Department of Pathology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
Department of Pathology, Capital Medical University, Beijing, China.
Cancer Biomark. 2023;36(2):103-116. doi: 10.3233/CBM-210407.
Acute myeloid leukemia (AML) is a significantly heterogeneous malignancy of the blood. Cytogenetic abnormalities are crucial for the prognosis of AML. However, since more than half of patients with AML are cytogenetically normal AML (CN-AML), predictive prognostic indicators need to be further refined. In recent years, gene abnormalities are considered to be strong prognostic factors of CN-AML, already having clinical significance for treatment. In addition, the relationship of methylation in some genes and AML prognosis predicting has been discovered. RASGEF1A is a guanine nucleotide exchange factors of Ras and widely expressed in brain tissue, bone marrow and 17 other tissues. RASGEF1A has been reported to be associated with a variety of malignant tumors, examples include Hirschsprung disease, renal cell carcinoma, breast cancer, diffuse large B cell lymphoma, intrahepatic cholangiocarcinoma and so on [1, 2]. However, the relationship between the RASGEF1A gene and CN-AML has not been reported.
By integrating the Cancer Genome Atlas (TCGA) database 75 patients with CN-AML and 240 Gene Expression Omnibus (GEO) database CN-AML samples, we examined the association between RASGEF1A's RNA expression level and DNA methylation of and AML patients' prognosis. Then, we investigated the RASGEF1A RNA expression and DNA methylation's prognostic value in 77 patients with AML after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) as well as 101 AML patients after chemotherapy respectively. We investigated the association between sensitivity to Crenolanib and expression level of RASGED1A in patients by integrating 191 CN-AML patients from BeatAML dadataset. We integrated the expression and methylation of RASGEF1A to predict the CN-AML patients' prognosis and investigated the relationship between prognostic of AML patients with different risk classification and expression levels or methylation levels of RASGEF1A.
We found that RASGEF1A gene high expression group predicted poorer event-free survival (EFS) (P< 0.0001) as well as overall survival (OS) (P< 0.0001) in CN-AML samples, and the identical results were found in AML patients receiving chemotherapy (P< 0.0001) and Allo-HSCT (P< 0.0001). RASGEF1A RNA expression level is an CN-AML patients' independent prognostic factor (EFS: HR = 5.5534, 95% CI: 1.2982-23.756, P= 0.0208; OS: HR = 5.3615, 95% CI: 1.1014-26.099, P= 0.0376). The IC50 (half maximal inhibitory concentration) of Crenolanib of CN-AML samples with RASGEF1A high expression level is lower. In addition, patients with high RASGEF1A methylation level had significant favorable prognosis (EPS: P< 0.0001, OS: P< 0.0001). Furthermore, the integrative analysis of expression and methylation of RASGEF1A could classify CN-AML patients into subgroups with different prognosis (EFS: P= 0.034, OS: P= 0.0024). Expression levels or methylation levels of RASGEF1A help to improve risk classification of 2010 European Leukemia Net.
Higher RASGEF1A RNA expression and lower DNA methylation predicts CN-AML patients' poorer prognosis. The RASGEF1A high expression level from patients with CN-AML have better sensitivity to Crenolanib. The integrative analysis of RASGEF1A RNA expression and DNA methylation can provide a more accurate classification for prognosis. Lower RASGEF1A expression is a favorable prognostic factor for AML patients receiving chemotherapy or Allo-HSCT. 2010 European Leukemia Net's risk classification can be improved by RASGEF1A expression levels or methylation levels.
急性髓系白血病（AML）是一种显著异质性的血液恶性肿瘤。细胞遗传学异常对 AML 的预后至关重要。然而，由于超过一半的 AML 患者为核型正常 AML（CN-AML），因此需要进一步细化预测预后的指标。近年来，基因异常被认为是 CN-AML 的强有力预后因素，已经对治疗具有临床意义。此外，已经发现一些基因的甲基化与 AML 预后预测之间存在关系。RASGEF1A 是 Ras 的鸟嘌呤核苷酸交换因子，广泛表达于脑组织、骨髓和 17 种其他组织中。已经有报道称 RASGEF1A 与多种恶性肿瘤有关，包括先天性巨结肠、肾细胞癌、乳腺癌、弥漫性大 B 细胞淋巴瘤、肝内胆管癌等[1,2]。然而，RASGEF1A 基因与 CN-AML 之间的关系尚未报道。
通过整合癌症基因组图谱（TCGA）数据库中的 75 例 CN-AML 患者和 240 例基因表达综合数据库（GEO）中的 CN-AML 样本，我们研究了 RASGEF1A 的 RNA 表达水平与 AML 患者的预后与 DNA 甲基化之间的关系。然后，我们分别研究了 77 例接受异基因造血干细胞移植（Allo-HSCT）和 101 例接受化疗的 AML 患者的 RASGEF1A RNA 表达和 DNA 甲基化的预后价值。我们通过整合来自 BeatAML 数据集的 191 例 CN-AML 患者，研究了 RASGED1A 表达水平与患者对 Crenolanib 敏感性之间的关系。我们整合了 RASGEF1A 的表达和甲基化来预测 CN-AML 患者的预后，并研究了不同风险分类的 AML 患者的预后与 RASGEF1A 的表达水平或甲基化水平之间的关系。
我们发现，在 CN-AML 样本中，RASGEF1A 基因高表达组预测无事件生存（EFS）（P<0.0001）和总生存（OS）（P<0.0001）较差，在接受化疗（P<0.0001）和 Allo-HSCT（P<0.0001）的 AML 患者中也得到了相同的结果。RASGEF1A RNA 表达水平是 AML 患者的独立预后因素（EFS：HR=5.5534，95%CI：1.2982-23.756，P=0.0208；OS：HR=5.3615，95%CI：1.1014-26.099，P=0.0376）。CN-AML 样本中 RASGEF1A 高表达水平的 Crenolanib 的半数最大抑制浓度（IC50）较低。此外，高 RASGEF1A 甲基化水平的患者具有显著的良好预后（EFS：P<0.0001，OS：P<0.0001）。此外，RASGEF1A 的表达和甲基化的综合分析可以将 CN-AML 患者分为具有不同预后的亚组（EFS：P=0.034，OS：P=0.0024）。RASGEF1A 的表达水平或甲基化水平有助于提高 2010 年欧洲白血病网的风险分类。
较高的 RASGEF1A RNA 表达和较低的 DNA 甲基化预示着 CN-AML 患者的预后较差。CN-AML 患者的 RASGEF1A 高表达水平对 Crenolanib 有更好的敏感性。RASGEF1A RNA 表达和 DNA 甲基化的综合分析可以为预后提供更准确的分类。AML 患者接受化疗或 Allo-HSCT 时，RASGEF1A 表达水平较低是一个有利的预后因素。RASGEF1A 的表达水平或甲基化水平可以提高 2010 年欧洲白血病网的风险分类。
