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：

---

miR-143/145 通过抑制经典 TGFβ 信号传导来差异调节造血干细胞和祖细胞活性。


5 号染色体长臂缺失的骨髓增生异常综合征患者的造血干细胞/祖细胞 (HSPC) 中 miR-143 和 miR-145 的表达降低。我们在此发现，缺乏 miR-143/145 的小鼠 HSPC 活性受损功能性造血干细胞 (HSC) 被耗尽，但祖细胞 (HPC) 被激活。我们将转化生长因子 β (TGFβ) 通路的成分确定为 miR-143/145 的关键靶标。 TGFβ衔接蛋白和miR-145靶标Disabled-2 (DAB2)的强制表达再现了在miR-143/145-/-小鼠中观察到的HSC缺陷。尽管 HSC 活性降低，但表达 miR-143/145-/- 和 DAB2 的老年小鼠表现出与 HPC 活性增加相关的白细胞计数升高。一部分小鼠出现可连续移植的骨髓恶性肿瘤，与 HPC 的扩张相关。因此，miR-143/145 通过调节 TGFβ/DAB2 激活在 HSPC 功能中发挥细胞背景依赖性作用，并且这些 miRNA 的丢失会产生白血病前期状态。