CDK6 - a potentical target to treat lymphoid leukemia?

AP-1 transcription factors are frequently deregulated in human cancer. Loss of the AP-1 transcription factor JunB has been observed in human leukemia and lymphoma but it remained unknown, if this loss is relevant to disease progression. So far, we have investigated the consequences of JunB deficiency using Abelson induced B-lymphoid leukemia as a model system. Mice deficient in JunB expression succumbed to Abelson induced leukemia with an increased incidence and significantly reduced latency. Similarly, leukemic cells devoid of JunB induce leukemia in recipient mice with a more malignant phenotype. We showed that JunB deficient leukemic cells proliferate faster than the control cells and that the proliferative advantage is associated with increased expression levels of the cell cycle kinase Cdk6. Loss of the AP-1 transcription factor and JunB-antagonist c-Jun mirrors this finding. Leukemic cells deficient for c-Jun induce disease with an increased latency and a reduced incidence. Most interestingly, c- Jun deficient leukemic cells lack expression of the cell cycle kinase Cdk6. We therefore propose Cdk6 as key regulator of leukemia development. This concept is further supported by findings in patients suffering from B lymphoid malignancies where translocations involving the cdk6 gene resulting in high Cdk6 expression have been described. Our project aims to characterize the effects of Cdk6 for the initiation and progression of lymphoid leukemia. Preliminary experiments have shown that Cdk6 may both - accelerate or inhibit leukemia progression depending on the molecular context. We intend to define the requirements for Cdk6 to act as a tumor suppressor or as a tumor promoter. Our study is of great therapeutic relevance, since inhibitors against cyclin dependent kinases have been developed and currently undergoing clinical evaluation.

Cell cycle alterations are a hallmark of cancer cells. Important cell cycle regulators are under the control of the AP-1 transcription factor family. In this study we investigated the role of the cell cycle kinase CDK6 and its regulation by AP-1 factors for tumor formation. We found that c-Jun and JunB both regulate CDK6 expression in an antagonistic manner. Whereas JunB suppresses CDK6 expression, c-Jun is required to prevent methylation of CpG islands within the CDK6 promoter which leads to down-regulation of CDK6. Interestingly, CDK6 - but not its close homologue CDK4 - is expressed at high levels in transformed lymphoid cells. We thus studied the impact of deregulated CDK6 levels in a p185BCR-ABL+ B-acute lymphoid leukaemia (B-ALL). In the absence of CDK6 tumor formation and leukemogenesis is significantly delayed. We found that CDK6 is not only required to allow appropriate cell cycle progression but also to regulate tumor angiogenesis. We show that CDK6 acts in concert with other transcription factors to induce the tumour suppressor p16INK4a and the pro-angiogenic factor VEGF-A. Further support for the dual role of CDK6 regulating cell growth as well as tumor angiogenesis was obtained in a murine T-cell lymphoma model driven by NPM-ALK. Thereby CDK6 connects cell-cycle progression to tumour angiogenesis. The findings confirm CDK6s unique role in hematopoietic transformation and explain the selection pressure to up-regulate CDK6 in murine and human lymphoma. As CDK6 is a major target for anti-cancer drug development, future therapeutic strategies should also consider the potential involvement of the proteins kinase-independent functions in transcriptional regulation.