DNA Methylation-Based Epigenetic Repression of SLC22A4 Promotes Resistance to Cytarabine in Acute Myeloid Leukemia.
DNA Methylation-Based Epigenetic Repression of SLC22A4 Promotes Resistance to Cytarabine in Acute Myeloid Leukemia.
复制标题
DOI：
10.1111/cts.12861
复制
发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Baker SD
中科院分区：
文献类型：
--
作者：
Buelow DR;Anderson JT;Pounds SB;Shi L;Lamba JK;Hu S;Gibson AA;Goodwin EA;Sparreboom A;Baker SD
据报道，摄取转运蛋白OCTN 1（SLC 22 A4）的表达降低是接受胞苷核苷类似物阿糖胞苷（Ara-C）治疗的多个急性髓性白血病（AML）患者队列中无事件生存期和总生存期较差的强预测因子。为了进一步了解AML中OCTN 1功能表达的个体间差异的机制基础，我们假设与基于DNA甲基化的SLC 22 A4表观遗传抑制存在机制联系。我们发现基础SLC 22 A4甲基化增加与AML细胞系中Ara-C摄取减少相关。与溶剂处理的细胞相比，用低甲基化剂、5-氮杂胞苷或地西他滨预处理可恢复SLC 22 A4 mRNA表达，增加细胞对Ara-C的摄取，并与细胞对Ara-C的敏感性增加相关。此外，较低的SLC 22 A4甲基化状态与成人和儿童AML患者的明显临床优势相关。这些发现表明，调节机制参与了对Ara-C反应的个体间差异，并为将低甲基化药物整合到基于Ara-C的治疗方案中提供了基础。
Reduced expression of the uptake transporter, OCTN1 (SLC22A4), has been reported as a strong predictor of poor event‐free and overall survival in multiple cohorts of patients with acute myeloid leukemia (AML) receiving the cytidine nucleoside analog, cytarabine (Ara‐C). To further understand the mechanistic basis of interindividual variability in the functional expression of OCTN1 in AML, we hypothesized a mechanistic connection to DNA methylation‐based epigenetic repression of SLC22A4. We found increased basal SLC22A4 methylation was associated with decreased Ara‐C uptake in AML cell lines. Pre‐treatment with hypomethylating agents, 5‐azacytidine, or decitabine, restored SLC22A4 mRNA expression, increased cellular uptake of Ara‐C, and was associated with increased cellular sensitivity to Ara‐C compared with vehicle‐treated cells. Additionally, lower SLC22A4 methylation status was associated with distinct clinical advantages in both adult and pediatric patients with AML. These findings suggest a regulatory mechanism is involved in the interindividual variability in response to Ara‐C, and provides a basis for the integration of hypomethylating agents into Ara‐C‐based treatment regimens.
登录
查看更多内容
DOI：
10.1111/cts.12366
发表时间：
2016-02
期刊：
Clinical and translational science
影响因子：
--
作者：
Drenberg CD;Hu S;Li L;Buelow DR;Orwick SJ;Gibson AA;Schuetz JD;Sparreboom A;Baker SD
通讯作者：
Baker SD
影响因子：
11.2
作者：
Eramo, A;Pallini, R;De Maria, R
通讯作者：
De Maria, R
影响因子：
3.9
作者：
Tschirka, Julia;Kreisor, Madlen;Gruendemann, Dirk
通讯作者：
Gruendemann, Dirk
影响因子：
11.2
作者：
Drenberg, Christina D.;Gibson, Alice A.;Sparreboom, Alex
通讯作者：
Sparreboom, Alex
影响因子：
20.3
作者：
Scandura, Joseph M.;Roboz, Gail J.;Feldman, Eric J.
通讯作者：
Feldman, Eric J.