Model of HOXB4-mediated HSC self-renewal. HOXB4 may promote self-renewal in HSCs by down-regulating the expression of lineage-specific genes and up-regulating “stemness-related” genes. As HSCs encounter microenvironmental changes that are conducive to differentiation, the binding partners of HOXB4 may change, resulting in a reversal of HOXB4 function and/or binding specificity, such that lineage-specific genes that were once down-regulated by HOXB4 directly or indirectly would no longer be down-regulated. In addition, “stemness-related” genes that were once up-regulated by HOXB4 would now be down-regulated as the cells differentiate.