Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, Hunan, PR China.
Department of Hematology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, PR China.
Eur J Pharmacol. 2021 Mar 15;895:173894. doi: 10.1016/j.ejphar.2021.173894. Epub 2021 Jan 19.
Acute myeloid leukemia (AML) is a hematopoietic disease with poor survival. Chemotherapy resistance is one of the determinant factors influencing AML prognosis. To identify genes possibly affecting the drug responses in AML, the Illumina Infinium MethylationEPIC (850K) was used to screen for differential DNA methylation loci between patients achieved complete remission (CR) or not (non-CR) after induction therapy in 37 AML patients. Then, 32 differentially methylated sites (DMS) were selected for replication in another 86 AML patients by next-generation sequencing. Nine sites including cg03988660, cg16804603, cg18166936, cg11308319, cg09095403, cg18493214, cg01443536, cg16030878 and cg10143426 were replicated. Analysis of the Gene Expression Omnibus (GEO) database showed that mRNA expression of TBC1D16 and HDAC4 was associated with AML prognosis. Methylation level of the cg16030878 in TBC1D16 3'-UTR correlated positively with TBC1D16 mRNA expression in samples both in the TCGA database and clinically collected in the study. Both higher cg16030878 methylation and higher TBC1D16 mRNA expression were associated with increased risk of non-CR and worse overall survival (OS) in AML patients. In AML cells, knockdown of TBC1D16 decreased cell proliferation and ERK phosphorylation levels, as well as increased sensitivity to mitoxantrone and decitabine indicated by IC. In patients with combined use of decitabine, those patients with CR showed significantly lower TBC1D16 mRNA expression. On the contrary, knockdown of TBC1D16 resulted in decreased sensitivity to cytarabine in U937 cells. Our findings implicated that TBC1D16 is a potential predictor for chemosensitivity and prognosis in adult AML patients.
急性髓系白血病（AML）是一种生存状况较差的造血系统疾病。化疗耐药是影响 AML 预后的决定因素之一。为了鉴定可能影响 AML 药物反应的基因，我们使用 Illumina Infinium MethylationEPIC（850K）对 37 例 AML 患者诱导治疗后达到完全缓解（CR）或未达到完全缓解（非 CR）的患者进行了差异 DNA 甲基化位点筛选。然后，通过下一代测序在另外 86 例 AML 患者中复制了 32 个差异甲基化位点（DMS）。包括 cg03988660、cg16804603、cg18166936、cg11308319、cg09095403、cg18493214、cg01443536、cg16030878 和 cg10143426 在内的 9 个位点得到了复制。对基因表达综合数据库（GEO）的分析表明，TBC1D16 和 HDAC4 的 mRNA 表达与 AML 的预后相关。TBC1D16 3'UTR 中的 cg16030878 的甲基化水平与 TCGA 数据库和本研究中临床收集的样本中的 TBC1D16 mRNA 表达呈正相关。较高的 cg16030878 甲基化和较高的 TBC1D16 mRNA 表达与 AML 患者非 CR 和总体生存（OS）不良的风险增加相关。在 AML 细胞中，TBC1D16 的敲低降低了细胞增殖和 ERK 磷酸化水平，以及米托蒽醌和地西他滨的 IC 所表明的敏感性。在联合使用地西他滨的患者中，达到 CR 的患者 TBC1D16 mRNA 表达明显降低。相反，在 U937 细胞中，TBC1D16 的敲低导致对阿糖胞苷的敏感性降低。我们的研究结果表明，TBC1D16 是成人 AML 患者化疗敏感性和预后的潜在预测因子。
