MicroRNA-223 dose levels fine tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia.
MicroRNA-223 dose levels fine tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia.
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DOI：
10.1016/j.exphem.2015.05.018
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发表时间：
2015-10
影响因子：
2.6
通讯作者：
Kuchenbauer F
中科院分区：
文献类型：
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作者：
Gentner B;Pochert N;Rouhi A;Boccalatte F;Plati T;Berg T;Sun SM;Mah SM;Mirkovic-Hösle M;Ruschmann J;Muranyi A;Leierseder S;Argiropoulos B;Starczynowski DT;Karsan A;Heuser M;Hogge D;Camargo FD;Engelhardt S;Döhner H;Buske C;Jongen-Lavrencic M;Naldini L;Humphries RK;Kuchenbauer F
miR-223在人类造血和急性髓细胞白血病（AML）发病机制中的作用仍然缺乏准确的理解。通过测量115例AML患者原始细胞中的miR-223表达，我们发现预后良好的患者中miR-223水平显著较高，而miR-223表达水平低的患者与预后较差相关。此外，miR-223在AML亚群中分级表达，在含有白血病干细胞的组分中表达较低。miR-223的基因缺失降低了骨髓单核细胞AML小鼠模型中的白血病起始细胞（LIC）频率，但对于快速发作的AML并非必需。为了将这些观察结果与生理性骨髓分化联系起来，我们使用慢病毒载体敲低或异位表达脐带血CD 34+细胞中的miR-223。尽管miR-223敲低在体外延迟了髓系红细胞前体分化，但在连续异种移植后，它在体内增加了髓系祖细胞。异位miR-223表达增加体内红细胞生成、T淋巴细胞生成和早期B淋巴细胞生成。这些发现拓宽了miR-223作为造血干细胞和祖细胞中扩增/分化平衡调节剂的作用，其中其影响是剂量和分化阶段依赖性的。这也解释了miR-223在AML中的复杂而微小的作用，AML是一种具有不同程度骨髓分化的异质性疾病。
A precise understanding of the role of miR-223 in human hematopoiesis and in the pathogenesis of acute myeloid leukemia (AML) is still lacking. By measuring miR-223 expression in blasts from 115 AML patients, we found significantly higher miR-223 levels in patients with favorable prognosis, whereas patients with low miR-223 expression levels were associated with worse outcome. Furthermore, miR-223 was hierarchically expressed in AML subpopulations, with lower expression in leukemic stem cell–containing fractions. Genetic depletion of miR-223 decreased the leukemia initiating cell (LIC) frequency in a myelomonocytic AML mouse model, but it was not mandatory for rapid-onset AML. To relate these observations to physiologic myeloid differentiation, we knocked down or ectopically expressed miR-223 in cord-blood CD34+ cells using lentiviral vectors. Although miR-223 knockdown delayed myeloerythroid precursor differentiation in vitro, it increased myeloid progenitors in vivo following serial xenotransplantation. Ectopic miR-223 expression increased erythropoiesis, T lymphopoiesis, and early B lymphopoiesis in vivo. These findings broaden the role of miR-223 as a regulator of the expansion/differentiation equilibrium in hematopoietic stem and progenitor cells where its impact is dose- and differentiation-stage-dependent. This also explains the complex yet minor role of miR-223 in AML, a heterogeneous disease with variable degree of myeloid differentiation.