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

• Published in: Blood Vol. 129; no. 18; pp. 2493 - 2506
• Main Authors: Naudin, Cécile, Hattabi, Aurore, Michelet, Fabio, Miri-Nezhad, Ayda, Benyoucef, Aissa, Pflumio, Françoise, Guillonneau, François, Fichelson, Serge, Vigon, Isabelle, Dusanter-Fourt, Isabelle, Lauret, Evelyne
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.05.2017; American Society of Hematology
• Subjects: Animals; Cancer; Cell Proliferation; Cellular Biology; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - genetics; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Hematopoiesis and Stem Cells; Hematopoietic Stem Cells - metabolism; Humans; Leukemia, Myeloid - genetics; Leukemia, Myeloid - metabolism; Life Sciences; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplastic Stem Cells - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Signal Transduction; Subcellular Processes
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2016-10-747436

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. •The RNA regulators PUMILIO sustain HSPC and acute myeloid leukemia cell growth by upregulating FOXP1 expression through direct binding to 2 FOXP1-3′UTR PUMILIO-binding elements.•FOXP1 mediates PUMILIO growth-promoting activities by repressing expression of p21CIP1 and p27KIP1cell cycle inhibitors.