Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA 19104.
Department of Genetics, University of Pennsylvania, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2021 Apr 13;118(15). doi: 10.1073/pnas.2014967118.
Most genes associated with acute myeloid leukemia (AML) are mutated in less than 10% of patients, suggesting that alternative mechanisms of gene disruption contribute to this disease. Here, we find a set of splicing events that alter the expression of a subset of AML-associated genes independent of known somatic mutations. In particular, aberrant splicing triples the number of patients with reduced functional EZH2 compared with that predicted by somatic mutation alone. In addition, we unexpectedly find that the nonsense-mediated decay factor DHX34 exhibits widespread alternative splicing in sporadic AML, resulting in a premature stop codon that phenocopies the loss-of-function germline mutations observed in familial AML. Together, these results demonstrate that classical mutation analysis underestimates the burden of functional gene disruption in AML and highlight the importance of assessing the contribution of alternative splicing to gene dysregulation in human disease.
大多数与急性髓细胞白血病（AML）相关的基因在不到 10%的患者中发生突变，这表明基因缺失的其他机制导致了这种疾病。在这里，我们发现了一组剪接事件，这些事件改变了一组与 AML 相关基因的表达，而这些基因与已知的体细胞突变无关。特别是，异常剪接使 EZH2 功能降低的患者数量比仅由体细胞突变预测的数量增加了两倍。此外，我们出人意料地发现，无意义介导的衰变因子 DHX34 在散发性 AML 中表现出广泛的选择性剪接，导致过早的终止密码子，其表型类似于在家族性 AML 中观察到的功能丧失性种系突变。总之，这些结果表明，经典的突变分析低估了 AML 中功能性基因缺失的负担，并强调了评估选择性剪接对人类疾病中基因失调的贡献的重要性。
