CDK8 - ein neues therapeutisches Ziel gegen lymphoide Leukämie

Wider research context / theoretical framework Cyclin-dependent kinase 8 (CDK8) is a transcriptional regulator and is under consideration as a target for cancer therapy. We have identified CDK8 as a key player in B cell Acute Lymphoblastic Leukemia (B-ALL), as loss of CDK8 in BCR-ABL1+ B-ALL significantly enhances disease latency. CDK8-deficiency in B-ALL is associated with downregulation of pathways abnormally activated by the BCR-ABL1 onco-protein. The effect on the leukemic cells is not recapitulated by inhibition of CDK8/19 activity, revealing that CDK8 has kinase-independent functions in leukemogenesis. Natural killer (NK) cells are crucial players in the fight against leukemia and the potent cytotoxicity of NK cells is exploited to treat hematological malignancies. We have also shown that NK cells lacking CDK8 have a heightened activity against different types of tumors. Hypotheses / research questions / objectives We hypothesize that in B-ALL CDK8 (in a kinase-independent manner) directly drives the expression of critical genes within pathways deregulated by BCR-ABL thereby promoting disease progression. We also propose that CDK8 limits NK cell functions independently of its kinase activity by directly repressing the transcription of genes contributing to cytotoxicity. If this is so, the simultaneous targeting of CDK8 protein in leukemia and NK cells will impair the growth of leukemic cells and enhance the immune response, resulting in a synergistic anti-leukemic effect. Approach / methods Using novel mice with Cre recombinase-driven expression of kinase-inactive CDK8 we will investigate the kinase-independent functions of CDK8 in leukemic transformation/progression and NK cell-mediated leukemia surveillance. To test whether kinase-inactive CDK8 directly drives the expression of genes from pathways downregulated in CDK8-deficient B-ALL and directly contributes to expression of cytotoxic genes in NK cells, we will employ high-throughput technologies such as RNA sequencing and Chromatin ImmunoPrecipitation DNA-Sequencing in the presence of wild-type or kinase-inactive CDK8. Level of originality / innovation The knowledge gained from this project will be essential to enable CDK8 inhibitors or CDK8 degraders to be used as cancer therapeutics in precision medicine. All available CDK8 inhibitors also inhibit CDK19 due to the high structural similarity between the two kinases. Our study will allow us to separate the contribution of CDK8 from that of CDK19 and will provide important insights into the molecular mechanisms by which CDK8 contributes to cancer progression and NK cell-mediated immune surveillance. Primary researchers involved The project will be led by the applicant Veronika Sexl, the head of the Institute of Pharmacology and Toxicology, VetMedUni Vienna. The experimental part will be performed by one experienced Postdoc (the co-author; Agnieszka Witalisz-Siepracka) and the data analysis will be performed by one bioinformatician.

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