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c-JUN promotes BCR-ABL–induced lymphoid leukemia by inhibiting methylation of the 5′ region of Cdk6

Karoline Kollmann, Gerwin Heller, Rene Georg Ott, Ruth Scheicher, Eva Zebedin-Brandl, Christine Schneckenleithner, Olivia Simma, Wolfgang Warsch, Eva Eckelhart, Andrea Hoelbl, Martin Bilban, Sabine Zöchbauer-Müller, Marcos Malumbres and Veronika Sexl

Abstract

The transcription factor c-JUN and its upstream kinase JNK1 have been implicated in BCR-ABL–induced leukemogenesis. JNK1 has been shown to regulate BCL2 expression, thereby altering leukemogenesis, but the impact of c-JUN remained unclear. In this study, we show that JNK1 and c-JUN promote leukemogenesis via separate pathways, because lack of c-JUN impairs proliferation of p185BCR-ABL–transformed cells without affecting their viability. The decreased proliferation of c-JunΔ/Δ cells is associated with the loss of cyclin-dependent kinase 6 (CDK6) expression. In c-JunΔ/Δ cells, CDK6 expression becomes down-regulated upon BCR-ABL–induced transformation, which correlates with CpG island methylation within the 5′ region of Cdk6. We verified the impact of Cdk6 deficiency using Cdk6−/− mice that developed BCR-ABL–induced B-lymphoid leukemia with significantly increased latency and an attenuated disease phenotype. In addition, we show that reexpression of CDK6 in BCR-ABL–transformed c-JunΔ/Δ cells reconstitutes proliferation and tumor formation in Nu/Nu mice. In summary, our study reveals a novel function for the activating protein 1 (AP-1) transcription factor c-JUN in leukemogenesis by antagonizing promoter methylation. Moreover, we identify CDK6 as relevant and critical target of AP-1–regulated DNA methylation on BCR-ABL–induced transformation, thereby accelerating leukemogenesis.

  • Submitted July 30, 2010.
  • Accepted January 9, 2011.
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