Bmi1 induction protects hematopoietic stem cells against pronounced long-term hematopoietic stress

The Polycomb complex protein Bmi1 is regarded as a master regulator of hematopoietic stem cells (HSCs). In the blood system, HSCs express Bmi1 most abundantly and Bmi1 expression vanes as cells differentiate. Furthermore, Bmi1 has been found overexpressed in several hematologic cancers. Most studies exploring the normal role of Bmi1 in HSC biology have utilized loss-of-function models, which have established Bmi1 as an important regulator for HSC maintenance. Additionally, gain-of-function studies using retroviral and lentiviral approaches have observed increased self-renewal of Bmi-1 transduced HSCs. However, the clinical and biological relevance of such studies are typically hampered by uncontrolled transgenic integration and supraphysiological expression levels. Here, we developed a novel Tetracycline-inducible gain-of-function Bmi1 (iBmi1) transgenic mouse model. We find that Bmi1 induction had minor, if any, effects on steady-state hematopoiesis or following 5-fluorouracil-induced cytostatic stress. On the contrary, secondary transplantation of iBmi1 HSCs into wild type recipients resulted in remarkable increases of HSC numbers and chimerism levels. These data, in concert with previous loss-of-function studies, suggest that while endogenous Bmi1 levels are required and sufficient for normal HSC maintenance, the stabilization of these levels over time protects HSC from transplantation-associated stress.