Blood：发现控制髓系分化的关键调节因子

近日，来自中国医学科学院研究员张俊武所在的课题组研究发现，miR-29a及miR-142-3p是髓系分化及急性髓细胞性白血病的关键调节因子。相关研究成果于5月24日发表在Blood上。

目前，microRNAs被发现与包括造血作用在内的不同生理学过程息息相关，但是，它们对髓系发育的作用还不明确。研究人员发现，白血病细胞系以及CD34+造血干/祖细胞在髓系分化期间，miR-29a及miR-142-3p表现上调。

研究发现，这两种miRNAs促进了佛波酯诱导的单核细胞及全反式视黄酸诱导的粒细胞的分化。而且，这两种miRNAs直接抑制了细胞周期蛋白T2基因，阻止了低磷酸化的Rb蛋白的释放，诱导了单核细胞的分化。

除此以外，他们还发现，miR-29a的靶点细胞周期素依赖性激酶6基因，以及miR-142-3p的靶点TGF-β激活的激酶1/MAP3K结合蛋白2基因，都与单核及粒细胞分化的调节有关。

在急性髓细胞性白血病，miR-29a及miR-142-3p水平表现出显著下降，而它们的靶蛋白水平则表现出明显的上升。

通过慢病毒介导的基因转染，在来自健康对照组以及急性髓细胞性白血病患者的造血干/祖细胞内表达miR-29a或miR-142-3p，都能够下调它们靶点的表达，并促进髓系分化。

总的来说，该研究表明，miR-29a及miR-142-3p是正常髓系分化的关键调节因子，而且，它们表达的降低还与急性髓细胞性白血病的发展有关。

doi: 10.1182/blood-2011-10-385716
PMC:
PMID:

MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia

Xiao-Shuang Wang, Jia-Nan Gong, Jia Yu, Fang Wang, Xin-Hua Zhang, Xiao-Lin Yin, Zhen-Qing Tan, Zi-Mian Luo, Gui-Hua Yang, Chao Shen, and Jun-Wu Zhang.

Although microRNAs (miRNAs) are increasingly linked to various physiologic processes, including hematopoiesis, their function in the myeloid development is poorly understood. We detected up-regulation of miR-29a and miR-142-3p during myeloid differentiation in leukemia cell lines and CD34+ hematopoietic stem/progenitor cells.By gain-of-function and loss-of-function experiments, we demonstrated that both miRNAs promote the phorbol 12-myristate 13-acetate–induced monocytic and all-trans-retinoic acid-induced granulocytic differentiation of HL-60, THP-1, or NB4 cells. Both the miRNAs directly inhibited cyclin T2 gene, preventing the release of hypophosphorylated retinoblastoma and resulting in induction of monocytic differentiation.In addition, a target of miR-29a, cyclin-dependent kinase 6 gene, and a target of miR-142-3p, TGF-β–activated kinase 1/MAP3K7 binding protein 2 gene, are involved in the regulation of both monocytic and granulocytic differentiation. A significant decrease of miR-29a and 142-3p levels and an obvious increase in their target protein levels were also observed in blasts from acute myeloid leukemia.By lentivirus-mediated gene transfer, we demonstrated that enforced expression of either miR-29a or miR-142-3p in hematopoietic stem/progenitor cells from healthy controls and acute myeloid leukemia patients down-regulated expression of their targets and promoted myeloid differentiation. These findings confirm that miR-29a and miR-142-3p are key regulators of normal myeloid differentiation and their reduced expression is involved in acute myeloid leukemia development.