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 Blood, 22 October 2009, Vol. 114, No. 17, pp. 3557-3566.
Prepublished online as a Blood First Edition Paper on August 27, 2009; DOI 10.1182/blood-2009-02-205815.

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HEMATOPOIESIS AND STEM CELLS

Loss of the Rho GTPase activating protein p190-B enhances hematopoietic stem cell engraftment potential

Haiming Xu1,2, Satyam Eleswarapu1, Hartmut Geiger1,3, Kathleen Szczur1, Deidre Daria1, Yi Zheng1, Jeffrey Settleman4, Edward F. Srour5, David A. Williams1, and Marie-Dominique Filippi1

1 Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation and 2 Cell and Molecular Biology Graduate Program, University of Cincinnati College of Medicine, OH; 3 Department of Dermatology and Allergic Diseases, Aging Research, University of Ulm, Ulm, Germany; 4 Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston; and 5 Department of Medicine, Indiana University School of Medicine, Indianapolis

Hematopoietic stem cell (HSC) engraftment is a multistep process involving HSC homing to bone marrow, self-renewal, proliferation, and differentiation to mature blood cells. Here, we show that loss of p190-B RhoGTPase activating protein, a negative regulator of Rho GTPases, results in enhanced long-term engraftment during serial transplantation. This effect is associated with maintenance of functional HSC-enriched cells. Furthermore, loss of p190-B led to marked improvement of HSC in vivo repopulation capacity during ex vivo culture without altering proliferation and multilineage differentiation of HSC and progeny. Transcriptional analysis revealed that p190-B deficiency represses the up-regulation of p16Ink4a in HSCs in primary and secondary transplantation recipients, providing a possible mechanism of p190-B–mediated HSC functions. Our study defines p190-B as a critical transducer element of HSC self-renewal activity and long-term engraftment, thus suggesting that p190-B is a target for HSC-based therapies requiring maintenance of engraftment phenotype.


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