Journal
MOLECULAR CELL
Volume 12, Issue 2, Pages 393-400Publisher
CELL PRESS
DOI: 10.1016/S1097-2765(03)00277-6
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Funding
- NCI NIH HHS [CA42971, CA66284] Funding Source: Medline
- NIGMS NIH HHS [GM07149] Funding Source: Medline
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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-Pbxl enhances expression of BMI-1, a lymphoid oncogene whose product functions as a transcriptional repressor of the INK4A-ARFtumor 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-Pbxl on pre-B cell survival and differentiation are partially bypassed by forced expression of p16(Ink4a). These results link E2aPbx1 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.
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