选择性拼接
髓系白血病
剪接体
细胞生物学
拼接因子
核糖核酸
诱导多能干细胞
小RNA
髓样
癌症干细胞
骨髓
作者
Leslie Crews,Larisa Balaian,Nathaniel Delos Santos,Heather Leu,Angela C. Court,Elisa Lazzari,Anil Sadarangani,Maria A. Zipeto,James J. La Clair,Reymundo Villa,Anna A. Kulidjian,Rainer Storb,Sheldon R. Morris,Edward D. Ball,Michael D. Burkart,Catriona Jamieson
出处
期刊:Cell Stem Cell
[Elsevier]
日期:2016-11-03
卷期号:19 (5): 599-612
被引量:64
标识
DOI:10.1016/j.stem.2016.08.003
摘要
Age-related human hematopoietic stem cell (HSC) exhaustion and myeloid-lineage skewing promote oncogenic transformation of hematopoietic progenitor cells into therapy-resistant leukemia stem cells (LSCs) in secondary acute myeloid leukemia (AML). While acquisition of clonal DNA mutations has been linked to increased rates of secondary AML for individuals older than 60 years, the contribution of RNA processing alterations to human hematopoietic stem and progenitor aging and LSC generation remains unclear. Comprehensive RNA sequencing and splice-isoform-specific PCR uncovered characteristic RNA splice isoform expression patterns that distinguished normal young and aged human stem and progenitor cells (HSPCs) from malignant myelodysplastic syndrome (MDS) and AML progenitors. In splicing reporter assays and pre-clinical patient-derived AML models, treatment with a pharmacologic splicing modulator, 17S-FD-895, reversed pro-survival splice isoform switching and significantly impaired LSC maintenance. Therapeutic splicing modulation, together with monitoring splice isoform biomarkers of healthy HSPC aging versus LSC generation, may be employed safely and effectively to prevent relapse, the leading cause of leukemia-related mortality.
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