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RESEARCH COMMUNICATION

The E3 ubiquitin ligase c-Cbl restricts development and functions of hematopoietic stem cells

¹ Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA; ² Division of Pathology, University of Western Australia, Crawley, WA 6009, Australia; ³ Department of Microbiology, Columbia University, New York, New York 10032, USA; ⁴ Howard Hughes Medical Institute, New Haven, Connecticut 06520, USA

Hematopoietic stem cells (HSCs) are multipotent progenitors that give rise to all types of blood cells. In the present study, we document that HSC development and functions are negatively regulated by the E3 ubiquitin ligase c-Cbl (casitas B-cell lymphoma). HSCs of c-Cbl^–/– mice exhibit augmented pool size, hyperproliferation, greater competence, and enhanced long-term repopulating capacity. Our mechanistic studies identified that c-Cbl^–/– HSCs are hyperresponsive to thrombopoietin (TPO) and display elevated levels of STAT5 phosphorylation, thus leading to increased c-Myc expression. In essence, our data unequivocally identify c-Cbl as a novel negative regulator of developmental and functional properties of HSCs.

[Keywords: Hematopoietic stem cells; c-Cbl; thrombopoietin; STAT5; self-renewal]]

Received January 15, 2008; revised version accepted February 25, 2008.

E-MAIL richard.flavell{at}yale.edu; FAX (203) 737-2958.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1651408.

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