评估全球mRNA替代剪接在急性髓样白血病患者中的临床意义
Evaluation of the clinical significance of global mRNA alternative splicing in patients with acute myeloid leukemia
影响因子:9.90000
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
摘要
异常替代剪接（AS）参与白血病。这项研究探讨了全球变化的临床影响，作为341例在台湾大学医院新诊断的341例急性髓样白血病（AML）患者的模式，并使用癌症基因组图集（TCGA）群体对其进行了验证。在研究正常的脐带血CD34 /CD38-细胞时，我们发现AML细胞表现出明显不同的全局剪接模式。具有突变TP53的AML在剪接模式中具有特别高的全基因组畸变。全球剪接模式的畸形是一种独立的不利预后因素，影响AML患者接受标准强化化学疗法的总体存活。在我们的实验和TCGA队列中，将全球剪接模式的整合到2022年的欧洲白血病风险分类中可以将AML患者分为四组具有不同预后的组。我们进一步确定了四个基因，它们具有改变这两个队列中预后意义的变化。此外，这些与生存相关的事件涉及几个重要的细胞过程，这些过程可能与对密集化疗的反应不佳有关。总而言之，我们的研究证明了AML患者差异全球剪接模式的临床和生物学意义。需要进行较大前瞻性队列的进一步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.