Author(s):  
Qiaoli Li
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
Cell Fate ◽  
Protein Interactions ◽  
Myeloid Leukemia ◽  
Sequence Data ◽  
Gene Expression Omnibus ◽  
Prognostic Biomarkers ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is one of the most common hematologic malignances with an ever-increasing incidence and high mortality. TFE3 and TFEB, two transcription factors that mediate cellular adaptation to stress by simultaneously promoting lysosomal biogenesis, autophagy induction, as well as expression of critical mitochondrial and metabolic regulators, which are substantial contributors to cell fate and cancer progress. However, the expression and prognostic values of TFE3/TFEB in AML have not been clarified.Objective: To explore the expression and role of TFE3/TFEB in AML and thus to find potential therapy. Methods: RNA sequence data from AML patients and healthy donors were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) analysis were performed by GEO2R. TFE3/TFEB related genes were obtained from UALCAN. Gene ontology (GO) and KEGG pathway were analyzed by WEB-based GEne SeT AnaLysis Toolkit (WebGestalt) and DAVID. Protein-protein interactions (PPIs) network construction and module analysis were performed by STRING and Cytoscape. The Kaplan-Meier survival curves were drawn in TCGA portal. Results: We found TFE3 and TFEB can be used prognostic factors for AML, and most of their positively related genes were worse prognostic factors too. ITGB2, FGR, ITGAM, ITGAX and SELPLG were identified as the most significant genes in survival-related genes contributed by TFE3 and TFEB.Conclusions: In this study, we performed a comprehensive analysis of gene expression and gene function to identify key prognostic biomarkers in AML.

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