Lyn kinase as a key regulator in the microenvironmental niche of B lymphoid tumors

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Targeting B cell receptor (BCR)-associated kinases by small molecule kinase inhibitors has generated tremendous advances of the therapy of B lymphoid malignancies such as chronic lymphocytic leukemia (CLL) (Hallek et al., Lancet 2018). Following the introduction of these inhibitors in routine therapy, compelling evidence has emerged showing that their efficacy does not only rely on the inhibition of B cell-autonomous functions. Instead, the mechanism of action of these inhibitors can be explained to a large extent by the modulation of distinct cell types within the lymphoid tumor microenvironment (TME) (Nguyen, Niesen, Hallek, Leukemia 2019).Recently, we have discovered an unexpected, potent functional role of Lyn kinase, a central signaling component of the BCR, for the creation of a pro-malignant leukemia microenvironment (Nguyen et al., Cancer Cell 2016). Particularly, we observed that the presence of Lyn kinase is required to maintain the leukemia supporting capacity of both hematopoietic and non-hematopoietic cells. Moreover, preliminary data of our laboratory suggest that Lyn-deficiency leads to profound proteomic changes in macrophages and fibroblasts in the TME. The proteomic profiling revealed little overlap of Lyn-induced changes in the two cell types, suggesting that Lyn activates distinct, cell-type specific functional pathways in leukemia-associated macrophages and fibroblasts. The central hypothesis of this project is that non-receptor tyrosine kinases such as Lyn function as central modulators of the pro-neoplastic microenvironment for B cell lymphoma. Therefore, an improved mechanistic understanding of the function of these kinases in the lymphoid TME will be useful to design improved anti-lymphoma therapies. In the first aim, we will validate the cell type-specific modulation of novel targets including transcriptional factors within the regulatory network of Lyn kinase in different TME cells. In parallel, we will explore the potential role of Lyn in fibroblast activation and induction of a cancer-promoting phenotype. In the second aim, we will determine the structural signaling domains responsible for the TME action of Lyn using diverse in vitro and in vivo genetic tools. In the third aim, we will employ a high-content, functional arrayed CRISPR-knockout approach to identify new therapeutic targets contributing to the cancer supportive capacity of TME cells. Altogether, the overall aim of the proposed working plan is to provide a deeper understanding of the TME-related functions of protein kinases, fostering the redesigning of therapeutic applications in clinical trials, given the broad availability of kinase inhibitors.