Improved ex vivo expansion of adult hematopoietic stem cells by overcoming CUL4-mediated degradation of HOXB4 Journal Article

   

Authors:	Lee, J.; Shieh, J.H.; Zhang, J. X.; Liu, L. R.; Zhang, Y.; Eom, J. Y.; Morrone, G.; Moore, M. A. S.; Zhou, P. B.
Article Title:	Improved ex vivo expansion of adult hematopoietic stem cells by overcoming CUL4-mediated degradation of HOXB4
Abstract:	Direct transduction of the homeobox (HOX) 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 (similar to 1 hour). We demonstrate here that HOXB4 protein levels are post-translationally regulated by the CUL4 ubiquitin ligase, and define the degradation signal sequence (degron) of HOXB4 required for CUL4-mediated destruction. Additional HOX paralogs share the conserved degron in the homeodomain and are also subject to CUL4-mediated degradation, indicating that CUL4 likely controls the stability of all HOX proteins. Moreover, we engineered a degradation-resistant HOXB4 that conferred a growth advantage over wild-type HOXB4 in myeloid progenitor cells. 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 transplanted NOD/SCID/IL2R-g null mice compared with 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.
Keywords:	proteins; dna; in-vitro; differentiation; fusion; gene-therapy; delivery; hoxa9; bone-marrow-cells; enforced expression; recombinant hoxb4
Journal Title:	Blood
Volume:	121
Issue:	20
ISSN:	0006-4971
Publisher:	American Society of Hematology
Date Published:	2013-05-16
Start Page:	4082
End Page:	4089
Language:	English
DOI:	10.1182/blood-2012-09-455204
ACCESSION:	WOS:000321871900013
PROVIDER:	wos
PMCID:	PMC3656448
PUBMED:	23520338
Notes:	--- - Article - "Source: Wos"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/46332