Erratum to: New CD20 alternative splice variants: molecular identification and differential expression within hematological B cell malignancies.
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ABSTRACT:
SUBMITTER: Gamonet C
PROVIDER: S-EPMC4831155 | biostudies-other | 2015
REPOSITORIES: biostudies-other
Similar Datasets
Project description:CD20 is a B cell lineage-specific marker expressed by normal and leukemic B cells and targeted by several antibody immunotherapies. We have previously shown that the protein from a CD20 mRNA splice variant (D393-CD20) is expressed at various levels in leukemic B cells or lymphoma B cells but not in resting, sorted B cells from the peripheral blood of healthy donors.Western blot (WB) analysis of B malignancy primary samples showed additional CD20 signals. Deep molecular PCR analysis revealed four new sequences corresponding to in-frame CD20 splice variants (D657-CD20, D618-CD20, D480-CD20, and D177-CD20) matching the length of WB signals. We demonstrated that the cell spliceosome machinery can process ex vivo D480-, D657-, and D618-CD20 transcript variants by involving canonical sites associated with cryptic splice sites. Results of specific and quantitative RT-PCR assays showed that these CD20 splice variants are differentially expressed in B malignancies. Moreover, Epstein-Barr virus (EBV) transformation modified the CD20 splicing profile and mainly increased the D393-CD20 variant transcripts. Finally, investigation of three cohorts of chronic lymphocytic leukemia (CLL) patients showed that the total CD20 splice variant expression was higher in a stage B and C sample collection compared to routinely collected CLL samples or relapsed refractory stage A, B, or C CLL.The involvement of these newly discovered alternative CD20 transcript variants in EBV transformation makes them interesting molecular indicators, as does their association with oncogenesis rather than non-oncogenic B cell diseases, differential expression in B cell malignancies, and correlation with CLL stage and some predictive CLL markers. This potential should be investigated in further studies.
| S-EPMC4774009 | biostudies-other
Project description:Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies. Here, we sought to determine how mutations affecting the 3' splice site recognition factor U2AF1 altered its normal role in RNA splicing. We find that U2AF1 mutations influence the similarity of splicing programs in leukemias, but do not give rise to widespread splicing failure. U2AF1 mutations cause differential splicing of hundreds of genes, affecting biological pathways implicated in myeloid disease such as DNA methylation (DNMT3B), X chromosome inactivation (H2AFY), the DNA damage response (ATR, FANCA), and apoptosis (CASP8). We show that U2AF1 mutations alter the preferred 3' splice site motif in vivo, in cell culture, and in vitro. Mutations affecting the first and second zinc fingers give rise to different alterations in splice site preference and largely distinct downstream splicing programs. These allele-specific effects are consistent with a computationally predicted model of U2AF1 in complex with RNA. Our findings suggest that U2AF1 mutations contribute to pathogenesis by causing quantitative changes in splicing that affect diverse cellular pathways, and give insight into the normal function of U2AF1’s zinc finger domains. mRNA profiles of K562 cells expressing U2AF1 WT, mutants and knockdown of U2AF1 generated by deep sequencing.
2014-09-23 | E-GEOD-58871 | biostudies-arrayexpress
Project description:Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies. Here, we sought to determine how mutations affecting the 3' splice site recognition factor U2AF1 altered its normal role in RNA splicing. We find that U2AF1 mutations influence the similarity of splicing programs in leukemias, but do not give rise to widespread splicing failure. U2AF1 mutations cause differential splicing of hundreds of genes, affecting biological pathways implicated in myeloid disease such as DNA methylation (DNMT3B), X chromosome inactivation (H2AFY), the DNA damage response (ATR, FANCA), and apoptosis (CASP8). We show that U2AF1 mutations alter the preferred 3' splice site motif in vivo, in cell culture, and in vitro. Mutations affecting the first and second zinc fingers give rise to different alterations in splice site preference and largely distinct downstream splicing programs. These allele-specific effects are consistent with a computationally predicted model of U2AF1 in complex with RNA. Our findings suggest that U2AF1 mutations contribute to pathogenesis by causing quantitative changes in splicing that affect diverse cellular pathways, and give insight into the normal function of U2AF1’s zinc finger domains.
2014-09-23 | GSE58871 | GEO
Project description:Whole-exome sequencing studies have identified common mutations affecting genes encoding components of the RNA splicing machinery in hematological malignancies. Here, we sought to determine how mutations affecting the 3' splice site recognition factor U2AF1 alter its normal role in RNA splicing. We find that U2AF1 mutations influence the similarity of splicing programs in leukemias, but do not give rise to widespread splicing failure. U2AF1 mutations cause differential splicing of hundreds of genes, affecting biological pathways such as DNA methylation (DNMT3B), X chromosome inactivation (H2AFY), the DNA damage response (ATR, FANCA), and apoptosis (CASP8). We show that U2AF1 mutations alter the preferred 3' splice site motif in patients, in cell culture, and in vitro. Mutations affecting the first and second zinc fingers give rise to different alterations in splice site preference and largely distinct downstream splicing programs. These allele-specific effects are consistent with a computationally predicted model of U2AF1 in complex with RNA. Our findings suggest that U2AF1 mutations contribute to pathogenesis by causing quantitative changes in splicing that affect diverse cellular pathways, and give insight into the normal function of U2AF1's zinc finger domains.
| S-EPMC4317169 | biostudies-literature
Project description:Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by a pronounced reduction of brain volume and intellectual disability. A current model for the microcephaly phenotype invokes a stem cell proliferation and differentiation defect, which has moved the disease into the spotlight of stem cell biology and neurodevelopmental science. Homozygous mutations of the Cyclin-dependent kinase-5 regulatory subunit-associated protein 2 gene CDK5RAP2 are one genetic cause of MCPH. To further characterize the pathomechanism underlying MCPH, we generated a conditional Cdk5rap2 LoxP/hCMV Cre mutant mouse. Further analysis, initiated on account of a lack of a microcephaly phenotype in these mutant mice, revealed the presence of previously unknown splice variants of the Cdk5rap2 gene that are at least in part accountable for the lack of microcephaly in the mice.
| S-EPMC4556188 | biostudies-literature
Project description:Globally, one out of every two reported cases of hematologic malignancies (HMs) results in death. Each year approximately 1.24 million cases of HMs are recorded, of which 58% become fatal. Early detection remains critical in the management and treatment of HMs. However, this is thwarted by the inadequate number of reliable biomarkers. In this study, we mined public databases for RNA-seq data on four common HMs intending to identify novel biomarkers that could serve as HM management and treatment targets. A standard RNA-seq analysis pipeline was strictly adhered to in identifying differentially expressed genes (DEGs) with DESeq2, limma+voom and edgeR. We further performed gene enrichment analysis, protein-protein interaction (PPI) network analysis, survival analysis and tumor immune infiltration level detection on the genes using G:Profiler, Cytoscape and STRING, GEPIA tool and TIMER, respectively. A total of 2,136 highly-ranked DEGs were identified in HM vs. non-HM samples. Gene ontology and pathway enrichment analyses revealed the DEGs to be mainly enriched in steroid biosynthesis (5.075×10-4), cholesterol biosynthesis (2.525×10-8), protein binding (3.308×10-18), catalytic activity (2.158×10-10) and biogenesis (5.929×10-8). The PPI network resulted in 60 hub genes which were verified with data from TCGA, MET500, CPTAC and GTEx projects. Survival analyses with clinical data from TCGA showed that high expression of SRSF1, SRSF6, UBE2Z and PCF11, and low expression of HECW2 were correlated with poor prognosis in HMs. In summary, our study unraveled essential genes that could serve as potential biomarkers for prognosis and may serve as drug targets for HM management.
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Project description:Structural variants (SV) are changes in the genomic landscape that can alter gene expression levels and thus lead to disease development. The most common and best studied SVs in hematological malignancies are chromosomal translocations. Here, parts of two genes that are normally on different chromosomes come into close proximity due to a failure in DNA repair. As a consequence, fusion proteins which show a different function and/or cellular localization compared to the two original proteins are expressed, sometimes even at different levels. The identification of chromosomal translocations is often used to identify the specific disease a patient is suffering from. In addition, SVs such as deletions, duplications, inversions and single nucleotide polymorphisms (SNPs) can occur in hematopoietic cells and lead to their malignant transformations. Changes in the 3D genome structure have also recently been shown to impact disease development. In this review, we describe a variety of SVs occurring in different subtypes of hematological malignancies. Currently, most therapeutic approaches target fusion proteins which are the cellular product of chromosomal translocations. However, amplifications and SNPs also play a role in disease progression and can be targeted. We present some examples for different types of structural variants and how they are currently treated.
| S-EPMC6722867 | biostudies-literature
Project description:BCL-X is a member of the BCL-2 family. It regulates apoptosis and plays a critical role in hematological malignancies. It is well-known that >90% of human genes undergo alternative splicing. A total of 10 distinct splicing transcripts of the BCL-X gene have been identified, including transcript variants 1-9 and ABALON. Different transcripts from the same gene have different functions. The present review discusses the progress in understanding the different alternative splicing transcripts of BCL-X, including their characteristics, functions and expression patterns. The potential use of BCL-X in targeted therapies for hematological malignancies is also discussed.
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Project description:Alternative splicing generates multiple transcript and protein isoforms from a single gene and controls transcript intracellular localization and stability by coupling to mRNA export and nonsense-mediated mRNA decay (NMD). RNA interference (RNAi) is a potent mechanism to modulate gene expression. However, its interactions with alternative splicing are poorly understood. We used artificial microRNAs (amiRNAs, also termed shRNAmiR) to knockdown all splice variants of selected target genes in Arabidopsis thaliana. We found that splice variants, which vary by their protein-coding capacity, subcellular localization and sensitivity to NMD, are affected differentially by an amiRNA, although all of them contain the target site. Particular transcript isoforms escape amiRNA-mediated degradation due to their nuclear localization. The nuclear and NMD-sensitive isoforms mask RNAi action in alternatively spliced genes. Interestingly, Arabidopsis SPL genes, which undergo alternative splicing and are targets of miR156, are regulated in the same manner. Moreover, similar results were obtained in mammalian cells using siRNAs, indicating cross-kingdom conservation of these interactions among RNAi and splicing isoforms. Furthermore, we report that amiRNA can trigger artificial alternative splicing, thus expanding the RNAi functional repertoire. Our findings unveil novel interactions between different post-transcriptional processes in defining transcript fates and regulating gene expression.
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Project description:Tumor immune tolerance remains a major barrier for effective anti-cancer therapy. A growing number of pathways whereby solid tumors escape immune surveillance have been characterized (1). This progress led us to revisit the "hallmarks of cancer" and brought forward many promising immunotherapies. Every growing bodies of research have brought forward many exciting treatment strategies for hematological cancers like chimeric antigen receptor T cells (CAR-T cells) and immune checkpoint inhibitors. Given the distinct characteristics of the different cancers, some benefited profoundly from such therapies while some remain challenging for scientists and physicians. Here, we discuss the unique aspect of hematological malignancies, and briefly review the history, existing and future of immunotherapies for this group of cancer.
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