| First Author | Lam J | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 2418 |
| PubMed ID | 29925839 | Mgi Jnum | J:266098 |
| Mgi Id | MGI:6208917 | Doi | 10.1038/s41467-018-04831-3 |
| Citation | Lam J, et al. (2018) miR-143/145 differentially regulate hematopoietic stem and progenitor activity through suppression of canonical TGFbeta signaling. Nat Commun 9(1):2418 |
| abstractText | 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 beta (TGFbeta) pathway as key targets of miR-143/145. Enforced expression of the TGFbeta 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 TGFbeta/DAB2 activation, and loss of these miRNAs creates a preleukemic state. |
