کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2106966 | 1083645 | 2015 | 13 صفحه PDF | دانلود رایگان |
• U2AF1 mutant mice develop leukopenia and hematopoietic progenitor cell expansion
• U2AF1 mutant stem cells are outcompeted by wild-type stem cells in vivo
• Mutant U2AF1 alters splicing similarly in mouse and human hematopoietic cells
• Mutant U2AF1 alters splicing of RNA processing and recurrently mutated MDS/AML genes
SummaryHeterozygous somatic mutations in the spliceosome gene U2AF1 occur in ∼11% of patients with myelodysplastic syndromes (MDS), the most common adult myeloid malignancy. It is unclear how these mutations contribute to disease. We examined in vivo hematopoietic consequences of the most common U2AF1 mutation using a doxycycline-inducible transgenic mouse model. Mice expressing mutant U2AF1(S34F) display altered hematopoiesis and changes in pre-mRNA splicing in hematopoietic progenitor cells by whole transcriptome analysis (RNA-seq). Integration with human RNA-seq datasets determined that common mutant U2AF1-induced splicing alterations are enriched in RNA processing genes, ribosomal genes, and recurrently mutated MDS and acute myeloid leukemia-associated genes. These findings support the hypothesis that mutant U2AF1 alters downstream gene isoform expression, thereby contributing to abnormal hematopoiesis in patients with MDS.
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Journal: - Volume 27, Issue 5, 11 May 2015, Pages 631–643