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

Blood. 2011 Apr 14;117(15):4065-75. doi: 10.1182/blood-2010-07-299644. Epub 2011 Feb 7.


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 p185(BCR-ABL)-transformed cells without affecting their viability. The decreased proliferation of c-Jun(Δ/Δ) cells is associated with the loss of cyclin-dependent kinase 6 (CDK6) expression. In c-Jun(Δ/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-Jun(Δ/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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions / physiology
  • Animals
  • Cell Division / physiology
  • Cell Transformation, Neoplastic / genetics
  • Cells, Cultured
  • Cyclin-Dependent Kinase 6 / genetics*
  • DNA Methylation / physiology*
  • Fusion Proteins, bcr-abl / genetics*
  • Gene Expression Regulation, Leukemic / physiology
  • Leukemia, Lymphoid* / etiology
  • Leukemia, Lymphoid* / genetics
  • Leukemia, Lymphoid* / metabolism
  • Liver / cytology
  • Mice
  • Mice, Mutant Strains
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism*
  • Signal Transduction / physiology


  • 5' Untranslated Regions
  • Proto-Oncogene Proteins c-jun
  • Fusion Proteins, bcr-abl
  • Cdk6 protein, mouse
  • Cyclin-Dependent Kinase 6
  • Mitogen-Activated Protein Kinase 8