title: PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells.
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-CIP1and p27-KIP1cell 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.
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Naudin
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Hattabi
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Fabio
authors.initials: F
authors.lastname: Michelet
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Ayda
authors.initials: A
authors.lastname: Miri-Nezhad
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives, DSV-IRCM-SCSR-LSHL, UMR 967, Fontenay-aux-Roses, France.|INSERM, U967, Fontenay-aux-Roses, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France.|Université Paris-Sud, UMR 967, Fontenay-aux-Roses, France; and.
authors.forename: Aissa
authors.initials: A
authors.lastname: Benyoucef
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives, DSV-IRCM-SCSR-LSHL, UMR 967, Fontenay-aux-Roses, France.|INSERM, U967, Fontenay-aux-Roses, France.|Université Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France.|Université Paris-Sud, UMR 967, Fontenay-aux-Roses, France; and.
authors.forename: Françoise
authors.initials: F
authors.lastname: Pflumio
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|3P5 Proteomic Facility, Paris Descartes University, Paris, France.
authors.forename: François
authors.initials: F
authors.lastname: Guillonneau
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Fichelson
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Vigon
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dusanter-Fourt
authors.affiliation: INSERM U1016, Institut Cochin, Paris, France.|Centre National de la Recherche Scientifique, Unité Mixte de Recherche (UMR) 8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lauret
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D009363:Neoplasm Proteins; C471242:PUM1 protein, human; C471243:PUM2 protein, human; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27