Alternative titles; symbols
HGNC Approved Gene Symbol: HOXB4
Cytogenetic location: 17q21.32 Genomic coordinates (GRCh38): 17:48,575,507-48,578,350 (from NCBI)
In an effort to characterize factors that distinguish the definitive adult hematopoietic stem cell (HSC) and primitive progenitors derived from yolk sac or embryonic stem (ES) cells, Kyba et al. (2002) examined the effect of ectopic expression of Hoxb4, a homeotic selector gene implicated in self-renewal of definitive HSCs, in mice. Expression of Hoxb4 in primitive progenitors combined with culture on hematopoietic stroma induced a switch to the definitive HSC phenotype. These progenitors engrafted lethally irradiated adults and contributed to long-term, multilineage hematopoiesis in primary and secondary recipients. These results suggested that primitive HSCs are poised to become definitive HSCs and that this transition can be promoted by HOXB4 expression.
Antonchuk et al. (2002) demonstrated the potency of Hoxb4 to enable high-level ex vivo HSC expansion in mice. Cultures of nontransduced or GFP-transduced murine bone marrow cells experienced large HSC losses over 10 to 14 days. In sharp contrast, cultures of Hoxb4-transduced cells achieved rapid, extensive, and highly polyclonal HSC expansions, resulting in levels more than 1,000-fold higher relative to controls and a 40-fold net HSC increase. These HSCs retained full lympho-myeloid repopulating potential and enhanced in vivo regenerative potential, demonstrating the feasibility of achieving significant ex vivo expansion of HSCs without functional impairment.
Hematopoietic stem cells have the ability to renew themselves and to give rise to all lineages of the blood. Reya et al. (2003) showed that the WNT signaling pathway has an important role in this process. Overexpression of activated beta-catenin (116806) expands the pool of HSCs in long-term cultures by both phenotype and function. Furthermore, HSCs in their normal microenvironment activate a LEF1/TCF (153245) reporter, which indicates that HSCs respond to WNT signaling in vivo. To demonstrate the physiologic significance of this pathway for HSC proliferation, Reya et al. (2003) showed that the ectopic expression of axin (603816) or a frizzled (603408) ligand-binding domain, inhibitors of the WNT signaling pathway, led to inhibition of HSC growth in vitro and reduced reconstitution in vivo. Furthermore, activation of WNT signaling in HSCs induced increased expression of HOXB4 and NOTCH1 (190198), genes previously implicated in self-renewal of HSCs. Reya et al. (2003) concluded that the WNT signaling pathway is critical for normal HSC homeostasis in vitro and in vivo, and provide insight into a potential molecular hierarchy of regulation of HSC development.
Krosl et al. (2003) used recombinant human TAT-HOXB4 protein carrying the protein transduction domain of the HIV transactivating protein (TAT) as a potential growth factor for stem cells. Hematopoietic stem cells exposed to TAT-HOXB4 for 4 days expanded by approximately 4- to 6-fold and were 8 to 20 times more numerous than hematopoietic stem cells in control cultures, indicating that hematopoietic stem cell expansion induced by TAT-HOXB4 was comparable to that induced by the human HOXB4 retrovirus during a similar period of observation. Krosl et al. (2003) concluded that their results showed that TAT-HOXB4-expanded hematopoietic stem cell populations retain their normal in vivo potential for differentiation and long-term repopulation.
Amsellem et al. (2003) showed that when cultured on stromal cells genetically engineered to secrete HOXB4, human long-term culture-initiating cells and nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mouse repopulating cells were expanded by more than 20- and 2.5-fold, respectively, over their input numbers. This expansion was associated with enhanced stem cell repopulating capacity in vivo and maintenance of pluripotentiality. Amsellem et al. (2003) concluded that their method provided a basis for developing cell therapy strategies using expanded hematopoietic stem cells that are not genetically modified.
As reviewed by Acampora et al. (1989), the HOXB4 (HOX2F) gene resides in the homeobox region-2 gene cluster on chromosome 17 between HOXB5 (HOX2A; 142960) and HOXB3 (HOX2G; 142966).
Acampora, D., D'Esposito, M., Faiella, A., Pannese, M., Migliaccio, E., Morelli, F., Stornaiuolo, A., Nigro, V., Simeone, A., Boncinelli, E. The human HOX gene family. Nucleic Acids Res. 17: 10385-10402, 1989. [PubMed: 2574852] [Full Text: https://doi.org/10.1093/nar/17.24.10385]
Amsellem, S., Pflumio, F., Bardinet, D., Izac, B., Charneau, P., Romeo, P.-H., Dubart-Kupperschmitt, A., Fichelson, S. Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein. Nature Med. 9: 1423-1427, 2003. [PubMed: 14578882] [Full Text: https://doi.org/10.1038/nm953]
Antonchuk, J., Sauvageau, G., Humphries, R. K. HOXB4-induced expansion of adult hematopoietic stem cells ex vivo. Cell 109: 39-45, 2002. [PubMed: 11955445] [Full Text: https://doi.org/10.1016/s0092-8674(02)00697-9]
Krosl, J., Austin, P., Beslu, N., Kroon, E., Humphries, R. K., Sauvageau, G. In vitro expansion of hematopoietic stem cells by recombinant TAT-HOXB4 protein. Nature Med. 9: 1428-1432, 2003. [PubMed: 14578881] [Full Text: https://doi.org/10.1038/nm951]
Kyba, M., Perlingeiro, R. C. R., Daley, G. Q. HoxB4 confers definitive lymphoid-myeloid engraftment potential on embryonic stem cell and yolk sac hematopoietic progenitors. Cell 109: 29-37, 2002. [PubMed: 11955444] [Full Text: https://doi.org/10.1016/s0092-8674(02)00680-3]
Reya, T., Duncan, A. W., Ailles, L., Domen, J., Scherer, D. C., Willert, K., Hintz, L., Nusse, R., Weissman, I. L. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423: 409-414, 2003. [PubMed: 12717450] [Full Text: https://doi.org/10.1038/nature01593]