c-JUN promotes BCR-ABL-induced lymphoid leukemia by inhibiting methylation of the 5' region of CDK6

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 downregulated upon BCR-ABL-induced transformation, which correlates with CpG island methylation within the 5' region of Cdk6. We verified the impact of Cdk6deficiency 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. © 2011 by The American Society of Hematology.