An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures

Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance

Advancing pneumonia virus drug discovery with virtual screening: A cutting-edge fast and resource efficient machine learning framework for predictive analysis

Pneumonia, a severe respiratory infection characterized by a significant morbidity and fatality rate, afflicts many individuals globally. The demand for highly effective antiviral medications has experienced a surge because of the emergence of novel pneumonia viruses, such as the COVID-19 coronavirus. Due to their inherent time and cost constraints, conventional drug development strategies sometimes need to be more manageable. Exploring alternative approaches is crucial to identifying and establishing effective therapy choices. This work introduces a computational methodology for analyzing the chemical space of medications targeting the pneumonia virus, employing Python-based data mining tools. Using computer-aided analysis in drug molecules aims to enhance the efficiency of identifying and evaluating potential new therapeutic candidates using Machine Learning (ML). The research successfully discovered two therapeutic compounds by utilizing the Bayesian Ridge approach, which is the most accurate with the least mean squared error, is less computationally expensive in terms of power, memory, and CPU, and is the fastest of the investigated approaches. It discovered the CHEMBL433378 and CHEMBL93653, with promising docking scores of −4.3 and −4.2, respectively. Additionally, both molecules demonstrated significant inhibitory activity against their respective targets, as seen by their IC50 values of 0.0018 and 0.001. Both compounds meet the criteria for the B. Mann Whitney U Test and Lipinski test

Rapid parallel acquisition of somatic mutations after NPM1 in acute myeloid leukaemia evolution

The steps in the progression from subclinical clonal haemopoiesis to acute myeloid leukaemia (AML) have not been defined, nor has its likelihood or latency. NPM1 mutations were not found to drive clonal haemopoiesis in haematologically normal individuals(Genovese et al, 2014; Jaiswal et al, 2014; Xie et al, 2014; McKerrell et al, 2015), highlighting their strong leukaemogenic pedigree, but making them difficult to capture at a stage prior to frank AML. As occasional cases of NPM1-mutated myelodysplastic syndrome/myeloproliferative neoplasm have been described(Caudill et al, 2006; Peng et al, 2016), we hypothesised that detailed analysis of such cases could offer insights into leukaemic evolution after the acquisition of NPM1 mutations. Here, we describe the genetic events driving rapid progression of a case of NPM1 mutant chronic myelomonocytic leukaemia (CMML) to full-blown AML

Therapeutic targeting of preleukemia cells in a mouse model of mutant acute myeloid leukemia

The initiating mutations that contribute to cancer development are sometimes present in premalignant cells. Whether therapies targeting these mutations can eradicate premalignant cells is unclear. Acute myeloid leukemia (AML) is an attractive system for investigating the effect of preventative treatment because this disease is often preceded by a premalignant state (clonal hematopoiesis or myelodysplastic syndrome). In mutant knock-in mice, a model of AML development, leukemia is preceded by a period of extended myeloid progenitor cell proliferation and self-renewal. We found that this self-renewal can be reversed by oral administration of a small molecule (VTP-50469) that targets the MLL1-Menin chromatin complex. These preclinical results support the hypothesis that individuals at high risk of developing AML might benefit from targeted epigenetic therapy in a preventative setting

Sf3b1 K700E Mutation Impairs Pre-mRNA Splicing and Definitive Hematopoiesis in a Conditional Knock-in Mouse Model

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by dysplastic hematopoiesis and peripheral blood cytopenias. Recently, somatic mutations affecting components of the spliceosomal machinery have been discovered in the majority of MDS patients. SF3B1 mutations are most frequent and strongly correlate with the presence of bone marrow ring sideroblasts and a favorable prognosis. SF3B1 mutations, including the K700E substitution which accounts for more than 50% of all mutations, are missense, heterozygous and cluster in a hotspot within the heat domain of the protein suggesting that they are gain-of-function variants. The molecular effects of SF3B1 mutations and the mechanisms through which they drive clonal expansion and dyserythropoiesis remain obscure. Therefore, to assess their molecular and phenotypic consequences, we generated a mouse model carrying a conditional floxed knock-in allele (Sf3b1flox-K700E/+) by homologous recombination of JM8 murine embryonic stem cells. To induce expression of Sf3b1 K700E in adult hematopoietic stem and progenitor cells, Sf3b1flox-K700E/+/Mx1-Cre+ were injected with pIpC from 4-8 weeks of age. Here we report the initial characterization of these animals. Monthly peripheral blood counts from mutants and wild-type (WT) littermates starting one month post-pIpC injection showed a reduction in hemoglobin levels (at 8 weeks WT=17g/dl mut=14.5g/dl, p<0.03). Additionally, flow cytometric analysis of bone marrow samples demonstrated a modest but consistent decrease in late erythroid progenitor cells (Ter119+ and CD71-/low). The myeloid compartment showed relative expansion of Gr1+/Mac1+ and Mac1+ cells whereas analysis of hematopoietic stem and progenitor cells (HSPCs) revealed a decrease in HSCs (% of total events WT=0.04%; Sf3b1flox-K700E/+=0.01%) in mutant mice. In competitive transplantation experiments into sub-lethally irradiated syngeneic recipients we observed a lower engraftment potential of Sf3b1flox-K700E Lin-ve HSPCs (CD45.2) compared to wild-type cells (CD45.1). Flow cytometric analysis of peripheral blood of recipient animals showed that Sf3b1flox-K700E cells contributed more to the myeloid lineage than wild-type cells (Sf3b1flox-K700E Mac1+/Gr1+ 8.95%; Mac1+ 15% vs WT Mac1+/Gr1+ 4.08%; Mac1+ 5.57%). At a median follow-up of 56 weeks, mutant animals did not show decreased survival or signs of illness as compared to WT controls. Finally, as Sfb31 mutations are predicted to affect splicing of pre-mRNA and consequently alter the gene expression, we performed RNAseq analysis in unselected and Lin-ve bone-marrow cells from mutant and controls animals. Comparison between wt and mutant samples showed deregulated expression of genes implicated in human MDS (Mmp9, Puma, Bcl2l1). We then looked at the pattern of aberrant splicing promoted by Sf3b1flox-K700E, and found that mutant animals have an increased use of cryptic 3'' splice sites (ss) throughout their genome. We showed that the majority of these alternative 3' ss are novel and we characterized them as being located 15 to 24 nucleotides upstream from the canonical 3' ss and associated with sequence features including a shorter polypyrimidine tract and an enrichment of adenines -8 to -18 bases upstream of the cryptic 3' ss. Interestingly, similar features have been reported in human cancers with SF3B1 hotspot mutations. We predict that ~33% of the mRNAs affected by aberrant splicing will include an aberrant premature termination codon, promoting RNA degradation through nonsense-mediated decay. In conclusion, our conditional Sf3b1K700E knock-in mouse is a faithful molecular model of the consequences of these mutations in the mouse hematopoietic system. The mild phenotype we observe in comparison to SF3B1-mutant human MDS may be explained by the requirement for additional mutations to progress to overt MDS and is more reminiscent of SF3B1-associated clonal hemopoiesis, relatively common phenomenon in elderly humans without overt hematological abnormalities. Additionally, our initial characterization of novel splice sites preferentially recognised by the mutant Sf3b1 protein suggests that transcriptional consequences of the mutation may differ between species, dependant on the degree of conservation of the relevant intronic regions