Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond-Blackfan anemia through induction of miR-26a.
Metformin-induced suppression of Nemo-like kinase improves erythropoiesis in preclinical models of Diamond-Blackfan anemia through induction of miR-26a.
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DOI：
10.1016/j.exphem.2020.09.187
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发表时间：
2020-11
影响因子：
2.6
通讯作者：
Sakamoto KM
中科院分区：
文献类型：
--
作者：
Wilkes MC;Siva K;Varetti G;Mercado J;Wentworth EP;Perez CA;Saxena M;Kam S;Kapur S;Chen J;Narla A;Glader B;Lin S;Serrano M;Flygare J;Sakamoto KM
Diamond Blackfan贫血（DBA）是由定向红细胞生成早期阶段造血祖细胞中核糖体蛋白亚基单倍不足引起的。Nemo样激酶（NLK）在多种DBA人类和小鼠模型中的定向红系祖细胞和前体细胞中长期过度活化。抑制NLK活性或抑制NLK表达均改善这些模型中的红系细胞扩增。二甲双胍是一种耐受性良好的治疗2型糖尿病的药物，具有多个细胞靶点。在这里，我们证明二甲双胍改善DBA的人类和斑马鱼模型中的红细胞生成。我们的数据表明二甲双胍对红系细胞增殖和分化的影响是通过诱导miR-26 a抑制NLK表达介导的，miR-26 a识别NLK 3 'UTR内的结合位点以促进转录物降解。我们认为，诱导miR-26 a是治疗DBA的一种潜在的新方法，可以改善DBA患者的贫血，而不会在DBA患者人群中产生二甲双胍的潜在不良副作用。
Diamond Blackfan Anemia (DBA) results from haploinsufficiency of ribosomal protein subunits in hematopoietic progenitors in the earliest stages of committed erythropoiesis. Nemo-like kinase (NLK) is chronically hyperactivated in committed erythroid progenitors and precursors in multiple human and murine models of DBA. Inhibition of NLK activity, or suppression of NLK expression, both improve erythroid expansion in these models. Metformin is a well-tolerated drug for type 2 diabetes mellitus with multiple cellular targets. Here we demonstrate that metformin improves erythropoiesis in human and zebrafish models of DBA. Our data shows that the effects of metformin on erythroid proliferation and differentiation is mediated by suppression of NLK expression through induction of miR-26a, which recognizes a binding site within the NLK 3’UTR to facilitate transcript degradation. We propose that induction of miR-26a is a potentially novel approach to treat DBA and could improve anemia in DBA patients without the potentially adverse side effects of metformin in a DBA patient population.
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