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

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

doi:10.1172/JCI32704

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

Journal article

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

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

The Journal of clinical investigation, Vol.118(3), pp.946-955

03/03/2008

DOI: 10.1172/JCI32704

PMCID: PMC2248325

PMID: 18292815

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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 .

Details

Title: Subtitle: Csf3r mutations in mice confer a strong clonal HSC advantage via activation of Stat5
Creators: Fulu Liu - Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA
Ghada Kunter - Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA
Maxwell M Krem - Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA
William C Eades - Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA
Jennifer A Cain - Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA
Michael H Tomasson - Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA
Lothar Hennighausen - Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA
Daniel C Link - Department of Medicine, Division of Oncology, Washington University School of Medicine, Saint Louis, Missouri, USA
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.118(3), pp.946-955
Publisher: American Society for Clinical Investigation
DOI: 10.1172/JCI32704
PMID: 18292815
PMCID: PMC2248325
ISSN: 0021-9738
eISSN: 1558-8238
Language: English
Date published: 03/03/2008
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094387102771

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