Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5.
A fundamental property of leukemic stem cells is clonal dominance of the bone marrow microenvironment. Truncation mutations of CSF3R, which encodes the G-CSF receptor (G-CSFR), are implicated in leukemic progression in patients with severe congenital neutropenia. Here we show that expression of a truncated mutant Csf3r in mice confers a strong clonal advantage at the HSC level that is dependent upon exogenous G-CSF. G-CSF-induced proliferation, phosphorylation of Stat5, and transcription of Stat5 target genes were increased in HSCs isolated from mice expressing the mutant Csf3r. Conversely, the proliferative advantage conferred by the mutant Csf3r was abrogated in myeloid progenitors lacking both Stat5A and Stat5B, and HSC function was reduced in mice expressing a truncated mutant Csf3r engineered to have impaired Stat5 activation. These data indicate that in mice, inappropriate Stat5 activation plays a key role in establishing clonal dominance by stem cells expressing mutant Csf3r.
Liu
Fulu
F
Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
Kunter
Ghada
G
Krem
Maxwell M
MM
Eades
William C
WC
Cain
Jennifer A
JA
Tomasson
Michael H
MH
Hennighausen
Lothar
L
Link
Daniel C
DC
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009503:Neutropenia / Q000151:congenital; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000502:physiology; D050799:STAT5 Transcription Factor / Q000502:physiology*
D016188:Receptors, Granulocyte Colony-Stimulating Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; C494093:Stat5a protein, mouse; D016179:Granulocyte Colony-Stimulating Factor