Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5
Fulu Liu, … , Lothar Hennighausen, Daniel C. Link
Fulu Liu, … , Lothar Hennighausen, Daniel C. Link
Published February 21, 2008
Citation Information: J Clin Invest. 2008;118(3):946-955. https://doi.org/10.1172/JCI32704.
View: Text | PDF
Research Article

Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5

Abstract

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.

Authors

Fulu Liu, Ghada Kunter, Maxwell M. Krem, William C. Eades, Jennifer A. Cain, Michael H. Tomasson, Lothar Hennighausen, Daniel C. Link

×

Figure 7

Competitive repopulation by HSC expressing the d715F G-CSFR is impaired.

Options: View larger image (or click on image) Download as PowerPoint
Competitive repopulation by HSC expressing the d715F G-CSFR is impaired....
(A and B) Wild-type or d715F G-CSFR KSL cells were treated in vitro for the indicated times with G-CSF (100 ng/ml) and then incubated with antibodies specific for pStat5 (A) or pStat3 (B). The MFI of triplicate experiments is shown. (C–E) Irradiated syngeneic mice were reconstituted with a 1:1 ratio of d715F G-CSFR and wild-type bone marrow cells. The resulting chimeric mice were treated 4 months after bone marrow transplantation with saline alone or G-CSF (10 μg/kg/d) for 21 days. The percentage of circulating neutrophils (C), B lymphocytes (D), and T lymphocytes (E) derived from d715F G-CSFR cells was determined at the indicated times (n = 3–4 for each group). Data represent the mean ± SEM. *P < 0.05 compared with saline-treated mice.