Bmi-1 regulation of INK4A-ARF is a downstream requirement for transformation of hematopoietic progenitors by E2a-Pbx1.
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.
Smith
Kevin S
KS
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Chanda
Sumit K
SK
Lingbeek
Merel
M
Ross
Douglas T
DT
Botstein
David
D
van Lohuizen
Maarten
M
Cleary
Michael L
ML
D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004171:Diploidy; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D014162:Transfection
C069077:BMI1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C089847:E2A-Pbx1 fusion protein; D063150:Polycomb Repressive Complex 1