scholarly journals The transcriptome‐wide landscape of molecular subtype‐specific mRNA expression profiles in acute myeloid leukemia

2021 ◽  
Author(s):  
Tian Mou ◽  
Yudi Pawitan ◽  
Matthias Stahl ◽  
Mattias Vesterlund ◽  
Wenjiang Deng ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mrna Expression ◽  
Myeloid Leukemia ◽  
Molecular Subtype ◽  
Expression Profiles ◽  
Acute Myeloid ◽  
Specific Mrna

DEAH-Box Splicing Factor Gene, Prp16 Amplification in Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4479-4479
Author(s):  
Yupo Ma ◽  
Tammy Barnett ◽  
Li Chai ◽  
Jianchang Yang ◽  
Zaida Alipio ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mrna Expression ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Mrna Splicing ◽  
Splicing Factor ◽  
Aberrant Expression ◽  
Factor Gene ◽  
Acute Myeloid

Abstract Aberrant mRNA splicing has been observed frequently in solid tumors and shown to play a functionally significant role in tumorgenesis. Here we demonstrate that the DEAH-Box splicing factor gene, Prp16, is amplified in fresh human acute myeloid leukemia (AML) and in established AML cell lines. Prp16, an RNA-dependent ATPase required for pre-mRNA splicing, maps to chromosome 16q22, a region frequently altered in AML. Amplification of the Prp16 gene was initially detected using digital karyotyping, a powerful technique for analyzing genome-wide alterations in DNA copy number and verified by quantitative real-time PCR. Analysis of mRNA expression profiles revealed that Prp16 transcripts were present at high levels in 22 of 39 cases of AML (56%) and in both AML cell lines examined. There was a strong correlation between gene amplification and mRNA expression levels. To our knowledge, this is the first demonstration linking aberrant expression of a splicing enzyme to leukemogenesis. The classification and clinical outcome of the AML cases is being correlated with the presence or absence of Prp16 amplification. The identification of leukemia-specific splicing event(s) may provide a novel target for therapeutic intervention.

Comprehensive Sequence Analysis of Relapse and Refractory Pediatric Acute Myeloid Leukemia Identifies miRNA and mRNA Transcripts Associated with Treatment Resistance - a Report from the COG/NCI-Target AML Initiative

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 687-687 ◽  
Author(s):  
Emilia L. Lim ◽  
Diane L. Trinh ◽  
Rhonda E. Ries ◽  
Yussanne Ma ◽  
James Topham ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mrna Expression ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Treatment Resistance ◽  
Ribosomal Genes ◽  
Survival Analyses ◽  
Pediatric Aml ◽  
Acute Myeloid ◽  
Cell Stem Cell

Abstract Introduction Induction chemotherapy results in complete remission in 80% of children with acute myeloid leukemia (AML). However, many patients either fail to achieve a remission, or relapse after an initial response and subsequently die of their disease. Although large numbers of somatic karyotypic and molecular alterations have been identified, the majority of them do not indicate a specific target or distinct pathway that can be readily exploited for therapeutic intervention. Materials & Methods As part of a genome-scale approach to identify prognostic markers and therapeutic targets, we provide a comprehensive characterization of the pediatric AML transcriptome, detailing miRNA & mRNA expression patterns and miRNA:mRNA interactions that are characteristic of the disease. A total of 676 patients were considered for this study. Our discovery cohort consisted of miRNA-seq from 259 primary, 22 refractory and 38 relapse samples, and mRNA-seq from 158 primary, 12 refractory and 47 relapse samples. We confirmed our survival analyses on a validation cohort that consisted of miRNA-seq and mRNA-seq from 378 and 87 primary samples, respectively. Unsupervised non-negative matrix factorization (NMF) was used to identify patient subgroups based on miRNA/mRNA expression. To identify miRNA/mRNA expression associated with patient survival, Cox proportional hazards analysis was performed. Wilcoxon tests were performed to identify differentially expressed miRNAs/mRNAs between samples. To screen for functional miRNA:mRNA interactions, we identified miRNA and mRNA pairs with anti-correlated expression profiles and miRNA binding site predictions consistent with miRNA:mRNA interaction. Results Survival analysis of both the discovery and validation cohorts revealed that 6 miRNAs were associated with overall survival (OS) and event free survival (EFS) (p-val<0.05, q-val<0.1): miR-181c-3p and miR-378c were associated with superior OS and EFS (Hazard Ratio (HR): 0.79-0.88), while miR-106a-3p, miR-106a-5p, miR-363-3p and miR-20b-5p were associated with inferior OS and EFS (HR: 1.14-1.36). All 4 of the miRNAs that were associated with inferior survival are members of the polycistronic miR-106a-363 cluster. Differential expression analysis revealed that miR-106a-363 was abundantly expressed in relapse and refractory samples and in primary samples of refractory patients (q-val<0.05). Integrative miRNA:mRNA expression analysis and luciferase reporter assays further revealed that targets of miR-106a-5p include NDUFC2, NDUFA10, UQCRB, ATP5J2-PTCD1 and ATP5S. Interestingly, these genes are involved in oxidative phosphorylation, a process that is suppressed in treatment-resistant leukemic cells[1]. NMF clustering of miRNA expression profiles revealed 2 groups of patients, with each group characterized by particular genomic alterations: Group 1 cases were enriched for NPM1 mutation and FLT3 -ITD, while Group 2 cases were enriched for t(8;21), inv(16), MLL rearrangements and CEBPA mutation (Fisher's exact test p-val<0.05). NMF clustering of mRNA expression revealed 5 groups of patients, in which the group with abundant expression of ribosomal genes was further distinguished by superior OS and EFS (log-rank p-val<0.05). Analysis of the mRNA data showed a decrease in expression of one mRNA isoform of ribosomal protein L28 (RPL28) in relapse samples (q-val<0.05). In addition, survival analyses revealed that abundant expression of ribosomal protein L10 (RPL10) is associated with superior OS in both the discovery and validation cohorts (p-val<0.05, q-val<0.1, HR: 0.78 & 0.47). Conclusions Through a detailed analysis of the transcriptome (Figure A), we identified miRNAs whose expression levels were significantly associated with clinical outcome. In addition, we showed that abundant expression of miR-106a-363 might contribute to treatment resistance by modulating genes involved in energy metabolism. We also demonstrated that reduced expression of ribosomal genes is associated with inferior outcomes, suggesting a dysregulation of protein translation in treatment resistance. Overall, our transcriptome profiles provide clinically meaningful data for risk and response identification and define novel pathways that may be amenable to therapeutic targeting. Figure 1. Summary of the pediatric AML transcriptome Lagadinou ED, et al. Cell Stem Cell. 2013. Figure 1. Summary of the pediatric AML transcriptome. / Lagadinou ED, et al. Cell Stem Cell. 2013. Disclosures No relevant conflicts of interest to declare.

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.

Patient-specific microRNA expression profiles as a marker for minimal residual disease in acute myeloid leukemia

Hematology ◽  
2013 ◽  
Vol 19 (1) ◽  
pp. 18-21 ◽  
Author(s):  
Velizar Shivarov ◽  
Angel Stoimenov ◽  
Branimir Spassov ◽  
Svetlana Angelova ◽  
Monika Niagolov ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Expression Profiles ◽  
Microrna Expression ◽  
Patient Specific ◽  
Minimal Residual ◽  
Acute Myeloid

scholarly journals TET2/IDH1/2/WT1 and NPM1 Mutations Influence the RUNX1 Expression Correlations in Acute Myeloid Leukemia

Medicina ◽  
2020 ◽  
Vol 56 (12) ◽  
pp. 637
Author(s):  
Sergiu Pasca ◽  
Ancuta Jurj ◽  
Ciprian Tomuleasa ◽  
Mihnea Zdrenghea
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mutational Analysis ◽  
Expression Profiles ◽  
Enrichment Analysis ◽  
Functional Enrichment Analysis ◽  
Functional Enrichment ◽  
Runx1 Expression ◽  
Acute Myeloid

Background and objectives: Mutational analysis has led to a better understanding of acute myeloid leukemia (AML) biology and to an improvement in clinical management. Some of the most important mutations that affect AML biology are represented by mutations in genes related to methylation, more specifically: TET2, IDH1, IDH2 and WT1. Because it has been shown in numerous studies that mutations in these genes lead to similar expression profiles and phenotypes in AML, we decided to assess if mutations in any of those genes interact with other genes important for AML. Materials and Methods: We downloaded the clinical data, mutational profile and expression profile from the TCGA LAML dataset via cBioPortal. Data were analyzed using classical statistical methods and functional enrichment analysis software represented by STRING and GOrilla. Results: The first step we took was to assess the 196 AML cases that had a mutational profile available and observe the mutations that overlapped with TET2/IDH1/2/WT1 mutations. We observed that RUNX1 mutations significantly overlap with TET2/IDH1/2/WT1 mutations. Because of this, we decided to further investigate the role of RUNX1 mutations in modulating the level of RUNX1 mRNA and observed that RUNX1 mutant cases presented higher levels of RUNX1 mRNA. Because there were only 16 cases of RUNX1 mutant samples and that mutations in this gene determined a change in mRNA expression, we further observed the correlation between RUNX1 and other mRNAs in subgroups regarding the presence of hypermethylating mutations and NPM1. Here, we observed that both TET2/IDH1/2/WT1 and NPM1 mutations increase the number of genes negatively correlated with RUNX1 and that these genes were significantly linked to myeloid activation. Conclusions: In the current study, we have shown that NPM1 and TET2/IDH1/2/WT1 mutations increase the number of negative correlations of RUNX1 with other transcripts involved in myeloid differentiation.

Acute Myeloid Leukemia With Biallelic CEBPA Gene Mutations and Normal Karyotype Represents a Distinct Genetic Entity Associated With a Favorable Clinical Outcome

2010 ◽  
Vol 28 (4) ◽  
pp. 570-577 ◽  
Author(s):  
Annika Dufour ◽  
Friederike Schneider ◽  
Klaus H. Metzeler ◽  
Eva Hoster ◽  
Stephanie Schneider ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Clinical Outcome ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Gene Mutations ◽  
Gene Expression Profiles ◽  
Similar Frequency ◽  
Favorable Clinical Outcome ◽  
Acute Myeloid

Purpose CEBPA mutations are found as either biallelic (biCEBPA) or monoallelic (moCEBPA). We set out to explore whether the kind of CEBPA mutation is of prognostic relevance in cytogenetically normal (CN) acute myeloid leukemia (AML). Patients and Methods Four hundred sixty-seven homogeneously treated patients with CN-AML were subdivided into moCEBPA, biCEBPA, and wild-type (wt) CEBPA patients. The subgroups were analyzed for clinical parameters and for additional mutations in the NPM1, FLT3, and MLL genes. Furthermore, we obtained gene expression profiles using oligonucleotide microarrays. Results Only patients with biCEBPA had an improved median overall survival when compared with patients with wtCEBPA (not reached v 20.4 months, respectively; P = .018), whereas patients with moCEBPA (20.9 months) and wtCEBPA had a similar outcome (P = .506). Multivariable analysis confirmed biCEBPA, but not moCEBPA, mutations as an independent favorable prognostic factor. Interestingly, biCEBPA mutations, compared with wtCEBPA, were never associated with mutated NPM1 (0% v 43%, respectively; P < .001) and rarely associated with FLT3 internal tandem duplication (ITD; 5% v 23%, respectively; P = .059), whereas patients with moCEBPA had a similar frequency of mutated NPM1 and a significantly higher association with FLT3-ITD compared with patients with wtCEBPA (44% v 23%, respectively; P = .037). Furthermore, patients with biCEBPA showed a homogeneous gene expression profile that was characterized by downregulation of HOX genes, whereas patients with moCEBPA showed greater heterogeneity in their gene expression profiles. Conclusion Biallelic disruption of the N and C terminus of CEBPA is required for the favorable clinical outcome of CEBPA-mutated patients and represents a distinct molecular subtype of CN-AML with a different frequency of associated gene mutations. These findings are of great significance for risk-adapted therapeutic strategies in AML.

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