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In vivo Functional Characterization of LYN Kinase in the Pathogenesis of Chronic Lymphocytic Leukemia

of the Dissertation Chronic lymphocytic leukemia (CLL) is the most common B cell leukemia in the elderly, which is still incurable by conventional chemoimmunotherapy. CLL cells are recognized as “addicted to the host” because of their tight dependence on a permissive tumor microenvironment consisting of various components such as macrophages, nurse-like cells, T cells, stromal and other cell types. Pro-survival signaling within CLL cells relies heavily on the B cell receptor (BCR) pathway, which is greatly enhanced in CLL cells compared to healthy B cells. The most widely used model for CLL studies is the Eμ-TCL1 transgenic mice, which develop a B lymphoproliferative disease highly similar to the aggressive form of human CLL. LYN kinase, a member of the SRC family kinases, is associated with the BCR complex and is one of the molecules activated very early following BCR stimulation. LYN is considered a modulator of B cell homeostasis due to its ability to phosphorylate both activators and inhibitors downstream of BCR signaling. LYN is found to be overexpressed in CLL cells, and is associated with CLL resistance to apoptosis. Besides, LYN is also reported to have important functions in a wide range of other cell types, both of the hematopoietic and non-hematopoietic compartments. Involvement of LYN in numerous cellular processes such as proliferation, migration, adherence, as well as oncogenic development renders this molecule a highly interesting target for cancer research. To provide more insights into the role of LYN kinase in CLL pathogenesis in vivo, we have generated Eμ-TCL1 transgenic LYN deficient mice (TCL1 LYN) and characterized the development of malignant CLL cells in these mice in comparison to the control Eμ-TCL1 transgenic mice (TCL1 LYN). Our study shows that complete ablation of LYN resulted in significantly hindered CLL development in vivo. In comparison to TCL1 LYN mice, TCL1 LYN mice had significantly reduced expansion of CLL cells, as well as reduced leukocyte count in the peripheral blood at the leukemic stage. Besides, TCL1 LYN mice displayed a decreased infiltration of malignant B cells in lymphoid tissues such as spleen, liver, lymph node and bone marrow. Although TCL1 LYN mice showed hindered development of TCL1-induced CLL, our data suggest it is not only due to LYN deficiency in the B cell compartment of these mice. Indeed, CLL cells of TCL1 LYN mice showed enhanced proliferation, early transformation, as well as comparable ex vivo survival to TCL1 LYN B cells. Furthermore, TCL1 LYN B cells also maintained the capability to induce full-blown leukemia in healthy recipients. Notably, TCL1 LYN mice developed a skewed microenvironment, which might contribute to CLL down regulation. The LYN mice did not support engraftment of TCL1-induced leukemic B cells in transplantation experiments, leading to a significantly delayed CLL progression and prolonged survival of LYN recipients. More strikingly, aged LYN mice totally rejected CLL transplantation. Additionally, loss of LYN, specifically in the hematopoietic system of chimeric recipients, led to a moderate reduction of CLL expansion compared to WT chimeras. Taken together, our results point to a complex regulation of LYN signaling in CLL involving not only the leukemic cells, but above all, the microenvironment that has never been reported until now. We suggest that expression of LYN in both hematopoietic and non-hematopoietic compartments might contribute to the progression of CLL in vivo.