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JunB is a gatekeeper for B-lymphoid leukemia

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 (junBΔ/Δ) cells induced leukemia in RAG2−/− mice displaying a more malignant phenotype. These observations indicated that cell intrinsic effects within the junBΔ/Δ tumor cells accounted for the accelerated leukemia development. Indeed, explantated bcr/abl p185 transformed junBΔ/Δ 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 p16INK4a. These alterations were due to irreversible reprogramming of the cell, because – once established – accelerated disease induced by junBΔ/Δ 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.

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Acknowledgements

We thank Udo Losert and the staff of the Biomedical Research Institute (MUW) for taking care of mice. We are grateful to Richard Moriggl, Robert Eferl, Peter Angel and Latifa Bakiri for helpful discussions and to Ursula Unterberger and Cornelia Stock for technical help. This work was supported by Grants P15865 and SFB-F28 of the Austrian Science Foundation (FWF) dedicated to VS and by a DOC stipend of the Austrian Academy of Sciences to RGO.

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Correspondence to V Sexl.

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Ott, R., Simma, O., Kollmann, K. et al. JunB is a gatekeeper for B-lymphoid leukemia. Oncogene 26, 4863–4871 (2007). https://doi.org/10.1038/sj.onc.1210285

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  • DOI: https://doi.org/10.1038/sj.onc.1210285

Keywords

  • JunB
  • bcr/abl
  • AP-1
  • leukemia

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