title: Wnts are dispensable for differentiation and self-renewal of adult murine hematopoietic stem cells.
abstract: Wnt signaling controls early embryonic hematopoiesis and dysregulated β-catenin is implicated in leukemia. However, the role of Wnts and their source in adult hematopoiesis is still unclear, and is clinically important as upstream Wnt inhibitors enter clinical trials. We blocked Wnt secretion in hematopoietic lineages by targeting Porcn, a membrane-bound O-acyltransferase that is indispensable for the activity and secretion of all vertebrate Wnts. Surprisingly, deletion of Porcn in Rosa-CreER(T2)/Porcn(Del), MX1-Cre/Porcn(Del), and Vav-Cre/Porcn(Del) mice had no effects on proliferation, differentiation, or self-renewal of adult hematopoietic stem cells. Targeting Wnt secretion in the bone marrow niche by treatment with a PORCN inhibitor, C59, similarly had no effect on hematopoiesis. These results exclude a role for hematopoietic PORCN-dependent Wnts in adult hematopoiesis. Clinical use of upstream Wnt inhibitors is not likely to be limited by effects on hematopoiesis.
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; Department of Biochemistry and.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Kabiri
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore;
authors.forename: Akihiko
authors.initials: A
authors.lastname: Numata
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore;
authors.forename: Akira
authors.initials: A
authors.lastname: Kawasaki
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore;
authors.lastname: Edison
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore; Harvard Stem Cell Institute, Harvard Medical School, Boston, MA; and.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Graduate Medical School, Singapore; Department of Biochemistry and Department of Pediatrics, Duke University School of Medicine, Durham, NC.
authors.forename: David M
authors.identifier: http://orcid.org/0000-0001-6976-850X
authors.initials: DM
authors.lastname: Virshup
mesh_terms: D000217:Acyltransferases; D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D008565:Membrane Proteins; D051153:Wnt Proteins; D000217:Acyltransferases; C491187:Porcn protein, mouse