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Computational analysis of heat shock proteins and ferroptosis-associated lncRNAs to predict prognosis in acute myeloid leukemia patients.

ABSTRACT: Owing to their functional diversity in many cancers, long noncoding RNAs (lncRNAs) are receiving special attention. LncRNAs not only function as oncogenes or tumor suppressors by participating in various signaling pathways but also serve as predictive markers for various types of cancer, including acute myeloid leukemia (AML). Considering this, we investigated lncRNAs that may act as a mediator between two processes, i.e., heat shock proteins and ferroptosis, which appear to be closely related in tumorigenesis. Using a comprehensive bioinformatics approach, we identified four lncRNAs (AL138716.1, AC000120.1, AC004947.1, and LINC01547) with prognostic value in AML patients. Of interest, two of them (AC000120.1 and LINC01547) have already been reported to be AML-related, and AC004947.1 is considered to have oncogenic potential. In particular, the signature obtained showed a lower survival probability with high-risk patients, and vice versa. To our knowledge, this is the first predictive model of lncRNA that may correlate with the processes of heat shock proteins and ferroptosis in AML. Nevertheless, validation using patient samples is warranted.

SUBMITTER: Ge F

PROVIDER: S-EPMC10436091 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Computational analysis of heat shock proteins and ferroptosis-associated lncRNAs to predict prognosis in acute myeloid leukemia patients.

Ge Fangfang F Wang Yulu Y Sharma Amit A Jaehde Ulrich U Essler Markus M Schmid Matthias M Schmidt-Wolf Ingo G H IGH

Frontiers in genetics 20230801

Owing to their functional diversity in many cancers, long noncoding RNAs (lncRNAs) are receiving special attention. LncRNAs not only function as oncogenes or tumor suppressors by participating in various signaling pathways but also serve as predictive markers for various types of cancer, including acute myeloid leukemia (AML). Considering this, we investigated lncRNAs that may act as a mediator between two processes, i.e., heat shock proteins and ferroptosis, which appear to be closely related i ...[more]

PMID: 37600655

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Project description:BackgroundAcute myeloid leukemia (AML) is a highly heterogeneous cluster of hematologic malignancies. Leukemic stem cells (LSCs) are one of the culprits for the persistence and relapse of AML. The discovery of copper-induced cell death, namely cuproptosis, gives bright insights into the treatment of AML. Analogous to copper ions, long non-coding RNAs (lncRNAs) are not bystanders for AML progression, especially for LSC physiology. Uncovering the involvement of cuproptosis-related lncRNAs in AML will benefit clinical management.MethodsDetection of prognostic relevant cuproptosis-related lncRNAs are carried out by Pearson correlation analysis and univariate Cox analysis with RNA sequencing data of The Cancer Genome Atlas-Acute Myeloid Leukemia (TCGA-LAML) cohort. After the least absolute shrinkage and selection operator (LASSO) regression and the subsequent multivariate Cox analysis, a cuproptosis-related risk score (CuRS) system was derived to weigh the risk of AML patients. Thereafter, AML patients were classified into two groups by their risk property which was validated with principal component analysis (PCA), risk curves, Kaplan-Meier survival analysis, the combined receiver operating characteristic (ROC) curves, and nomogram. Variations in biological pathways and divergences in immune infiltration and immune-related processes between groups were resolved by GSEA and CIBERSORT algorism, respectively. Response to chemotherapies were scrutinized as well. The expression profiles of the candidate lncRNAs were examined by real-time quantitative polymerase chain reaction (RT-qPCR) and the specific mechanisms of lncRNA FAM30A were determined by transcriptomic analysis.ResultsWe fabricated an efficient prognostic signature named CuRS incorporating 4 lncRNAs (TRAF3IP2-AS1, NBR2, TP53TG1, and FAM30A) relevant to immune environment and chemotherapy responsiveness. The relevance of lncRNA FAM30A with proliferation, migration ability, Daunorubicin resistance and its reciprocal action with AUF1 were demonstrated in an LSC cell line. Transcriptomic analysis suggested correlations between FAM30A and T cell differentiation and signaling, intercellular junction genes.ConclusionsThe prognostic signature CuRS can guide prognostic stratification and personalized AML therapy. Analysis of FAM30A offers a foundation for investigating LSC-targeted therapies.

Project description:BackgroundThe human immunodeficiency virus type I enhancer binding protein (HIVEP) family, which contains zinc finger and acid-rich (ZAS) domains, has been demonstrated to be implicated in vital biological processes, such as cell survival, tumor necrosis factor (TNF) signaling, and tumor formation. However, its expression patterns, prognostic relevance, and functional implications in acute myeloid leukemia (AML) remain elusive.MethodsWe inspected HIVEP mRNA expression levels in datasets from The Cancer Genome Atlas (TCGA) and GSE24006. Survival analyses were orchestrated using the web-based bioinformatics platforms and R studio in two AML cohorts. Prognostic value and capacity were assessed by Cox regression analyses. Association of HIVEP3 expression levels with clinical characteristics were analyzed with R and UALCAN. Subsequentially, functional enrichment analyses were operated to interpret HIVEP3 co-expressed gene clusters. A prognostic gene signature was created by the least absolute shrinkage and selection operator (LASSO) regression algorithm. Moreover, bone marrow aspirate smears of AML patients were stained for HIVEP3 by immunohistochemistry (IHC). HIVEP3 expression was examined by qRT-PCR in leukemia cell lines treated with ferroptosis compounds in vitro.ResultsAugmented transcriptional levels of HIVEP2 and 3 were noted in AML patients (p<0.001). HIVEP3 not only could confer adverse prognosis independently in AML patients, but also was associated with AML subtypes, age, cytogenetic risk, and disease-related molecules. Co-expressed gene clusters of HIVEP3 were enriched in functional pathways related to AML leukemogenesis, such as ribosome, metabolism, and calcium signaling. Combined with multiple tumorigenesis signaling pathways, we proposed an integrated LASSO model with HIVEP3 and ferroptosis regulators AIFM2 and LPCAT3, to predict the outcome for AML patients. Furthernore, altered HIVEP3 expression at the mRNA or protein level was confirmed in sorted leukemia cells and blast cells in bone marrow tissues. In vitro experiments authenticated the involvement of HIVEP3 in ferroptosis signaling pathways.ConclusionsOur findings suggest that HIVEP3 is a de novo independent prognostic indicator, and the crosstalk between HIVEP3 and ferroptosis signaling pathways may inspire a specific perspective on the oncological network of AML.

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Dataset Information

Computational analysis of heat shock proteins and ferroptosis-associated lncRNAs to predict prognosis in acute myeloid leukemia patients.

Publications

Computational analysis of heat shock proteins and ferroptosis-associated lncRNAs to predict prognosis in acute myeloid leukemia patients.

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