Role of the polycomb group gene BMI1 in normal and leukemic hematopoietic stem and progenitor cells

Abstract

The polycomb group gene BMI1 fulfills essential roles in both normal and leukemic stem cells. The underlying molecular mechanisms are beginning to become unraveled and an overview of the current knowledge on BMI1 signaling in normal and leukemic stem cells will be presented here. In addition to a role in bypassing senescence and the orchestration of the symmetry of hematopoietic stem cell divisions, it has recently become clear that BMI1 also functions in the protection against oxidative stress. In the absence of BMI1, reactive oxygen species accumulate, associating with activation of DNA damage response pathways and increased apoptosis. BMI1-mediated control over reactive oxygen species levels might occur independently of the INK4a/ARF pathway, but rather involves impaired mitochondrial functions. In human hematopoietic malignancies, BMI1 is frequently overexpressed, which associates with poor prognosis. Down modulation of BMI1 impairs self-renewal and long-term expansion of leukemic stem cells. Understanding molecular mechanisms by which BMI1 affects stem cell fate will increase our insights into the biology of hematopoietic stem cells and will also aid in understanding the process of leukemic transformation and ultimately in the identification of drugable targets that might facilitate the eradication of leukemic stem cells.