Department of Hematology, The Affiliated Hospital of Guilin Medical University, Guilin, China.
Institute of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjing, China.
IUBMB Life. 2020 Jul;72(7):1481-1490. doi: 10.1002/iub.2273. Epub 2020 Mar 17.
We investigated the role of leukemia stem cells in chemoresistance and recurrence of acute myeloid leukemia. Total RNA was isolated from cells or tissues using TRIzol reagent. Cell viability was assessed with the tetrazolium assay. MicroRNA-34a (miR-34a), which acts on cell death regulation pathways, was noticeably downregulated in non-M3 acute myeloid leukemia stem cells compared with normal hematopoietic stem cells. Furthermore, inhibition of miR-34a-mediated suppression in leukemia stem cells was associated with poor clinical outcomes and impaired treatment efficacy in acute myeloid leukemia. Transfection with a miR-34a mimic triggered leukemia stem cell death and prevented leukemia. Bioinformatics analysis and a dual-luciferase reporter assay showed that miR-34a targeted the 3'-untranslated region of histone deacetylase 2, and the reinforced expression of miR-34a remarkably stimulated the expression of histone deacetylase 2 in leukemia stem cells. Ectopic miR-34a expression triggered death of leukemia stem cells via pathways involving the Janus kinase 1-signal transducer and activator of transcription 2-p53 axis. Targeting leukemia stem cells to trigger cell death through upregulation of miR-34a expression could be used to diagnose and treat acute myeloid leukemia.
我们研究了白血病干细胞在急性髓系白血病化疗耐药和复发中的作用。使用 TRIzol 试剂从细胞或组织中分离总 RNA。用四唑测定法评估细胞活力。miR-34a（miR-34a）作用于细胞死亡调节途径，在非 M3 急性髓系白血病干细胞中明显下调，与正常造血干细胞相比。此外，抑制 miR-34a 在白血病干细胞中的抑制作用与急性髓系白血病不良的临床结局和治疗效果受损有关。转染 miR-34a 模拟物可触发白血病干细胞死亡并预防白血病。生物信息学分析和双荧光素酶报告基因检测表明，miR-34a 靶向组蛋白去乙酰化酶 2 的 3'-非翻译区，增强表达 miR-34a 可显著刺激白血病干细胞中组蛋白去乙酰化酶 2 的表达。外源性 miR-34a 表达通过 Janus 激酶 1-信号转导子和转录激活子 2-p53 轴途径触发白血病干细胞死亡。通过上调 miR-34a 表达靶向白血病干细胞引发细胞死亡可用于诊断和治疗急性髓系白血病。
