TitleBmi-1 regulation of INK4A-ARF is a downstream requirement for transformation of hematopoietic progenitors by E2a-Pbx1.
Publication TypeJournal Article
Year of Publication2003
AuthorsSmith, KS, Chanda, SK, Lingbeek, M, Ross, DT, Botstein, D, van Lohuizen, M, Cleary, ML
JournalMol Cell
Date Published2003 Aug
KeywordsApoptosis, 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 JournalMol. Cell