| First Author | Kollmann K | Year | 2011 |
| Journal | Blood | Volume | 117 |
| Issue | 15 | Pages | 4065-75 |
| PubMed ID | 21300982 | Mgi Jnum | J:172844 |
| Mgi Id | MGI:5009110 | Doi | 10.1182/blood-2010-07-299644 |
| Citation | Kollmann K, et al. (2011) c-JUN promotes BCR-ABL-induced lymphoid leukemia by inhibiting methylation of the 5' region of Cdk6. Blood 117(15):4065-75 |
| abstractText | 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(Delta/Delta) cells is associated with the loss of cyclin-dependent kinase 6 (CDK6) expression. In c-Jun(Delta/Delta) 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(Delta/Delta) 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. |
