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TRANSLATIONAL AND CLINICAL RESEARCH

Effects of HOXB4 Overexpression on Ex Vivo Expansion and Immortalization of Hematopoietic Cells from Different Species

^aClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA;
^bDepartment of Radiation Oncology, University of Washington School of Medicine, Seattle, Washington, USA;
^cTerry Fox Laboratory, British Columbia Cancer Agency and Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada;
^dDepartment of Medicine, University of Washington, Seattle, Washington, USA

Key Words. Gene therapy • HOXB4 • Hematopoietic stem cells • Monkey • Mice • Dogs • Nonhuman primates

Correspondence: Hans-Peter Kiem, M.D., Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Mail Stop D1-100, P.O. Box 19024, Seattle, Washington 98109-1024, USA Telephone: 206-667-4425; Fax: 206-667-6124; e-mail: hkiem{at}fhcrc.org

Received November 15, 2006; accepted for publication April 20, 2007.
First published online in STEM CELLS EXPRESS   May 17, 2007.



Overexpression of the human HOXB4 has been shown to induce the expansion and self-renewal of murine hematopoietic stem cells. In preparation for clinical studies, we wished to investigate the effects of HOXB4 on cells from other species, in particular preclinical large animals such as dogs and nonhuman primates. Thus, we transduced CD34⁺ cells from nonhuman primates, dogs, and humans with a HOXB4-expressing gammaretroviral vector and a yellow fluorescent protein-expressing control vector. Compared with the control vector, HOXB4 overexpression resulted in a much larger increase in colony-forming cells in dog cells (28-fold) compared with human peripheral blood, human cord blood, and baboon cells (two-, four-, and fivefold, respectively). Furthermore, we found that HOXB4 overexpression resulted in immortalization with sustained growth (>12 months) of primitive hematopoietic cells from mice and dogs but not from monkeys and humans. This difference correlated with increased levels of retrovirally overexpressed HOXB4 in dog and mouse cells compared with human and nonhuman primate cells. The immortalized cells did not show any evidence of insertional mutagenesis or chromosomal abnormalities. Competitive congenic transplantation experiments showed that HOXB4-expanded mouse cells engrafted well after 1 or 3 months of expansion, and no leukemia was observed in mice. Our findings suggest that the growth promoting effects of HOXB4 are critically dependent on HOXB4 expression levels and that this can result in important species-specific differences in potency.

Disclosure of potential conflicts of interest is found at the end of this article.