期刊
NEOPLASIA
卷 22, 期 9, 页码 447-457出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neo.2020.06.004
关键词
Acute myeloid leukemia; Alternative splicing; Prognosis; European LeukemiaNet; Splicing factor
类别
资金
- National Key Research and Development Program of China [2019YFA0905900]
- National Natural Science Foundation Grants of China [81530003, 81890994, 81770153, 81911530240]
The dysregulation of alternative splicing (AS) has emerged as a mechanism of acute myeloid leukemia (AML). However, the prognostic impact of AS events remains under-explored in AML. Here we report the prognostic value of AS events and associated splicing factors based on three datasets of AML patients. We defined the landscape of AS events in AML and identified 7033 AS events associated with the survival of AML patients. Based on these events, we further developed a composite 15 AS event-based prognostic signature, which was independent of the cytogenetic risk stratification and patient age, and showed a better performance than known gene expression signatures. More importantly, our new signature markedly improved the European LeukemiaNet (ELN) risk classification, indicating a broad applicability in the clinical management of AML. Furthermore, the splicing-regulatory network established the correlations between prognostic AS events and associated splicing factors. The finding was validated by CRISPR-based data, which indicated that the increased expression of RBM39 contributed to the higher exon inclusion of SETD5 and conferred a poor outcome. Together, AS events may serve as a novel assortment of prognosticators for AML and could refine the ELN risk stratification. The splicing regulatory network provides dues regarding the splicing factor-mediated mechanisms of AML.
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