A central issue in stem cell biology is to understand the mechanisms that 
regulate the self-renewal of haematopoietic stem cells (HSCs), which are 
required for haematopoiesis to persist for the lifetime of the animal. We found 
that adult and fetal mouse and adult human HSCs express the proto-oncogene 
Bmi-1. The number of HSCs in the fetal liver of Bmi-1-/- mice was normal. In 
postnatal Bmi-1-/- mice, the number of HSCs was markedly reduced. Transplanted 
fetal liver and bone marrow cells obtained from Bmi-1-/- mice were able to 
contribute only transiently to haematopoiesis. There was no detectable 
self-renewal of adult HSCs, indicating a cell autonomous defect in Bmi-1-/- 
mice. A gene expression analysis revealed that the expression of stem cell 
associated genes, cell survival genes, transcription factors, and genes 
modulating proliferation including p16Ink4a and p19Arf was altered in bone 
marrow cells of the Bmi-1-/- mice. Expression of p16Ink4a and p19Arf in normal 
HSCs resulted in proliferative arrest and p53-dependent cell death, 
respectively. Our results indicate that Bmi-1 is essential for the generation of 
self-renewing adult HSCs.