MiR-17/20/93/106 promote hematopoietic cell expansion by targeting sequestosome 1-regulated pathways in mice

Annemarie Meenhuis, PA van Veelen, Hans de Looper, Nicole Boxtel, Iris Berge, Su ming Sun, Erdogan Taskesen, P Stern, AH de Ru, AJ van Adrichem, Jeroen Demmers, Mojca Jongen - Lavrencic, Bob Löwenberg, Ivo Touw, PA Sharp, Stefan Erkeland

Research output: Contribution to journalArticleAcademicpeer-review

120 Citations (Scopus)

Abstract

MicroRNAs (miRNAs) are pivotal for regulation of hematopoiesis but their critical targets remain largely unknown. Here, we show that ectopic expression of miR-17, -20,-93 and -106, all AAAGUGC seed-containing miRNAs, increases proliferation, colony outgrowth and replating capacity of myeloid progenitors and results in enhanced P-ERK levels. We found that these miRNAs are endogenously and abundantly expressed in myeloid progenitors and down-regulated in mature neutrophils. Quantitative proteomics identified sequestosome 1 (SQSTM1), an ubiquitin-binding protein and regulator of autophagy-mediated protein degradation, as a major target for these miRNAs in myeloid progenitors. In addition, we found increased expression of Sqstm1 transcripts during CSF3-induced neutrophil differentiation of 32D-CSF3R cells and an inverse correlation of SQSTM1 protein levels and miR-106 expression in AML samples. ShRNA-mediated silencing of Sqstm1 phenocopied the effects of ectopic miR-17/20/93/106 expression in hematopoietic progenitors in vitro and in mice. Further, SQSTM1 binds to the ligand-activated colony-stimulating factor 3 receptor (CSF3R) mainly in the late endosomal compartment, but not in LC3 positive autophagosomes. SQSTM1 regulates CSF3R stability and ligand-induced mitogen-activated protein kinase signaling. We demonstrate that AAAGUGC seed containing miRNAs promote cell expansion, replating capacity and signaling in hematopoietic cells by interference with SQSTM1-regulated pathways. (Blood. 2011;118(4):916-925)
Original languageUndefined/Unknown
Pages (from-to)916-925
Number of pages10
JournalBlood
Volume118
Issue number4
DOIs
Publication statusPublished - 2011

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