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Träfflista för sökning "WFRF:(Lehmann Sylvain) srt2:(2020)"

Sökning: WFRF:(Lehmann Sylvain) > (2020)

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1.
  • Anande, Govardhan, et al. (författare)
  • RNA Splicing Alterations Induce a Cellular Stress Response Associated with Poor Prognosis in Acute Myeloid Leukemia
  • 2020
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 26:14, s. 3597-3607
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: RNA splicing is a fundamental biological process that generates protein diversity from a finite set of genes. Recurrent somatic mutations of splicing factor genes are common in some hematologic cancers but are relatively uncommon in acute myeloid leukemia (AML, < 20% of patients). We examined whether RNA splicing differences exist in AML, even in the absence of splicing factor mutations.Experimental Design: We developed a bioinformatics pipeline to study alternative RNA splicing in RNA-sequencing data from large cohorts of patients with AML.Results: We have identified recurrent differential alternative splicing between patients with poor and good prognosis. These splicing events occurred even in patients without any discernible splicing factor mutations. Alternative splicing recurrently occurred in genes with specific molecular functions, primarily related to protein translation. Developing tools to predict the functional impact of alternative splicing on the translated protein, we discovered that approximately 45% of the splicing events directly affected highly conserved protein domains. Several splicing factors were themselves misspliced and the splicing of their target transcripts were altered. Studying differential gene expression in the same patients, we identified that alternative splicing of protein translation genes in ELNAdv patients resulted in the induction of an integrated stress response and upregulation of inflammation-related genes. Finally, using machine learning techniques, we identified a splicing signature of four genes which refine the accuracy of existing risk prognosis schemes and validated it in a completely independent cohort.Conclusions: Our discoveries therefore identify aberrant alternative splicing as a molecular feature of adverse AML with clinical relevance.
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2.
  • Österroos, Albin, et al. (författare)
  • Integrated transcriptomic and genomic analysis improves prediction of complete remission and survival in elderly patients with acute myeloid leukemia
  • 2020
  • Ingår i: Blood Cancer Journal. - : NATURE PUBLISHING GROUP. - 2044-5385. ; 10:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Relevant molecular tools for treatment stratification of patients >= 65 years with acute myeloid leukemia (AML) are lacking. We combined clinical data with targeted DNA- and full RNA-sequencing of 182 intensively and palliatively treated patients to predict complete remission (CR) and survival in AML patients >= 65 years. Intensively treated patients withNPM1andIDH2(R172)mutations had longer overall survival (OS), whereas mutatedTP53conferred lower CR rates and shorter OS.FLT3-ITDandTP53mutations predicted worse OS in palliatively treated patients. Gene expression levels most predictive of CR were combined with somatic mutations for an integrated risk stratification that we externally validated using the beatAML cohort. We defined a high-risk group with a CR rate of 20% in patients with mutatedTP53, compared to 97% CR in low-risk patients defined by high expression ofZBTB7AandEEPD1withoutTP53mutations. Patients without these criteria had a CR rate of 54% (intermediate risk). The difference in CR rates translated into significant OS differences that outperformed ELN stratification for OS prediction. The results suggest that an integrated molecular risk stratification can improve prediction of CR and OS and could be used to guide treatment in elderly AML patients.
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