E2F1 rs3213150 多态性影响急性髓系白血病患者阿糖胞苷的敏感性和预后。

E2F1 rs3213150 polymorphism influences cytarabine sensitivity and prognosis in patients with acute myeloid leukemia.

机构信息

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China.

Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410008, China.

出版信息

Ann Hematol. 2023 Dec;102(12):3345-3355. doi: 10.1007/s00277-023-05431-y. Epub 2023 Sep 4.

DOI:10.1007/s00277-023-05431-y

PMID:37665348

Abstract

UNLABELLED

Cytarabine (Ara-C) plays an irreplaceable role in the treatment of acute myeloid leukemia (AML). However, there are significant differences in efficacy among patients. Our previous studies found that E2F1 rs3213150 polymorphism was associated with remission rate of Ara-C chemotherapy, but the specific mechanism is not clear. This study aimed to further confirm the correlation between E2F1 rs3213150 polymorphism and Ara-C resistance and prognosis in AML patients, and to provide valuable information for elucidating the molecular mechanisms involved.

METHODS

Rs3213150 genotyping was performed in 922 AML patients by Sanger sequencing, and the effects of different genotypes on chemosensitivity and prognosis were analyzed by Logistic regression and Cox regression. Meanwhile, a prediction model of Ara-C chemotherapy resistance was established. The impact of rs3213150 polymorphism on E2F1 expression level was determined by luciferase reporter gene assay, and differentially expressed genes between patients with different genotypes were identified by RNA sequencing.

RESULTS

Compared with rs3213150 G allele carriers, patients with AA genotype had more obvious Ara-C resistance (41.94% vs. 27.94%, P = 0.002), shorter overall survival (529 d vs. 644 d, P = 0.008) and disease-free survival (519 d vs. 556 d, P = 0.023). Rs3213150G > A mutation resulted in decreased E2F1 expression.

CONCLUSION

E2F1 rs3213150 polymorphism influences the chemosensitivity and prognosis of Ara-C in Chinese AML patients.

摘要

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阿糖胞苷（Ara-C）在急性髓系白血病（AML）的治疗中发挥着不可替代的作用。然而，患者之间的疗效存在显著差异。我们之前的研究发现，E2F1 rs3213150 多态性与 Ara-C 化疗的缓解率有关，但具体机制尚不清楚。本研究旨在进一步证实 E2F1 rs3213150 多态性与 AML 患者对 Ara-C 耐药性和预后的相关性，并为阐明相关的分子机制提供有价值的信息。

方法

通过 Sanger 测序对 922 例 AML 患者进行 rs3213150 基因分型，通过 Logistic 回归和 Cox 回归分析不同基因型对化疗敏感性和预后的影响。同时，建立了 Ara-C 化疗耐药的预测模型。通过荧光素酶报告基因检测确定 rs3213150 多态性对 E2F1 表达水平的影响，并通过 RNA 测序鉴定不同基因型患者之间差异表达的基因。

结果

与 rs3213150 G 等位基因携带者相比，AA 基因型患者对 Ara-C 的耐药性更为明显（41.94% vs. 27.94%，P=0.002），总生存期（529 d vs. 644 d，P=0.008）和无病生存期（519 d vs. 556 d，P=0.023）更短。rs3213150G>G 突变导致 E2F1 表达降低。