Crucial role of the polycomb group gene product BMI-1 in the maintenance of self-renewing hematopoietic stem cells

Abstract

Epigenetic regulation is critical for biological development and homeostasis. The polycomb group (PcG) proteins form the Polycomb Repressive Complexes (PRC) 1 and 2, and are responsible for reversibly silencing gene expression via histone modifications. BMI1, a component of PRC1, plays an important role in the maintenance of self-renewal of somatic stem cells as well as cancer cells, and is also involved in cellular differentiation and reactive oxygen species signaling. Loss of Bmi1 in mice results in the progressive depletion of HSCs, ultimately leading to lethal pancytopenia. This depletion is mediated primarily by the derepression of the Ink4a/Arf locus, resulting in cellular senescence and apoptosis. BMI1 appears to function in a similar capacity in most malignancies, where overexpression or ectopic expression of BMI1 silences tumor suppressor gene loci including the INK4A/ARF locus, enabling malignant growth of the tumor. Overexpression of Bmi1 is not sufficient to induce malignancies in mice, though it does accelerate tumorigenesis in certain model systems. Bmi1-overexpressing hematopoietic cells are significantly more resistant to stresses such as ex vivo culture and serial transplantation. BMI1 can function as both an oncogene and a tumor suppressor, depending on the cellular context. When functioning as an oncogene, BMI1 targets tumor suppressor gene loci including the INK4A/ARF locus, as is reported in numerous types of cancer. In line with recent reports that suggest PcG components can act as tumor suppressors, however, Bmi1 was recently found to act as a tumor suppressor in an Ink4a/Arf-deficient background. Future research on BMI1 will likely be focused on how to manipulate the PcG-mediated epigenetic machineries for regenerative medicine and cancer therapy.