Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis.
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.
Hofmann
Inga
I
Division of Hematology, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
Stover
Elizabeth H
EH
Cullen
Dana E
DE
Mao
Junhao
J
Morgan
Kelly J
KJ
Lee
Benjamin H
BH
Kharas
Michael G
MG
Miller
Peter G
PG
Cornejo
Melanie G
MG
Okabe
Rachel
R
Armstrong
Scott A
SA
Ghilardi
Nico
N
Gould
Stephen
S
de Sauvage
Frederic J
FJ
McMahon
Andrew P
AP
Gilliland
D Gary
DG
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
D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor