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CDK6 in transcription - turning a foe in a friend

Periodic Reporting for period 3 - CDK6-DrugOpp (CDK6 in transcription - turning a foe in a friend)

Reporting period: 2019-09-01 to 2021-02-28

Although we have made significant progress in cancer research and in the development of novel diagnostic and therapeutic strategies, many cancer types remain an unresolved issue and people die. Among the tumor types lacking adequate therapeutic strategies are certain forms of blood cancer. Many of these upregulate a certain molecule called cyclin-dependent kinase 6 (CDK6). We have shown that CDK6 not only exerts it proposed function to regulate cell proliferation by governing the cells through the cell cycle but also regulates the transcription of genes important for tumor formation explaining the selective pressure of up-regulating this molecule. We are here trying to understand how CDK6 contributes to gene transcription relevant for driving cancer in order to understand the vulnerable nodes where novel therapeutics may interfere. Our work thereby will open novel avenues for the development of new drugs to battle cancer.
We have initiated all experiments aiming at understanding how CDK6 regulates transcription. First important insights were obtained. We could show that CDK6 not only allows for cell proliferation but also antagonizes p53-induced cell death when a cell evolves into a tumor cell. P53 is considered the gate keeper of the genome and will induce cellular suicide called apoptosis when a cell is not capable to repair or antagonize any damage evolving. CDK6 is required to allow the birth of leukemic cells to block the suicidal actions of p53 within a cell (Bellutti et al 2018). In this publication we could unravel the underlying molecular mechanisms for this novel function of CDK6.
To allow the detailed study of CDK6 in leukemic stem cells we have generated novel cellular tools. Hematopoietic stem cells are on top of the hierarchy of the blood system. A few stem cells suffice to generate the entire blood flowing through our body. This limited cell numbers make it particularly difficult to study these cells. We have succeeded in generated a hematopoietic stem/progenitor cell line that can replenish the entire blood system in a mouse. This novel cell lines can also be used to generate different versions of leukemic stem cells that drive leukemia formation. These novel leukemic stem cell lines faithfully recapitulate human blood cancer in mice and will serve as valuable novel tool to understand the molecular mechanisms of cellular transformation underlying blood cancer.
We have also started to unravel how DK6 drives transformation and which features of the molecule is needed to drive transcription.
We expect to unravel an entire new function for CDK6 in tumor formation and to understand whether this moelcule represent s a suitable novel target fro drug development.