|Title||Bmi-1 regulation of INK4A-ARF is a downstream requirement for transformation of hematopoietic progenitors by E2a-Pbx1.|
|Publication Type||Journal Article|
|Year of Publication||2003|
|Authors||Smith, KS, Chanda, SK, Lingbeek, M, Ross, DT, Botstein, D, van Lohuizen, M, Cleary, ML|
|Date Published||2003 Aug|
|Keywords||Apoptosis, Blotting, Western, Cell Aging, Cell Line, Cell Transformation, Neoplastic, Cyclin-Dependent Kinase Inhibitor p16, Diploidy, Down-Regulation, Fibroblasts, Flow Cytometry, Gene Expression Regulation, Genotype, Hematopoietic Stem Cells, Homeodomain Proteins, Humans, Nuclear Proteins, Oligonucleotide Array Sequence Analysis, Oncogene Proteins, Fusion, Polycomb Repressive Complex 1, Proto-Oncogene Proteins, Repressor Proteins, Retroviridae, Time Factors, Transfection|
Loss-of-function alterations of INK4A are commonly observed in lymphoid malignancies, but are consistently absent in pre-B cell leukemias induced by the chimeric oncoprotein E2a-Pbx1 created by t(1;19) chromosomal translocations. We report here that experimental induction of E2a-Pbx1 enhances expression of BMI-1, a lymphoid oncogene whose product functions as a transcriptional repressor of the INK4A-ARF tumor suppressor locus. Bmi-1-deficient hematopoietic progenitors are resistant to transformation by E2a-Pbx1; however, the requirement for Bmi-1 is alleviated in cells deficient for both Bmi-1 and INK4A-ARF. Furthermore, the adverse effects of E2a-Pbx1 on pre-B cell survival and differentiation are partially bypassed by forced expression of p16(Ink4a). These results link E2a-Pbx1 with Bmi-1 on an oncogenic pathway that is likely to play a role in the pathogenesis of human lymphoid leukemias through downregulation of the INK4A-ARF gene.
|Alternate Journal||Mol. Cell|