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The transcriptional repressor BMI-1 was first identified as a proto-oncogene frequently activated by Moloney murine leukemia proviral insertions in mice and cooperating with c-myc in the generation of mouse lymphomas. BMI-1 is involved in segment specification, cell growth and maintenance, transcriptional regulation, and chromatin modification. A major target of BMI-1 is the ink4a locus which encodes tumor suppressor proteins p16 and p19Arf, which are important in tumor progression and thought to be critical in cell proliferation and senescence. Recent studies have also shown that BMI-1 is required for the maintenance of adult normal and leukemic stem cells, suggesting that BMI-1 could an attractive therapeutic target for stem cell proliferation and renewal as well as for anti-cancer strategies.