Understanding the mechanistic function of protein kinases in macrophage phenotype and leukemia support
Chronic lymphocytic leukemia (CLL) is the most frequent leukemia among elderly people, a disease of high clinical relevance. In the last decades, CLL research has been focusing more and more on the tumor microenvironment (TME) since CLL cells are strongly relying on interactions with other cells in their microenvironmental niche.
Macrophages represent one of the most important cell types supporting tumor growth. Using a functional arrayed CRISPR/Cas9 knockout screen, we discovered a dozen of single gene knockouts with consistently reduced support for CLL cell survival in vitro. The targets include the SRC family kinase (SFK) LYN and its regulator CSK, which involve in many signaling cascades, rendering these protein kinases potential targets for novel tumor-supportive targeting strategies.
In my project, I will validate the previously generated results regarding the role of these identified protein kinases using diverse macrophage cell lines and explore the phenotypic changes in CLL-supportive macrophages in the absence of these kinases. Particularly, I will also use the primary human myeloid cell lineage for genetic modification, as it is a crucial step towards implementing the knowledge from bench to bedside.