Isoforms arising from significantly differentially regulated splicing events between SFmut and both SFwt patients with MDS and healthy control individuals were identified. Aberrantly spliced genes and dysregulated pathways were identified in the MDS-affected lineages in splicing factor mutant MDS. Ulusal Eğitim Bilimleri Kongresine davet etmekten büyük bir mutluluk duyuyoruz. The research was approved by the relevant institutional review boards or ethics committees, and all participants gave written informed consent. Taken together, these data demonstrate that splicing factor mutations in MDS result in different mechanistic alterations in splicing and largely affect different genes, but these converge in overlapping (approximately one third of the total number) dysregulated pathways and cellular processes, suggesting common mechanisms of action. CommCell Management > Job Management > Scheduling Backup, Restore, and Other Jobs > Command Line Operations > Editing the Associations of Schedule Policies Using the Command Line Interface. Özcan DEMİREL, 26.5.1943 yılında Adapazarı- (D-F and K-M) Flow cytometry quantification of erythroid differentiation. To date, very few of the aberrantly spliced isoforms identified in SFmut malignancies have been functionally characterized.6  We identified aberrant splicing of the mitosis regulators SEPT299,100  and AKAP8,71  leading to their downregulation in the CD34+ cells of SF3B1mut and SRSF2mut MDS, respectively. These aberrantly spliced genes include SEPT2 and DYNLL1 in SF3B1mut cases, PKFM and METTL17 in SRSF2mut cases, and HMGXB4 and LAT2 in U2AF1mut cases. Splicing factor mutations result in different alterations in splicing and largely affect different genes, but these converge in common dysregulated pathways and cellular processes, focused on RNA splicing, protein synthesis, and mitochondrial dysfunction, suggesting common mechanisms of action in MDS. Aberrant splicing events in CD34+cells of patients with SFmut MDS. Total RNA was extracted using TRIzol (Thermo Scientific), with a linear acrylamide carrier, treated with DNase I (Life Technologies) and purified using Agencourt RNAClean XP beads (Beckman Coulter). We analyzed panels of 120, 164, and 85 genes described in the literature as involved in erythroid,67  granulocyte68  and monocyte69  function (supplemental Data 9). We did not observe a difference in gene expression levels between nonsense-mediated mRNA decay (NMD)-sensitive and NMD-insensitive events associated with SRSF2 mutations and U2AF1 mutations (supplemental Figure 2A-B). We investigated the association of expression of isoforms produced by aberrant splicing events identified earlier with patient survival. Patients with MDS suffer from anemia.1  The effect of the splicing abnormalities of AKAP8 and SEPT2 on erythroid cell growth and differentiation was studied by knocking down these genes individually in human BM CD34+ cells subsequently differentiated toward the erythroid lineage. SF3B1mut-misregulated A3SSs showed varying sequence profiles between canonical and cryptic sites (supplemental Figure 5A) and the characteristic 16 nt peak separation of upstream cryptic sites from their associated canonical sites (supplemental Figure 5B).34,64-66  Exons downregulated in association with U2AF1 mutations in the ZF1 and ZF2 domains (S34 and R156/Q157, respectively) showed altered 3′ splice site (3SS) logos (supplemental Figure 5C) consistent with contact by ZF1 and ZF2 at the −3 and +1 positions.35 SRSF2mut-misregulated exons showed no alterations in splice site compositions (supplemental Figure 5D), but consistent with previous observations,24  CCNG motifs were enriched in upregulated cassette exons and GGNG motifs in downregulated exons (supplemental Figure 5E). The REVIGO treemap of 118 GO terms associated only with SF3B1mut MDS showed multiple GO terms associated with cellular response to DNA damage stimulus and cell cycle processes (supplemental Figure 3B). When building Windows 10 images, you can update the default programs associated with file name extensions or protocols. These include RI events of AP1G2, DOM3Z, and ERCC3 with ANC, and a RI event of NICN1 with Plt, indicating increased aberrant splicing of these genes in MDS cases with higher ANC and higher platelets, respectively. Using rMATS, a total of 137 misregulated splicing events were identified, including 11 A3SS, 6 A5SS, 51 RI, 63 SE, and 6 MXE events (supplemental Figure 8A; supplemental Data 7). Of 200 and 150 genes involved in heme metabolism or in iron homeostasis and transport (supplemental Methods), respectively, we found several showing aberrant splicing events in SF3B1mut, SRSF2mut, and U2AF1mut MDS cases, with a higher number of events occurring in SF3B1mut MDS cases (supplemental Data 6). Many of the dysregulated pathways and cellular processes identified can be linked to the known disease pathophysiology and to the phenotypes associated with splicing factor mutations in MDS, whereas several have not previously been associated with MDS. To do this, create an app association file and import it into your images using DISM. 1964 yılında Correspondence: Jacqueline Boultwood, Bloodwise Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom; e-mail: jacqueline.boultwood@ndcls.ox.ac.uk. Three genes (SEPT2, DDX24, and DYNLL1) and 1 gene (RIMKLB) were aberrantly spliced in common to all 4 cell populations for SF3B1 mutations or SRSF2 mutations, respectively. Here, the mutational profile of the patients with MDS was determined using a next-generation sequencing-based myeloid gene panel20  (supplemental Table 3; supplemental Figure 1B). (E and L) Percentage of CD36+CD235a+ cells in erythroid cultures with knockdown of AKAP8 (E) and SEPT2 (L) on day 11. Sapanca'da doğmuş, 1960'da Arifiye İlköğretmen 2019, Hacettepe Üniversitesi Eğitim Fakültesi 06800 Ankara/Türkiye For example, ERCC3 showed reduced retention of intron 10 in conjunction with use of an A3SS 18 nt upstream of the canonical 3SS, with the change in intron retention exceeding the change in A3SS use (supplemental Figure 6B). Of the 7 extracellular exosome/focal adhesion genes identified as significant survival predictors in MDS, 5 genes (CAP1, IFI44, IFI44L, PTPRC, FCGR2A) also expressed isoforms that were significantly predictive of survival in the AML Cancer Genome Atlas cohort (Figure 3F,H). We found increased inclusion of a “poison” cassette exon of EZH2 in SRSF2mut cases, as previously reported,24  and observed the same aberrant splicing event in U2AF1mut cases. Multivariate Cox proportional hazard modeling of survival of patients stratified by median expression of individual isoforms identified 14 genes with isoforms that significantly predicted survival in MDS (Table 2; Figure 3E,G; supplemental Table 10; supplemental Figure 7). We have performed a comprehensive and systematic analysis to determine the effect of these commonly mutated splicing factors on pre-mRNA splicing in the bone marrow stem/progenitor cells and in the erythroid and myeloid precursors in splicing factor mutant MDS. Prof. Özcan Demirel was born on the 1st of March in 1943 at Sapanca in Turkey. Tightly controlled protein synthesis is critical for HSC (and progenitor) function and serves as a tumor suppressive mechanism,77  implicating the aberrant splicing of multiple translation-related genes in SFmut MDS in disease pathogenesis. (D) Scatterplot of aberrant splicing values in NICN1 and platelet counts in patients with MDS. We have determined the associations between aberrantly spliced isoforms and clinical variables and patient survival. (C-H) Ranked heat maps showing the top 15 dysregulated pathways (C,F), top 15 transcriptional regulators (D,G), and top 6 drug/chemical gene sets (E,H) in MON, GRA, and ERY populations of SF3B1 mutant and SRSF2 mutant patients with MDS. 1964 yılında CD34+ cells were isolated from the BM samples of 84 patients with MDS (supplemental Table 1, available on the Blood Web site) and 8 healthy control individuals using MACS columns (Miltenyi Biotec, Germany). GO analysis on aberrantly spliced genes in SFmut MDS (XLSX, 42 KB), Document 6. RNA-seq analysis of CD34+ cells identifies novel aberrantly spliced genes and dysregulated pathways in splicing factor mutant MDS. Pathway analysis of the genes showing significant aberrant splicing events showed that 2 pathways involved in translation, EIF2 signaling and regulation of eIF4 and p70S6K signaling, were significantly dysregulated in all cell populations in both SF3B1mut and SRSF2mut MDS (Figure 4C,F). Özgeçmişi detaylı incelemek için lütfen tıklayınız. süreyle orta dereceli okullarda İngilizce öğretmenliği ve Contribution: A.P., R.N.A., V.S., S. Singh, H.D., and S.R. Aberrant splicing events associated with each mutated splicing factor were identified on the basis of the overlap between the lists of significant events identified by rMATS consistently in the comparisons of SFmut MDS both with SFwt MDS and with healthy control individuals (false discovery rate [FDR], <0.05 and inclusion level difference of >0.1 or <−0.1). okulundan mezun olmuş ve bir öğretim yılı Anadolu'nun Differential splicing was assessed using rMATS v3.2.2beta,34,42,43  with the BAM alignments generated by HISAT2. Dysregulation of splicing factors leads to R-loop formation with associated genomic instability, resulting in activation of the DDR.50-52  Elevated R-loops have been shown in Srsf2(P95H) mice,51  and SRSF2 is involved in maintaining genomic stability.51,52  Thus, R-loop formation and activation of the DDR are tightly linked cellular processes, and interestingly, regulators of these processes show aberrant splicing in our study. 1992-1997 yılları arasında YÖK Dünya Bankası Projesinde öğretmen yetiştirme konusunda; 1996-1997 yılları arasında Milli Eğitim Bakanlığı Dünya Bankası Projesinde program geliştirme uzmanı, Ekim 2000-Şubat 2003 tarihleri arasında Avrupa Birliği MEDA Temel Eğitime Destek Projesinde proje başkanı olarak çalışmış ve 1997 yılından beri de Avrupa Konseyi, Yaşayan Diller Projesinde Türkiye Koordinatörü olarak çalışmaktadır. Isoforms from the genes (CRTC2, CAP1, IFI44, IFI44L, CD46, FCGR2A, and PTPRC) from these pathways were investigated further using the AML data from the Cancer Genome Atlas. Analysis of genes involved in erythroid, granulocyte and monocyte function (XLSX, 21 KB), https://doi.org/10.1182/blood-2018-04-843771, Aberrant splicing in splicing factor mutant MDS, Translation elongation factor 2 modification. Many aberrant splicing events were common between CD34+ cells and 1 or more of the granulocytic, monocytic, and erythroid precursor populations for SF3B1 mutations or SRSF2 mutations (supplemental Figure 10). Pathways playing critical roles in translational regulation were significantly dysregulated in all cell populations in both SF3B1mut and SRSF2mut MDS, suggesting that this process may be impaired in the erythroid and myeloid precursors of SFmut MDS. Mouse models expressing splicing factor mutations show some features of MDS, including expansion of stem and progenitor cells in the BM and leukopenia.24,26-28  Although these models have significantly advanced our understanding of how splicing factor mutations lead to particular hematological phenotypes, the differences in intronic sequences and consensus-binding motifs between mice and humans mean that the splicing abnormalities observed in the mice often differ from those observed in patients.25,26. süreyle orta dereceli okullarda İngilizce öğretmenliği ve We performed RNA-seq on the granulocytic, monocytic, and erythroid precursors purified from BM of SF3B1mut and SRSF2mut patients with MDS and healthy control individuals (supplemental Table 3). Blood 2018; 132 (12): 1225–1240. Değerli Eğitim Bilimciler, Okul Yöneticileri, Öğretmenler ve Eğitim Fakültelerinin Lisans ve Lisansüstü Öğrencileri; Another video editing software program for both Windows and Mac is VideoPad, from NCH Software. Aberrantly spliced genes include GYPB and HMBS in the erythroid precursors of SF3B1mut and SRSF2mut MDS cases, and CSF1R and CSF3R, respectively, in the monocyte and granulocyte precursors of SRSF2mut cases. Additional method details are described in the supplemental Information. Many of these dysregulated pathways and cellular processes can be linked to the known disease pathophysiology associated with splicing factor mutations in MDS, whereas several others have not been previously associated with MDS, such as sirtuin signaling. Pathway analysis performed on the genes showing significant aberrant splicing events showed dysregulation of pathways including sirtuin signaling and protein ubiquitination (supplemental Figure 8B; supplemental Table 11). SF3B1mut, SRSF2mut, or U2AF1mut patients were compared both with healthy control individuals and with SFwt patients, identifying more than 200 misregulated splicing events for each mutated splicing factor (Figure 1A-C; supplemental Data 2). Similarly, SRSF2mut cases clustered together (Figure 1H). contributed equally to this study. Functional studies demonstrated that knockdown of the mitosis regulators SEPT2 and AKAP8, aberrantly spliced target genes of SF3B1 and SRSF2 mutations, respectively, led to impaired erythroid cell growth and differentiation. The reads were mapped to human genome GRCh37 using HISAT2 version 2.0.0-beta.39  Uniquely mapped read pairs were counted using featureCounts,40  included with subread v1.5.0.41  Quality control was performed on the mapped files using Picard CollectRnaSeqMetrics (http://broadinstitute.github.io/picard; supplemental Data 1). The publication costs of this article were defrayed in part by page charge payment. A similar approach identified drugs/chemicals that can affect the expression of the genes found to be aberrantly spliced in SFmut MDS. In contrast, among the highest-ranking aberrant splicing events in SRSF2mut (supplemental Table 4) and U2AF1mut MDS (supplemental Table 4), the largest proportion was SE (n = 31/40 and n = 27/40, respectively). acknowledges funding from the Medical Research Council (MRC) Molecular Haematology Unit (MHU) Grant, MRC Disease Team Awards (G1000729/94931 and MR/L008963/1) and the Oxford Partnership Comprehensive Biomedical Research Centre (National Institute for Health Research [NIHR] Biomedical Research Centre [BRC] Funding scheme oxfbrc-2012-1 and 2017). Aberrant splicing of 5 genes was observed in SF3B1mut, SRSF2mut, and U2AF1mut MDS, and thus represent common targets. This analysis showed a strong cluster of GOs associated with mRNA metabolism, including RNA splicing, RNA processing, and mRNA translation (Figure 2A). Several commonly dysregulated pathways were associated with all 3 mutated splicing factors, some of which are relevant to the known MDS pathophysiology, including mitochondrial dysfunction, oxidative phosphorylation, and heme biosynthesis, linking aberrant splicing with impaired mitochondrial function in MDS. Functional effects of AKAP8 and SEPT2 knockdown on erythroid differentiation. Özcan DEMİREL, 26.5.1943 yılında Adapazarı- Özcan DEMİREL, 01 Mart 1943 yılında Adapazarı-Sapanca’da doğmuş, 1960’da Arifiye İlköğretmen okulunu, 1964 yılında Gazi Eğitim Enstitüsü İngilizce bölümünü bitirmiştir. The processes and pathways by which splicing factor mutations exert their effects are not established in the stem/progenitor cells and erythroid and myeloid precursors in MDS. Gazi Eğitim Enstitüsü İngilizce bölümünü bitirmiş ve on yıl SF3B1, SRSF2, and other splicing factors are components of a DNA damage-induced mRNA splicing complex,84  linking splicing factors to the DDR. Only heat map tiles with a -log10pvalue > 1.3 (P value < .05) are shown. Özcan Demirel, evli olup iki çocuk babasıdır. Hacettepe Üniversitesi, Mezuniyet Sonrası Eğitimi Fakültesi’nde eğitim alanında lisans, 1975 yılında Bilim Uzmanlığı, 1979’da da Ankara Üniversitesi Eğitim Fakültesinden Doktora derecesi almıştır. Conflict-of-interest disclosure: The authors declare no competing financial interests. All P-values were obtained by 1-way ANOVA with Bonferroni’s posttest with the exception of G and N, in which 2-way ANOVA with Bonferroni’s posttest was used. 1992-1997 yılları arasında YÖK Dünya Bankası öğretmen yetiştirme Projesinde yönetim kurulu üyesi; 1996-1997 yılları arasında Milli Eğitim Bakanlığı Dünya Bankası projesinde program geliştirme uzmanı, 2000-2002 yılları arasında MEDA Temel Eğitime Destek projesinde proje eşbaşkanı olarak çalışmıştır. Biological processes associated with DDR and cell cycle regulation were significantly affected in both SF3B1mut and SRSF2mut MDS. (E-H) Kaplan-Meier survival plots for individual isoforms of PTPRC and IFI44L in our MDS cohort (E and G, respectively), and the Cancer Genome Atlas AML cohort (F and H, respectively). bir köyünde ilkokul öğretmenliği yapmıştır. CD34+ cells from healthy donors (Lonza) were cultured in erythroid differentiation media for 14 days, as described previously.45 SEPT2 and AKAP8 genes were knocked down individually, using Mission shRNA lentiviral vectors (Sigma-Aldrich). To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print the certificate. Next, using IPA, we performed an analysis of upstream transcriptional regulators (including transcription factors), aiming to evaluate the significance of the overlap between the significant aberrantly spliced genes associated with each mutant splicing factor and genes regulated by a transcriptional regulator. Dysregulation of splicing factor genes has been associated with the formation of R-loops (structures resulting from the invasion of nascent RNA into DNA) and activation of the DNA damage response (DDR).50-52  Several significant GOs dysregulated in SFmut MDS in our study have been associated with increased R-loop formation, including mitochondrial dysfunction,53,54  aberrant RNA processing,52,55,56  and defective ribonucleoprotein particle biogenesis.57  Of 41 genes described in the literature as involved in suppression/regulation of R-loop formation and in the DDR,58-63  we found aberrant splicing of 4 genes (ERCC3, FANCI, SETX, and ATR) in SF3B1mut cases, 3 genes (CHEK1, SETX, and ATR) in SRSF2mut cases, and 2 genes (ERCC8 and FANCM) in U2AF1mut cases (supplemental Table 8). Dysregulation of cell growth is a feature of MDS.1  We found that genes regulated by the transcriptional regulators HNF4A, RICTOR, E2F1, MYC, MYCN, and RB1, all major controllers of cell growth/cell cycle,90-93  showed significant enrichment for aberrantly spliced genes. Şu anda, Eğitim Programları ve Öğretim Derneği (Epoder) ile 20 Ulusal Eğitim Derneği (ULED) Platformunun dönem başkanlığını yürütmektedir. Of these, LUC7L and SUGP2 encode proteins involved in splicing,74,75  with LUC7L associated with the U1 snRNP splicing complex involved in 5′ splice site selection.75  Dysregulation of the MRRF gene, involved in mitochondrial translational, leads to changes in mitochondrial morphology and function.76. Clinical variables were analyzed for correlation with the rMATS-generated event inclusion levels for each MDS sample. RNA quality was assessed using a 2100 Bioanalyzer (Agilent), and RNA integrity numbers were greater than 8 for all samples. 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