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, Aly Karsan

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2418
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Jun 20 2018

Fingerprint

stem cells
Transforming Growth Factors
Hematopoietic Stem Cells
Stem cells
stems
retarding
mice
Chemical activation
activation
leukocytes
deletion
chromosomes
Chromosomes
cells
MicroRNAs
set theory
Chromosomes, Human, Pair 5
depletion
Myelodysplastic Syndromes
proteins

Keywords

  • Adaptor Proteins, Vesicular Transport/genetics
  • Animals
  • Bone Marrow/pathology
  • Bone Marrow Transplantation
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Neoplastic
  • Hematopoietic Stem Cells/metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs/genetics
  • Myelodysplastic Syndromes/genetics
  • Signal Transduction/genetics
  • Transforming Growth Factor beta/metabolism
  • Transplantation Chimera

Cite this

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

In: Nature Communications, Vol. 9, No. 1, 20.06.2018, p. 2418.

Research output: Contribution to journalArticle

Lam, J, van den Bosch, M, Wegrzyn, J, Parker, J, Ibrahim, R, Slowski, K, Chang, L, Martinez-Høyer, S, Condorelli, G, Boldin, M, Deng, Y, Umlandt, P, Fuller, M & Karsan, A 2018, 'miR-143/145 differentially regulate hematopoietic stem and progenitor activity through suppression of canonical TGFβ signaling', Nature Communications, vol. 9, no. 1, pp. 2418. https://doi.org/10.1038/s41467-018-04831-3
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. / miR-143/145 differentially regulate hematopoietic stem and progenitor activity through suppression of canonical TGFβ signaling. In: Nature Communications. 2018 ; Vol. 9, No. 1. pp. 2418.
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