miR-143/145 differentially regulate hematopoietic stem and progenitor activity through suppression of canonical TGFβ signaling

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.
Myelodysplastic syndrome (MDS) is characterized by altered hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) regulation and reduction of miR-143 and miR-145 in some subtypes. Here the authors show that miR-143/145 loss leads to HSC depletion, HPC expansion and malignancy through Dab2 -mediated TGFβ pathway activation.