Abstract
Abstract Direct transduction of the homeobox protein HOXB4 promotes the proliferation of hematopoietic stem cells (HSCs) without induction of leukemogenesis, but requires frequent administration to overcome its short protein half-life. We demonstrate here that the CUL4A ubiquitin ligase regulates the post-translational stability of multiple HOX proteins, including HOXB4, and we defined the degron of HOXB4 required for CUL4A-mediated degradation. Ectopic expression of degradation-resistant HOXB4 in myeloid progenitor cells confers a growth advantage over wild-type HOXB4-expressing cells. Finally, direct transduction of recombinant degradation-resistant HOXB4 protein to human adult HSCs significantly enhanced their maintenance in a more primitive state both in vitro and in vivo compared to transduction with wild-type HOXB4 protein. Our studies demonstrate the feasibility of engineering a stable HOXB4 variant to overcome a major technical hurdle in the ex vivo expansion of adult HSCs and early progenitors for human therapeutic use. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 211. doi:1538-7445.AM2012-211
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