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

• Published in: Nature communications Vol. 9; no. 1; pp. 2418 - 14
• Main Authors: Lam, Jeffrey, van den Bosch, Marion, Wegrzyn, Joanna, Parker, Jeremy, Ibrahim, Rawa, Slowski, Kate, Chang, Linda, Martinez-Høyer, Sergio, Condorelli, Gianluigi, Boldin, Mark, Deng, Yu, Umlandt, Patricia, Fuller, Megan, Karsan, Aly
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 20.06.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: Activation; Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport - genetics; Adaptor Proteins, Vesicular Transport - metabolism; Animals; Apoptosis Regulatory Proteins; Bone Marrow - pathology; Bone Marrow Transplantation; Cell Line, Tumor; Cells (biology); Chromosome 5; Chromosome deletion; Chromosomes; Clonal deletion; Disease Models, Animal; Female; Gene expression; Gene Expression Regulation, Neoplastic; Growth factors; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Humans; Kinases; Leukocytes; Male; Malignancy; Medical research; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Myelodysplastic syndrome; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Progenitor cells; Proteins; Signal Transduction - genetics; Stem cell transplantation; Stem cells; Transforming growth factor; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Transplantation Chimera
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04831-3

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.