The role of the splenic microenvironment in Chronic Lymphocytic Leukemia

Abstract

Abstract Chronic Lymphocytic Leukemia (CLL), the most prevalent adult leukemia, is characterized by the clonal expansion of CD5+ CD19+ B cells within lymphoid organs and accumulation of quiescent cells in the blood. Eμ-Tcl1 transgenic mice expressing the Tcl1 oncogene in a B cell-specific manner develop CLL and adoptive transfer of CLL cells from these mice induces CLL growth in C57BL/6 mice. These models typically cause splenomegaly as the CLL burden increases, and CLL cells localize mainly in the spleen within the first 10 days post-injection. We hypothesized that the splenic microenvironment is vital for CLL expansion. Accordingly, we found that splenectomy significantly delayed and decreased CD5+ CD19+ CLL cell burden. The role of the splenic microenvironment was further explored by isolating splenic stromal cells from Eμ-Tcl1 mice and establishing stable cell lines (EMST cells). In cell culture, CLL cells divide poorly and remain mostly quiescent. The EMST cells induced proliferation in a majority of mouse and human CLL cells without the addition of any cytokines or growth factors commonly used to accomplish in vitro proliferation of CLL cells. They do not express CD40L, an important stimulatory molecule for B cell proliferation. EMST cells lack conventional immune cell markers, but they express the cytokines and chemokines BAFF, CCL2, CXCL12, and Wnt4. CCL2 levels dramatically increased upon co-culture with CLL. EMST cells also enhance IL-10 secretion by the CLL cells and thus may enhance an immunosuppressive environment to prevent anti-CLL immunity from developing. Our studies support the hypothesis that the spleen is vital for the establishment of CLL and EMST cells produce specific factors that may play a role in CLL growth.