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

Jeffrey Lam, Marion van den Bosch, Joanna Wegrzyn, Jeremy Parker, Rawa Ibrahim, Kate Slowski, Linda Chang, Sergio Martinez-Høyer, Gianluigi Condorelli, Mark Boldin, Yu Deng, Patricia Umlandt, Megan Fuller and Aly Karsan ()
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Jeffrey Lam: BC Cancer Research Centre
Marion van den Bosch: BC Cancer Research Centre
Joanna Wegrzyn: BC Cancer Research Centre
Jeremy Parker: BC Cancer Research Centre
Rawa Ibrahim: BC Cancer Research Centre
Kate Slowski: BC Cancer Research Centre
Linda Chang: BC Cancer Research Centre
Sergio Martinez-Høyer: BC Cancer Research Centre
Gianluigi Condorelli: Humanitas Clinical and Research Center
Mark Boldin: Beckman Research Institute, City of Hope
Yu Deng: BC Cancer Research Centre
Patricia Umlandt: BC Cancer Research Centre
Megan Fuller: BC Cancer Research Centre
Aly Karsan: BC Cancer Research Centre

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-04831-3

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