Key Laboratory of Gene Engineering of Ministry of Education, State Key Laboratory, for Biocontrol, Sun Yat-sen University, Guangzhou 510275, China.
Mol Cancer. 2011 Sep 1;10:108. doi: 10.1186/1476-4598-10-108.
Although current chemotherapy regimens have remarkably improved the cure rate of pediatric acute promyelocytic leukemia (APL) over the past decade, more than 20% of patients still die of the disease, and the 5-year cumulative incidence of relapse is 17%. The precise gene pathways that exert critical control over the determination of cell lineage fate during the development of pediatric APL remain unclear.
In this study, we analyzed miR-125b expression in 169 pediatric acute myelogenous leukemia (AML) samples including 76 APL samples before therapy and 38 APL samples after therapy. The effects of enforced expression of miR-125b were evaluated in leukemic cell and drug-resistant cell lines.
miR-125b is highly expressed in pediatric APL compared with other subtypes of AML and is correlated with treatment response, as well as relapse of pediatric APL. Our results further demonstrated that miR-125b could promote leukemic cell proliferation and inhibit cell apoptosis by regulating the expression of tumor suppressor BCL2-antagonist/killer 1 (Bak1). Remarkably, miR-125b was also found to be up-regulated in leukemic drug-resistant cells, and transfection of a miR-125b duplex into AML cells can increase their resistance to therapeutic drugs,
These findings strongly indicate that miR-125b plays an important role in the development of pediatric APL at least partially mediated by repressing BAK1 protein expression and could be a potential therapeutic target for treating pediatric APL failure.
尽管过去十年中，当前的化疗方案显著提高了儿科急性早幼粒细胞白血病（APL）的治愈率，但仍有超过 20%的患者死于该疾病，5 年累积复发率为 17%。在儿科 APL 的发展过程中，精确的基因途径对细胞谱系命运的决定起着关键的控制作用，但目前仍不清楚。
在这项研究中，我们分析了 169 例儿科急性髓系白血病（AML）样本中的 miR-125b 表达，包括治疗前的 76 例 APL 样本和治疗后的 38 例 APL 样本。在白血病细胞和耐药细胞系中评估了强制表达 miR-125b 的效果。
miR-125b 在儿科 APL 中的表达水平高于其他 AML 亚型，与治疗反应以及儿科 APL 的复发相关。我们的结果进一步表明，miR-125b 可以通过调节肿瘤抑制因子 BCL2 拮抗剂/杀伤因子 1（Bak1）的表达来促进白血病细胞的增殖和抑制细胞凋亡。值得注意的是，miR-125b 在白血病耐药细胞中也被上调，并且将 miR-125b 双链体转染到 AML 细胞中可以增加其对治疗药物的耐药性。
这些发现强烈表明，miR-125b 在儿科 APL 的发展中起着重要作用，至少部分通过抑制 BAK1 蛋白表达来介导，并且可能是治疗儿科 APL 失败的潜在治疗靶点。
