Expression of miR-143 and miR-145 is reduced in hematopoietic stem/progenitor cells (HSPCs) of myelodysplastic syndrome patients with a deletion in the long arm of chromosome 5. Here we show that mice lacking miR-143/145 have impaired HSPC activity with depletion of functional hematopoietic stem cells (HSCs), but activation of progenitor cells (HPCs). We identify components of the transforming growth factor β (TGFβ) pathway as key targets of miR-143/145. Enforced expression of the TGFβ adaptor protein and miR-145 target, Disabled-2 (DAB2), recapitulates the HSC defect seen in miR-143/145-/- mice. Despite reduced HSC activity, older miR-143/145-/- and DAB2-expressing mice show elevated leukocyte counts associated with increased HPC activity. A subset of mice develop a serially transplantable myeloid malignancy, associated with expansion of HPC. Thus, miR-143/145 play a cell context-dependent role in HSPC function through regulation of TGFβ/DAB2 activation, and loss of these miRNAs creates a preleukemic state.

中文翻译：

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miR-143 / 145通过抑制经典的TGFβ信号传导来差异调节造血干和祖细胞的活性。

在骨髓增生异常综合症患者的造血干/祖细胞（HSPC）中，miR-143和miR-145的表达减少，第5号染色体的长臂缺失。这里我们显示缺乏miR-143 / 145的小鼠的HSPC活性受损功能性造血干细胞（HSC）耗竭，但祖细胞（HPC）激活。我们确定转化生长因子β（TGFβ）途径的组成部分为miR-143 / 145的关键目标。TGFβ衔接蛋白和miR-145靶标Disabled-2（DAB2）的强制表达概括了在miR-143 / 145-/-小鼠中看到的HSC缺陷。尽管降低了HSC活性，但表达miR-143 / 145-/-和DAB2的小鼠表现出与HPC活性增加相关的白细胞计数升高。一部分小鼠会发展出一系列可移植的骨髓恶性肿瘤，与HPC的扩张有关。