title: 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 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.
authors.affiliation: Institute of Pharmacology, Center of Biomolecular Medicine and Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Karoline
authors.initials: K
authors.lastname: Kollmann
authors.forename: Gerwin
authors.initials: G
authors.lastname: Heller
authors.forename: Rene Georg
authors.initials: RG
authors.lastname: Ott
authors.forename: Ruth
authors.initials: R
authors.lastname: Scheicher
authors.forename: Eva
authors.initials: E
authors.lastname: Zebedin-Brandl
authors.forename: Christine
authors.initials: C
authors.lastname: Schneckenleithner
authors.forename: Olivia
authors.initials: O
authors.lastname: Simma
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Warsch
authors.forename: Eva
authors.initials: E
authors.lastname: Eckelhart
authors.forename: Andrea
authors.initials: A
authors.lastname: Hoelbl
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Sabine
authors.initials: S
authors.lastname: Zöchbauer-Müller
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
mesh_terms: D020121:5' Untranslated Regions / Q000502:physiology; D000818:Animals; D002455:Cell Division / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics*; D019175:DNA Methylation / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D007945:Leukemia, Lymphoid / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000166:cytology; D051379:Mice; D008817:Mice, Mutant Strains; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D020121:5' Untranslated Regions; D016755:Proto-Oncogene Proteins c-jun; D016044:Fusion Proteins, bcr-abl; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6; D048055:Mitogen-Activated Protein Kinase 8