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 wanes as cells differentiate. Furthermore, Bmi1 has been found to be overexpressed in several hematologic cancers. Most studies exploring the normal role of Bmi1 in HSC biology have used 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 Bmi1-transduced HSCs. However, the clinical and biological relevance of such studies is typically hampered by uncontrolled transgenic integration and supraphysiological expression levels. Here, we describe how we developed a novel tetracycline-inducible gain-of-function Bmi1 (iBmi1) transgenic mouse model. We found that Bmi1 induction had minor, if any, effects on steady-state hematopoiesis or after 5-fluorouracil-induced cytostatic stress. On the contrary, secondary transplantation of iBmi1 HSCs into wild-type recipients resulted in marked increases in the number and chimerism of HSCs. These data, in concert with previous loss-of-function studies, suggest that although endogenous Bmi1 levels are required and sufficient for normal HSC maintenance, the stabilization of these levels over time protects HSCs from transplantation-associated stress.