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Blood. 2017 May 4;129(18):2493-2506. doi: 10.1182/blood-2016-10-747436. Epub 2017 Feb 23.

PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells.

Naudin C1,2,3, Hattabi A1,2,3, Michelet F1,2,3, Miri-Nezhad A1,2,3, Benyoucef A4,5,6,7, Pflumio F4,5,6,7, Guillonneau F1,2,3,8, Fichelson S1,2,3, Vigon I1,2,3, Dusanter-Fourt I1,2,3, Lauret E1,2,3.

Author information

1
INSERM U1016, Institut Cochin, Paris, France.
2
Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 8104, Paris, France.
3
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
4
Commissariat à l'Energie Atomique et aux Energies Alternatives, DSV-IRCM-SCSR-LSHL, UMR 967, Fontenay-aux-Roses, France.
5
INSERM, U967, Fontenay-aux-Roses, France.
6
Université Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France.
7
Université Paris-Sud, UMR 967, Fontenay-aux-Roses, France; and.
8
3P5 Proteomic Facility, Paris Descartes University, Paris, France.

Abstract

RNA-binding proteins (RBPs) have emerged as important regulators of invertebrate adult stem cells, but their activities remain poorly appreciated in mammals. Using a short hairpin RNA strategy, we demonstrate here that the 2 mammalian RBPs, PUMILIO (PUM)1 and PUM2, members of the PUF family of posttranscriptional regulators, are essential for hematopoietic stem/progenitor cell (HSPC) proliferation and survival in vitro and in vivo upon reconstitution assays. Moreover, we found that PUM1/2 sustain myeloid leukemic cell growth. Through a proteomic approach, we identified the FOXP1 transcription factor as a new target of PUM1/2. Contrary to its canonical repressive activity, PUM1/2 rather promote FOXP1 expression by a direct binding to 2 canonical PUM responsive elements present in the FOXP1-3' untranslated region (UTR). Expression of FOXP1 strongly correlates with PUM1 and PUM2 levels in primary HSPCs and myeloid leukemia cells. We demonstrate that FOXP1 by itself supports HSPC and leukemic cell growth, thus mimicking PUM activities. Mechanistically, FOXP1 represses the expression of the p21-CIP1 and p27-KIP1 cell cycle inhibitors. Enforced FOXP1 expression reverses shPUM antiproliferative and proapoptotic activities. Altogether, our results reveal a novel regulatory pathway, underscoring a previously unknown and interconnected key role of PUM1/2 and FOXP1 in regulating normal HSPC and leukemic cell growth.

Comment in

PMID:
28232582
PMCID:
PMC5429137
DOI:
10.1182/blood-2016-10-747436
[Indexed for MEDLINE]
Free PMC Article

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