The ERC grant enabled us to understand how CDK6 regulates gene transcription of distinct genes to drive leukemia. It also enabled us to understand how CDK6 interferes with p53, an important check point in cancer and considered the gate keeper of the genome. CDK6 not only allows for cell proliferation but also antagonizes p53-induced cell death when a cell evolves into a tumor cell. P53 triggers cellular suicide when a cell enters the state of transformation, a function blocked by high CDK6 levels. Thereby, CDK6 is required to allow the birth of leukemic cells (Bellutti et al 2018). In this publication we could unravel the underlying molecular mechanisms for this novel function of CDK6.
Cancer cells require a distinct metabolic state. Also in this area CDK6 contributes to changes in the mitochondrial pathway, a project that is still ongoing. To target the metabolism of a tumor cell is currently considered key to treat cancer and our findings will help to finally understand the switches in metabolism of a tumor cell.
Leukemic stem cells are hard to target and studies on this small population of cells difficult. WE thus generated a novel cellular tool and found a way how to maintain the small population of hematopoietic stem cells (HSCs) and their leukemic counterparts (LSCs) in culture. Few stem cells suffice to generate the entire blood flowing through our body, which we now can keep in culture (Doma et al. 2021). These cell lines expressing various versions of CDK6 allowed us to unravel CDK6’s function in hematopoiesis and leukemogenesis. We found that CDK6 supports HSC dormancy as well as HSC repopulation with distinct functions – these distinct features being unraveled by the use of different mutations driving unique gene expression patterns. These results now help to understand how HSCs and their activation are regulated by CDK6 and may be further exploited in therapeutic settings.
This novel cell lines have also been used to generate different versions of leukemic stem cells that faithfully recapitulate human blood cancer in mice and represent a valuable novel tool. First studies are ongoing in the lab to understand the molecular mechanisms of cellular transformation and the role of CDK6 therein. A first publication shows that the expression of the INK proteins, CDK6 kinase inhibitors, dictate the responsiveness of the cells to current CDK6 targeting options in leukemia (Schmalzbauer et al. 2022).
Results have been presented at several conferences and seminars whenever possible. Publications are under progress and students will finish their PhD thesis. Numerous collaborations could be made thanks to new research areas which have been opened during the project.
