title: Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis.
abstract: We report the unexpected finding that loss of Hh signaling through conditional deletion of Smoothened (Smo) in the adult hematopoietic compartment has no apparent effect on adult hematopoiesis, including peripheral blood count, number or cell-cycle status of stem or progenitor cells, hematopoietic colony-forming potential, long-term repopulating activity in competitive repopulation assays, or stress response to serial 5-fluorouracil treatment. Furthermore, pharmacologic inhibition of Hh signaling with a potent and selective small molecule antagonist has no substantive effect on hematopoiesis in the mouse. In addition, Hh signaling is not required for the development of MLL-AF9-mediated acute myeloid leukemia (AML). Taken together, these data demonstrate that Hh signaling is dispensable for normal hematopoietic development and hematopoietic stem cell function, indicating that targeting of Hh signaling in solid tumors is not likely to result in hematopoietic toxicity. Furthermore, the Hh pathway may not be a compelling target in certain hematopoietic malignancies.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Inga
authors.initials: I
authors.lastname: Hofmann
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Stover
authors.forename: Dana E
authors.initials: DE
authors.lastname: Cullen
authors.forename: Junhao
authors.initials: J
authors.lastname: Mao
authors.forename: Kelly J
authors.initials: KJ
authors.lastname: Morgan
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Lee
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kharas
authors.forename: Peter G
authors.initials: PG
authors.lastname: Miller
authors.forename: Melanie G
authors.initials: MG
authors.lastname: Cornejo
authors.forename: Rachel
authors.initials: R
authors.lastname: Okabe
authors.forename: Scott A
authors.initials: SA
authors.lastname: Armstrong
authors.forename: Nico
authors.initials: N
authors.lastname: Ghilardi
authors.forename: Stephen
authors.initials: S
authors.lastname: Gould
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.forename: D Gary
authors.initials: DG
authors.lastname: Gilliland
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology; D000818:Animals; D053823:Hedgehog Proteins / Q000502:physiology*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000209:etiology; D051379:Mice; D009374:Neoplasms, Experimental / Q000209:etiology; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency; D015398:Signal Transduction / Q000502:physiology*; D000072086:Smoothened Receptor
chemical_list: D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor