急性髓性白血病患者中全局mRNA可变剪接的临床意义评估
Evaluation of the clinical significance of global mRNA alternative splicing in patients with acute myeloid leukemia
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影响因子:9.9
分区:医学1区 Top / 血液学2区
发表日期:2023 May
作者:
Yi-Tsung Yang, Chi-Yuan Yao, Po-Ju Chiu, Chein-Jun Kao, Hsin-An Hou, Chien-Chin Lin, Wen-Chien Chou, Hwei-Fang Tien
DOI:
10.1002/ajh.26893
摘要
异常的可变剪接（AS）参与白血病发生。本研究探讨了341例新诊断的急性髓性白血病（AML）患者中全局AS模式改变的临床影响，并使用台湾癌症基因组图谱（TCGA）队列进行验证。在研究正常脐带血CD34+ /CD38-细胞时发现AML细胞表现出明显不同的全局剪接模式。TP53突变的AML表现出特别高的基因组范围内剪接异常。全局剪接异常是影响AML患者接受标准强化化疗总体生存的独立不良预后因素。将全局剪接模式纳入2022年欧洲白血病网络（ELN）风险分类，可以将AML患者分为四个具有不同预后的组，在我们的实验组和TCGA队列中均得到验证。我们进一步鉴定出四个具有预后意义的AS基因。这些与生存相关的AS事件涉及多个重要的细胞过程，可能与对强化化疗反应不佳有关。总之，本研究展示了AML患者中差异化全局剪接模式的临床及生物学意义。未来需要更大规模的前瞻性队列研究以确认这些发现。
Abstract
Aberrant alternative splicing (AS) is involved in leukemogenesis. This study explored the clinical impact of alterations in global AS patterns in 341 patients with acute myeloid leukemia (AML) newly diagnosed at the National Taiwan University Hospital and validated it using The Cancer Genome Atlas (TCGA) cohort. While studying normal cord blood CD34+ /CD38- cells, we found that AML cells exhibited significantly different global splicing patterns. AML with mutated TP53 had a particularly high degree of genome-wide aberrations in the splicing patterns. Aberrance in the global splicing pattern was an independent unfavorable prognostic factor affecting the overall survival of patients with AML receiving standard intensive chemotherapy. The integration of global splicing patterns into the 2022 European LeukemiaNet risk classification could stratify AML patients into four groups with distinct prognoses in both our experimental and TCGA cohorts. We further identified four genes with AS alterations that harbored prognostic significance in both of these cohorts. Moreover, these survival-associated AS events are involved in several important cellular processes that might be associated with poor response to intensive chemotherapy. In summary, our study demonstrated the clinical and biological implications of differential global splicing patterns in AML patients. Further studies with larger prospective cohorts are required to confirm these findings.