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Oncogene ; 26(33): 4863-71, 2007 Jul 19.
Article in English | MEDLINE | ID: mdl-17297445

ABSTRACT

Loss of JunB has been observed in human leukemia and lymphoma, but it remains unknown, whether this loss is relevant to disease progression. Here, we investigated the consequences of JunB deficiency using Abelson-induced B-lymphoid leukemia as a model system. Mice deficient in JunB expression succumbed to Abelson-induced leukemia with increased incidence and significantly reduced latency. Similarly, bcr/abl p185-transformed JunB-deficient (junB(Delta/Delta)) cells induced leukemia in RAG2(-/-) mice displaying a more malignant phenotype. These observations indicated that cell intrinsic effects within the junB(Delta/Delta) tumor cells accounted for the accelerated leukemia development. Indeed, explantated bcr/abl p185 transformed junB(Delta/Delta) cells proliferated faster than the control cells. The proliferative advantage emerged slowly after the initial transformation process and was associated with increased expression levels of the cell cycle kinase cdk6 and with decreased levels of the cell cycle inhibitor p16(INK4a). These alterations were due to irreversible reprogramming of the cell, because - once established - accelerated disease induced by junB(Delta/Delta) cells was not reverted by re-introducing JunB. Consistent with this observation, we found that the p16 promoter was methylated. Thus, JunB functions as a gatekeeper during tumor evolution. In its absence, transformed leukemic cells acquire an enhanced proliferative capacity, which presages a more malignant disease.


Subject(s)
Leukemia, Lymphoid/pathology , Proto-Oncogene Proteins c-jun/physiology , Animals , Blotting, Western , Cell Line , Cell Line, Tumor , Cell Proliferation , Cell Survival , Cells, Cultured , Cyclin-Dependent Kinase 6/genetics , Cyclin-Dependent Kinase 6/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/physiology , Flow Cytometry , Fusion Proteins, bcr-abl/genetics , Fusion Proteins, bcr-abl/metabolism , Fusion Proteins, bcr-abl/physiology , Gene Expression , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Leukemia, Experimental/genetics , Leukemia, Experimental/metabolism , Leukemia, Experimental/pathology , Leukemia, Lymphoid/genetics , Leukemia, Lymphoid/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Nude , Proto-Oncogene Proteins c-jun/genetics , Proto-Oncogene Proteins c-jun/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Transfection
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