Abstract
HOXB4 overexpression has been previously shown to increase hematopoietic stem cell renewal and enhance murine HSC competitive repopulation without compromising differentiation or homeostatic regulation of HSC pool size. However, recent studies on human HSC have indicated that forced expression of HOXB4 may dysregulate lymphoid and myeloid differentiation. In this study the effects of HOXB4 forced expression were examined on the distribution and lineage specification of HOXB4 expressing cells in a congenic competitive repopulation assay. Retroviral HOXB4 overexpression in hematopoietic cells (HSCs) resulted in increased frequency of long-term culture initiating cells (LTC-IC) in vitro, indicative of selective growth advantage but with no significant difference in mean CFC/LTC-IC ratio, an indicator of balanced differentiation. Competitive in vivo repopulation assays in congenic transplants with different combinations of HOXB4- and GFP-transduced bone marrow cells showed long-term engraftment and a selective growth advantage of HOXB4 transduced cells in bone marrow, thymus, blood, and spleen. Engraftment levels were disproportionately high in bone marrow and thymus relative to spleen and peripheral blood, while multilineage analysis of bone marrow showed a predominance of myeloid lineages. Thymic analysis revealed a HOXB4-dependent increase in thymic size due to increased numbers of mature CD4 and CD8 T cells consistent with an abnormality of release of lymphocytes from the thymus, and the abnormalities persisted in secondary transplants. These results support the potential of HOXB4 forced expression to alter the balance and distribution of hematopoiesis and suggest fundamental alterations induced by HOXB4 in thymic T-cell trafficking. These results emphasize the need for a careful evaluation of clinical gene therapy applications with HOXB4.
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© 2009 Humana Press, a part of Springer Science+Business Media, LLC, a part of Springer Science+Business Media, LLC
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Vemuri, M.C. (2009). HOXB4 in Hematopoietic Stem Cell Regulation. In: Rajasekhar, V.K., Vemuri, M.C. (eds) Regulatory Networks in Stem Cells. Stem Cell Biology and Regenerative Medicine. Humana Press. https://doi.org/10.1007/978-1-60327-227-8_10
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DOI: https://doi.org/10.1007/978-1-60327-227-8_10
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