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The metabolomic landscape in myelodysplastic syndrome (MDS) is highly deregulated and presents promising avenues for understanding disease pathogenesis and potential molecular dependencies. Here, we evaluated the transcriptomic landscape in MDS in multiple independent studies focusing more on metabolomics pathways. Identifying molecular dependencies will pave the way for a more precise disease stratification as well as the development of novel personalized treatment strategies. The study adopted a retrospective, cross-sectional approach, utilizing transcriptomic data from multiple MDS studies. The transcriptomic data were then subjected to comprehensive analyses, including differential gene expression, gene enrichment analysis, gene co-expression analysis, protein-protein interaction analyses, and survival analyses. PSAT1 showed a significant upregulation profile in MDS patients. This observed upregulation is correlated with the deregulation of immune-related pathways in MDS samples. This observation suggests a novel role for PSAT1 in immune modulation and potentially in augmenting immune evasion, which may lead to poor prognosis. This was evident in other tumors in the TCGA database, where cancer patients with high PSAT1 expression have a shorter overall survival. This study unveils a novel potential therapeutic avenue in MDS. Identifying the role of the PSAT1 gene sheds light on the disease’s intricate biology, highlighting the ongoing cross-talk between metabolism and immune regulation, which may pave the way for innovative treatment modalities.

SF3B1 gene mutations are prevalent in myelodysplastic syndrome (MDS) and define a distinct disease subtype. These mutations are associated with dysregulated genes and pathways, offering potential for novel therapeutic approaches. However, the aberrant mRNA alternative splicing landscape in SF3B1 -deficient MDS cells remains underexplored. In this study, we investigated the influence of SF3B1 gene alterations on the pre-mRNA splicing landscape in MDS cells using transcriptomic data from two independent MDS cohorts. we identified over 5000 significant differential alternative splicing events associated with SF3B1 mutation. This work corroborates previous studies, showing significant enrichment of MYC activity and heme metabolism in SF3B1 mutant cells. A key novel finding of this study is the identification of a gene expression signature driven by SF3B1 mutations, centered on protein post-translational modifications. Notably, we discovered aberrant alternative splicing of the tumor suppressor gene UBA7 , leading to significantly reduced gene expression. This dysregulation implicates UBA7 as a critical player in MDS pathogenesis. Importantly, the clinical relevance of this finding is underscored by the observation that low UBA7 gene expression was associated with poor overall survival in chronic lymphocytic leukemia (CLL), another hematological malignancy with frequent SF3B1 mutations. Furthermore, a similar association between low UBA7 gene expression and poor survival outcomes was observed across multiple tumor types in the TCGA database, highlighting the broader implications of UBA7 dysregulation in cancer biology. These findings provide new insights into the mechanisms by which SF3B1 mutations reshape the pre-mRNA splicing landscape and drive disease pathogenesis in MDS. Furthermore, they underscore the potential of UBA7 as a biomarker to stratify SF3B1-mutant MDS and CLL patients, offering a refined approach for risk assessment and highlighting opportunities for targeted therapeutic interventions.

Ischemic stroke poses a notable global public health challenge, with the Kingdom of Saudi Arabia (KSA) being no exception. This multifaceted condition is affected by a combination of factors, including hypertension, diabetes, and genetic influences. The purpose of the present study was to examine the linkage of long noncoding RNAs (such as ANRIL), plasminogen activator inhibitor-1 (PAI-1), and hepatocyte nuclear factor 1 alpha (HNF1α) gene variations with stroke. Leveraging a substantial cohort comprising both stroke patients and healthy individuals from KSA, our research revealed numerous uncommon genetic variations linked to an increased predisposition to stroke. This insight enhances our comprehension of stroke's genetic underpinnings and can be invaluable in formulating preventive measures, not only in KSA but also on a global scale. In this study we included 100 stroke patients and 100-120 healthy controls from Saudi population. We utilized the amplification refractory mutation system-PCR to genotype the chromosome 9p21 locus, the long noncoding RNA-ANRIL (lncRNA-ANRIL), Hepatocyte Nuclear Factor 1 alpha (HNF1α-A > C [p.I27L]) gene, and the plasminogen activator inhibitor-1 (PAI-1) gene to investigate the association of these gene variations with a stroke. Additionally, WES was performed for 10 stroke patients using the Illumina NovaSeq 6000 platform. Our investigation revealed significant associations between stroke patients and healthy controls concerning polymorphic variants of lncRNA-ANRIL (A > C), ANRIL (G > A), HNF1α-A > C, and PAI-1-4G > 5G genes (p < 0.05). Notably, the ANRIL rs1333048-GA genotype exhibited a strong connection with stroke susceptibility in both codominant (OR 2.29, RR 1.54, P < 0.007) and dominant (OR 1.83, RR 1.35, P < 0.034) models, while an overdominant inheritance model demonstrated a protective correlation (OR 0.42, RR 0.64, p < 0.004). Similarly, the ANRIL rs10757278-GG genotype was significantly associated with stroke susceptibility in the codominant (OR 2.80, RR 1.66, P < 0.004) and recessive (OR 3.14, RR 1.62, P < 0.0003) models, with the G allele also displaying a significant association. The HNF1α-TT genotype strongly correlated with stroke risk in the codominant (OR 18.36, RR 9.96, P < 0.048) and recessive (OR 22.14, RR 10.18, P < 0.034) models, with the HNF1α-T allele following a similar trend. The PAI-1-4G-5G genotype was also linked to stroke predisposition (OR 2.09, RR 1.34, P < 0.034) and an increased risk in the dominant model (OR 2.27, RR 1.43, P < 0.006). Furthermore, our study identified several novel and common gene variants in stroke patients through WES, including COL4A2, PSEN2, NOTCH3, and RNF2. Our findings underscore the significant role of genetic determinants in chromosome 9p21, the lncRNA-ANRIL, HNF1α-A > C (p.I27L), and PAI-1-4G > 5G genes in elevating the risk of stroke. Additionally, we report low, novel, and intermediate-genetic-risk variants in COL4A2, PSEN2, NOTCH3, and RNF2 through WES, emphasizing the need for further investigation in larger cohort studies.

Ischemic stroke poses a notable global public health challenge, with the Kingdom of Saudi Arabia (KSA) being no exception. This multifaceted condition is affected by a combination of factors, including hypertension, diabetes, and genetic influences. The purpose of the present study was to examine the linkage of long noncoding RNAs (such as ANRIL), plasminogen activator inhibitor-1 (PAI-1), and hepatocyte nuclear factor 1 alpha (HNF1[alpha]) gene variations with stroke. Leveraging a substantial cohort comprising both stroke patients and healthy individuals from KSA, our research revealed numerous uncommon genetic variations linked to an increased predisposition to stroke. This insight enhances our comprehension of stroke's genetic underpinnings and can be invaluable in formulating preventive measures, not only in KSA but also on a global scale. In this study we included 100 stroke patients and 100-120 healthy controls from Saudi population. We utilized the amplification refractory mutation system-PCR to genotype the chromosome 9p21 locus, the long noncoding RNA-ANRIL (lncRNA-ANRIL), Hepatocyte Nuclear Factor 1 alpha (HNF1[alpha]-A > C [p.I27L]) gene, and the plasminogen activator inhibitor-1 (PAI-1) gene to investigate the association of these gene variations with a stroke. Additionally, WES was performed for 10 stroke patients using the Illumina NovaSeq 6000 platform. Our investigation revealed significant associations between stroke patients and healthy controls concerning polymorphic variants of lncRNA-ANRIL (A > C), ANRIL (G > A), HNF1[alpha]-A > C, and PAI-1-4G > 5G genes (p < 0.05). Notably, the ANRIL rs1333048-GA genotype exhibited a strong connection with stroke susceptibility in both codominant (OR 2.29, RR 1.54, P < 0.007) and dominant (OR 1.83, RR 1.35, P < 0.034) models, while an overdominant inheritance model demonstrated a protective correlation (OR 0.42, RR 0.64, p < 0.004). Similarly, the ANRIL rs10757278-GG genotype was significantly associated with stroke susceptibility in the codominant (OR 2.80, RR 1.66, P < 0.004) and recessive (OR 3.14, RR 1.62, P < 0.0003) models, with the G allele also displaying a significant association. The HNF1[alpha]-TT genotype strongly correlated with stroke risk in the codominant (OR 18.36, RR 9.96, P < 0.048) and recessive (OR 22.14, RR 10.18, P < 0.034) models, with the HNF1[alpha]-T allele following a similar trend. The PAI-1-4G-5G genotype was also linked to stroke predisposition (OR 2.09, RR 1.34, P < 0.034) and an increased risk in the dominant model (OR 2.27, RR 1.43, P < 0.006). Furthermore, our study identified several novel and common gene variants in stroke patients through WES, including COL4A2, PSEN2, NOTCH3, and RNF2. Our findings underscore the significant role of genetic determinants in chromosome 9p21, the lncRNA-ANRIL, HNF1[alpha]-A > C (p.I27L), and PAI-1-4G > 5G genes in elevating the risk of stroke. Additionally, we report low, novel, and intermediate-genetic-risk variants in COL4A2, PSEN2, NOTCH3, and RNF2 through WES, emphasizing the need for further investigation in larger cohort studies.

Chronic lymphocytic leukaemia (CLL) is a neoplasm of mature B cells and it is considered the most common type of leukaemia in the western world. CLL is an extremely heterogeneous disease in which patients show a diverse clinical course driven among other factors by driver mutations. The most common CLL cytogenetic aberration are deletions in the 13q14 and 11q22.3 which are associated with early and later events during disease progression, respectively. Interestingly, these cytogenetic alterations affect genes encoding for DNA damage response proteins members. RNASEH2B gene resides in 13q14 region and it is a member of RNase H2 complex involved in Ribonucleotide excision repair (RER). ATM on the other hand is located to 11q22.3 regions and it is an essential kinase in the DNA double-strand break (DSB). While the consequences of ATM and RNASEH2B dysfunction on DNA repair in cancer cells are reasonably well understood, their impact on the epigenetic landscape remains to be elucidated. The frequent alterations in these DDR genes suggests that CLL cells use cellular addictions in form of alternative pathways and mechanisms to maintain their survival. Thus, identifying different levels of these cellular addictions is the first step towards the design of personalized, targeted therapy. Here, I generated chromatin accessibility, histone modifications and variants, and gene expression profiles using genome-wide methodologies on CLL cell lines that harbour defects in RNASEH2B and ATM. CLL cells harboring defects in ATM showed a unique pattern of chromatin accessibility, which was correlated with changes in gene expression. Global histone modification changes were observed and the epigenetic regulator KDM5B, a histone demethylase, were found to be upregulated in ATM-defective cells demonstrating a potential vulnerability that can be targeted therapeutically. On the other hand, RNASEH2B- defective CLL cells showed a unique transcriptional program associated with increased DNA-RNA hybrid levels. The results suggest that RUNX Transcription Factors (TF) were required to maintain the proliferation of RNASEH2B defective cells and this was confirmed by CRISPR KO screen. Together, these results provide novel insights into the mechanisms underlying CLL cells survival and pave the way for therapeutic agents targeting tumours cells harbouring mutations in ATM and RNASEH2B genes.

BackgroundIschemic stroke poses a notable global public health challenge, with the Kingdom of Saudi Arabia (KSA) being no exception. This multifaceted condition is affected by a combination of factors, including hypertension, diabetes, and genetic influences. The purpose of the present study was to examine the linkage of long noncoding RNAs (such as ANRIL), plasminogen activator inhibitor-1 (PAI-1), and hepatocyte nuclear factor 1 alpha (HNF1α) gene variations with stroke. Leveraging a substantial cohort comprising both stroke patients and healthy individuals from KSA, our research revealed numerous uncommon genetic variations linked to an increased predisposition to stroke. This insight enhances our comprehension of stroke's genetic underpinnings and can be invaluable in formulating preventive measures, not only in KSA but also on a global scale.MethodsIn this study we included 100 stroke patients and 100-120 healthy controls from Saudi population. We utilized the amplification refractory mutation system-PCR to genotype the chromosome 9p21 locus, the long noncoding RNA-ANRIL (lncRNA-ANRIL), Hepatocyte Nuclear Factor 1 alpha (HNF1α-A > C [p.I27L]) gene, and the plasminogen activator inhibitor-1 (PAI-1) gene to investigate the association of these gene variations with a stroke. Additionally, WES was performed for 10 stroke patients using the Illumina NovaSeq 6000 platform.ResultsOur investigation revealed significant associations between stroke patients and healthy controls concerning polymorphic variants of lncRNA-ANRIL (A > C), ANRIL (G > A), HNF1α-A > C, and PAI-1-4G > 5G genes (p < 0.05). Notably, the ANRIL rs1333048-GA genotype exhibited a strong connection with stroke susceptibility in both codominant (OR 2.29, RR 1.54, P < 0.007) and dominant (OR 1.83, RR 1.35, P < 0.034) models, while an overdominant inheritance model demonstrated a protective correlation (OR 0.42, RR 0.64, p < 0.004). Similarly, the ANRIL rs10757278-GG genotype was significantly associated with stroke susceptibility in the codominant (OR 2.80, RR 1.66, P < 0.004) and recessive (OR 3.14, RR 1.62, P < 0.0003) models, with the G allele also displaying a significant association. The HNF1α-TT genotype strongly correlated with stroke risk in the codominant (OR 18.36, RR 9.96, P < 0.048) and recessive (OR 22.14, RR 10.18, P < 0.034) models, with the HNF1α-T allele following a similar trend. The PAI-1-4G-5G genotype was also linked to stroke predisposition (OR 2.09, RR 1.34, P < 0.034) and an increased risk in the dominant model (OR 2.27, RR 1.43, P < 0.006). Furthermore, our study identified several novel and common gene variants in stroke patients through WES, including COL4A2, PSEN2, NOTCH3, and RNF2.ConclusionOur findings underscore the significant role of genetic determinants in chromosome 9p21, the lncRNA-ANRIL, HNF1α-A > C (p.I27L), and PAI-1-4G > 5G genes in elevating the risk of stroke. Additionally, we report low, novel, and intermediate-genetic-risk variants in COL4A2, PSEN2, NOTCH3, and RNF2 through WES, emphasizing the need for further investigation in larger cohort studies.

Background: The findings of earlier investigations of antiapoptotic gene genotypes and allele variants on lymphoma risk are ambiguous. This study aimed to examine the relationship between the mutation in the antiapoptotic genes and lymphoma risk among Saudi patients. Methods: This case–control study included 205 patients, 100 of whom had lymphoma (cases) and 105 who were healthy volunteers (controls). We used tetra amplification refractory mutation polymerase chain reaction (PCR) to identify antiapoptotic genes such as B-cell lymphoma-2 (BCL2-938 C > A), MCL1-rs9803935 T > G, and survivin (BIRC5-rs17882312 G > C and BIRC5-rs9904341 G > C). Allelic-specific PCR was used to identify alleles such as BIRC5-C, MCL1-G, and BIRC5-G. Results: The dominant inheritance model among cases showed that mutations in all four antiapoptotic genes were more likely to be associated with the risk of lymphoma by the odds of 2.0-, 1.98-, 3.90-, and 3.29-fold, respectively, compared to controls. Apart from the BCL-2-A allele, all three specified alleles were more likely to be associated with lymphoma by the odds of 2.04-, 1.65-, and 2.11-fold, respectively. Conclusion: Unlike healthy individuals, lymphoma patients are more likely to have antiapoptotic gene genotypes and allele variants, apart from BCL-2-A alterations. In the future, these findings could be used to classify and identify patients at risk of lymphoma.