Bmi-1 regulation of INK4A-ARF is a downstream requirement for transformation of hematopoietic progenitors by E2a-Pbx1.

Abstract	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.
Authors	Kevin S Smith, Sumit K Chanda, Merel Lingbeek, Douglas T Ross, David Botstein, Maarten van Lohuizen, Michael L Cleary
Journal	Molecular cell (Mol Cell) Vol. 12 Issue 2 Pg. 393-400 (Aug 2003) ISSN: 1097-2765 [Print] United States
PMID	14536079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	BMI1 protein, human Cyclin-Dependent Kinase Inhibitor p16 Homeodomain Proteins Nuclear Proteins Oncogene Proteins, Fusion Proto-Oncogene Proteins Repressor Proteins E2A-Pbx1 fusion protein Polycomb Repressive Complex 1
Topics	Apoptosis Blotting, Western Cell Line Cell Transformation, Neoplastic Cellular Senescence Cyclin-Dependent Kinase Inhibitor p16 (genetics, metabolism) Diploidy Down-Regulation Fibroblasts (metabolism) Flow Cytometry Gene Expression Regulation Genotype Hematopoietic Stem Cells (metabolism) Homeodomain Proteins (genetics, metabolism) Humans Nuclear Proteins (genetics, metabolism) Oligonucleotide Array Sequence Analysis Oncogene Proteins, Fusion (genetics, metabolism) Polycomb Repressive Complex 1 Proto-Oncogene Proteins (genetics, metabolism) Repressor Proteins Retroviridae (genetics) Time Factors Transfection

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