The long non-coding RNA landscape in juvenile myelomonocytic leukemia.
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ABSTRACT:
SUBMITTER: Hofmans M
PROVIDER: S-EPMC6278979 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Juvenile myelomonocytic leukemia (JMML) treatment primarily relies on hematopoietic stem cell transplantation and results in long-term overall survival of 50-60%, demonstrating a need to develop novel treatments. Dysregulation of the non-coding RNA transcriptome has been demonstrated before in this rare and unique disorder of early childhood. In this study, we investigated the therapeutic potential of targeting overexpressed long non-coding RNAs (lncRNAs) in JMML. Total RNA sequencing of bone marrow and peripheral blood mononuclear cell preparations from 19 untreated JMML patients and three healthy children revealed 185 differentially expressed lncRNA genes (131 up- and 54 downregulated). LNA GapmeRs were designed for 10 overexpressed and validated lncRNAs. Molecular knockdown (≥ 70% compared to mock control) after 24 h of incubation was observed with two or more independent GapmeRs in 6 of them. For three lncRNAs (lnc-THADA-4, lnc-ACOT9-1 and NRIR) knockdown resulted in a significant decrease of cell viability after 72 h of incubation in primary cultures of JMML mononuclear cells, respectively. Importantly, the extent of cellular damage correlated with the expression level of the lncRNA of interest. In conclusion, we demonstrated in primary JMML cell cultures that knockdown of overexpressed lncRNAs such as lnc-THADA-4, lnc-ACOT9-1 and NRIR may be a feasible therapeutic strategy.
| S-EPMC7854679 | biostudies-literature
Project description:Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.
| S-EPMC4626387 | biostudies-literature
Project description:Juvenile myelomonocytic leukemia (JMML) is a rare myelodysplastic/myeloproliferative neoplasm of early childhood. Most of JMML patients experience an aggressive clinical course of the disease and require hematopoietic stem cell transplantation, which is currently the only curative treatment. JMML is characterized by RAS signaling hyperactivation, which is mainly driven by mutations in one of five genes of the RAS pathway, including PTPN11, KRAS, NRAS, NF1, and CBL. These driving mutations define different disease subtypes with specific clinico-biological features. Secondary mutations affecting other genes inside and outside the RAS pathway contribute to JMML pathogenesis and are associated with a poorer prognosis. In addition to these genetic alterations, JMML commonly presents aberrant epigenetic profiles that strongly correlate with the clinical outcome of the patients. This observation led to the recent publication of an international JMML stratification consensus, which defines three JMML clinical groups based on DNA methylation status. Although the characterization of the genomic and epigenomic landscapes in JMML has significantly contributed to better understand the molecular mechanisms driving the disease, our knowledge on JMML origin, cell identity, and intratumor and interpatient heterogeneity is still scarce. The application of new single-cell sequencing technologies will be critical to address these questions in the future.
| S-EPMC8909150 | biostudies-literature
Project description:Non-coding RNAs have emerged as crucial regulators of gene expression and cell fate decisions. However, their expression patterns and regulatory functions during normal and malignant human hematopoiesis are incompletely understood. Here we present a comprehensive resource defining the non-coding RNA landscape of the human hematopoietic system. Based on highly specific non-coding RNA expression portraits per blood cell population, we identify unique fingerprint non-coding RNAs-such as LINC00173 in granulocytes-and assign these to critical regulatory circuits involved in blood homeostasis. Following the incorporation of acute myeloid leukemia samples into the landscape, we further uncover prognostically relevant non-coding RNA stem cell signatures shared between acute myeloid leukemia blasts and healthy hematopoietic stem cells. Our findings highlight the importance of the non-coding transcriptome in the formation and maintenance of the human blood hierarchy.While micro-RNAs are known regulators of haematopoiesis and leukemogenesis, the role of long non-coding RNAs is less clear. Here the authors provide a non-coding RNA expression landscape of the human hematopoietic system, highlighting their role in the formation and maintenance of the human blood hierarchy.
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Project description:Currently, cardiovascular diseases continue to be the leading cause of death worldwide; therefore, atherosclerosis remains one of the most crucial public health problems. This chronic and complex disease is considered to be a result of aberrant lipid homeostasis and inflammation of the inner wall of arteries that leads to plaque development. In recent years, a specific class of non-coding RNAs that are characterised by transcript lengths longer than 200 nucleotides, called long non-coding RNAs (lncRNAs), has emerged. Moreover, a growing body of evidence indicates that deregulation of lncRNA expression may contribute to the development of many diseases. Despite continuous efforts in deciphering the molecular basis of atherosclerotic plaque (AP) formation, many aspects of this process remain elusive. Therefore, continuing efforts in this area should remain the highest priority in the coming years. Establishment of a standardised experimental pipeline and validation of lncRNAs as possible relevant biomarkers for cardiovascular disease would enable the translation of gathered findings into clinical practice.
| S-EPMC6879443 | biostudies-literature
Project description:BackgroundGrowing evidence indicates that RNA methylation plays a fundamental role in epigenetic regulation, which is associated with the tumorigenesis and drug resistance. Among them, acute myeloid leukemia (AML), as the top acute leukemia for adults, is a deadly disease threatening human health. Although N7-methylguanosine (m7G) has been identified as an important regulatory modification, its distribution has still remained elusive.MethodsThe present study aimed to explore the long non-coding RNA (lncRNA) functional profile of m7G in AML and drug-resistant AML cells. The transcriptome-wide m7G methylation of lncRNA was analyzed in AML and drug-resistant AML cells. RNA MeRIP-seq was performed to identify m7G peaks on lncRNA and differences in m7G distribution between AML and drug-resistant AML cells. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to predict the possible roles and m7G-associated pathway.ResultsUsing m7G peak sequencing, it was found that a sequence motif was necessary for m7G methylation in drug-resistant AML lncRNA. Unsupervised hierarchical cluster analysis confirmed that lncRNA m7G methylation occurred more frequently in drug-resistant AML cells than in AML cells. RNA sequencing demonstrated that more genes were upregulated by methylation in drug-resistant AML cells, while methylation downregulated more genes in AML cells. The GO and KEGG pathway enrichment analyses revealed that genes having a significant correlation with m7G sites in lncRNA were involved in drug-resistant AML signaling pathways.ConclusionSignificant differences in the levels and patterns of m7G methylation between drug-resistant AML cells and AML cells were revealed. Furthermore, the cellular functions potentially influenced by m7G in drug-resistant AML cells were predicted, providing evidence implicating m7G-mediated lncRNA epigenetic regulation in the progression of drug resistance in AML. These findings highlight the involvement of m7G in the development of drug resistance in AML.
| S-EPMC10375699 | biostudies-literature
Project description:Juvenile myelomonocytic leukemia (JMML) is a rare pediatric leukemia characterized by mutations in five canonical RAS pathway genes. The diagnosis is made by typical clinical and hematological findings associated with a compatible mutation. Although this is sufficient for clinical decision-making in most JMML cases, more in-depth analysis can include DNA methylation class and panel sequencing analysis for secondary mutations. NRAS-initiated JMML is heterogeneous and adequate management ranges from watchful waiting to allogeneic hematopoietic stem cell transplantation (HSCT). Upfront azacitidine in KRAS patients can achieve long-term remissions without HSCT; if HSCT is required, a less toxic preparative regimen is recommended. Germline CBL patients often experience spontaneous resolution of the leukemia or exhibit stable mixed chimerism after HSCT. JMML driven by PTPN11 or NF1 is often rapidly progressive, requires swift HSCT and may benefit from pretransplant therapy with azacitidine. Because graft-versus-leukemia alloimmunity is central to cure high risk patients, the immunosuppressive regimen should be discontinued early after HSCT.
| S-EPMC8305558 | biostudies-literature
Project description:Simple Summary Survival rates for children with acute myeloid leukemia have significantly improved in recent decades. Still, 20–30% will succumb to therapy-related toxicity and relapse. Research has shown that leukemic stem cells (LSCs) in particular are responsible for relapse. Therefore, the characterization of the LSC is needed to improve the current treatment options for and survival of these pediatric patients. Previously, research has focused mainly on the protein-coding part of the human genome, but recently the focus has also shifted to non-coding genes, including long non-coding RNA (lncRNA) and microRNA (miRNA). The aim of this study was to investigate the expression of lncRNAs and miRNAs in pediatric AML subpopulations (LSCs and leukemic blasts) and their normal counterparts (hematopoietic stem cells and control myeloblasts). We provide here a unique set of non-coding RNAs with a potential role in the pathogenesis of pediatric AML, paving the way for further translational research studies. Abstract Pediatric acute myeloid leukemia (pedAML) is a heterogeneous blood cancer that affects children. Although survival rates have significantly improved over the past few decades, 20–30% of children will succumb due to treatment-related toxicity or relapse. The molecular characterization of the leukemic stem cell, shown to be responsible for relapse, is needed to improve treatment options and survival. Recently, it has become clear that non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), play a role in the development of human diseases, including pediatric cancer. Nevertheless, non-coding RNA expression data in pedAML are scarce. Here, we explored lncRNA (n = 30,168) and miRNA (n = 627) expression in pedAML subpopulations (leukemic stem cells (LSCs) and leukemic blasts (L-blasts)) and their normal counterparts (hematopoietic stem cells and control myeloblasts). The potential regulatory activity of differentially expressed lncRNAs in LSCs (unique or shared with the L-blast comparison) on miRNAs was assessed. Moreover, pre-ranked gene set enrichment analyses of (anti-) correlated protein-coding genes were performed to predict the functional relevance of the differentially upregulated lncRNAs in LSCs (unique or shared with the L-blast comparison). In conclusion, this study provides a catalog of non-coding RNAs with a potential role in the pathogenesis of pedAML, paving the way for further translational research studies.
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Project description:Long non-coding RNAs (lncRNAs) constitute a poorly studied class of transcripts with emerging roles in key cellular processes. Despite efforts to characterize lncRNAs across a wide range of species, these molecules remain largely unexplored in most eukaryotic microbes, including yeast pathogens of the Candida clade. Here, we analyze thousands of publicly available sequencing datasets to infer and characterize the lncRNA repertoires of five major Candida pathogens: Candida albicans, Candida tropicalis, Candida parapsilosis, Candida auris and Candida glabrata. Our results indicate that genomes of these species encode hundreds of lncRNAs that show levels of evolutionary constraint intermediate between those of intergenic genomic regions and protein-coding genes. Despite their low sequence conservation across the studied species, some lncRNAs are syntenic and are enriched in shared sequence motifs. We find co-expression of lncRNAs with certain protein-coding transcripts, hinting at potential functional associations. Finally, we identify lncRNAs that are differentially expressed during infection of human epithelial cells for four of the studied species. Our comprehensive bioinformatic analyses of Candida lncRNAs pave the way for future functional characterization of these transcripts.
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Project description: Not available
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