Elucidation of the pathophysiological contribution of CD44 expressed on myeloid and endothelial compartments to the development of chronic lymphocytic leukemia in vivo
Cell Biology
Final Report Abstract
Chronic lymphocytic leukemia (CLL) is a malignancy of mature B-cells that accumulate in the blood, bone marrow, and secondary lymphoid organs. The proliferation of CLL cells heavily relies on their interactions with immune cells and stromal components of lymphoid organs, including endothelial cells. Adhesion molecules, such as CD44, are expressed on various immune and stromal cell subtypes, and play a central role in these interactions, as we previously demonstrated. Based on these findings, we hypothesized that CD44 expression on microenvironmental components contributes to CLL development. We focused on CD44 involvement on the myeloid compartment and the endothelium and tested both human and murine (TCL1) CLL cells, as well as a mantle cell lymphoma line (MAVER-1) for comparison with a non-antigen-experienced B-cell neoplasm. Loss of CD44 expression in the myeloid compartment of healthy mice did not cause significant changes, but in CLL-transplanted mice, it resulted in reduced monocyte counts and delayed engraftment in the peritoneal cavity, associated with increased leukocytosis. PD-1 expression on T cells was slightly elevated, suggesting increased T cell activation and proliferation. Our studies also showed that CLL- endothelium interactions contribute to the long-term persistence of CLL cells in blood and lymph nodes. CD44 expression on endothelial cells favored the survival and proliferation of malignant naïve B cells and CLL cells, while limiting T cell activation, indicating an immunosuppressive and tumor-supportive role. Transcriptomics of endothelium lacking CD44 revealed changes in antigen presentation-related genes. Moreover, CD44 expression on endothelial cells enhanced the production of hyaluronan (HA), its own ligand, suggesting a feed-forward loop. To further investigate the interaction between endothelial cells and human T cells, we developed an innovative spectral flow cytometry panel with 38 markers, providing deeper insights into the immune responses. In addition to the main objectives of this project, the joint funding enabled successful research on acute myeloid leukemia (AML). Our CLL data are currently being compiled into a manuscript and supplemented with additional investigations.
Publications
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CD44 engagement enhances acute myeloid leukemia cell adhesion to the bone marrow microenvironment by increasing VLA-4 avidity. Haematologica, 106(8), 2102-2113.
Julia C. Gutjahr, Elisabeth Bayer; Xiaobing Yu, Julia M. Laufer; Jan P. Höpner, Suzana Tesanovic; Andrea Härzschel, Georg Auer; Tanja Rieß, Astrid Salmhofer; Eva Szenes, Theresa Haslauer; Valerie Durand-Onayli, Andrea Ramspacher; Sandra P. Pennisi, Marc Artinger; Nadja Zaborsky, Alexandre Chigaev; Fritz Aberger ... & Tanja N. Hartmann
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CD44 loss of function sensitizes AML cells to the BCL-2 inhibitor venetoclax by decreasing CXCL12-driven survival cues. Blood, 138(12), 1067-1080.
Yu, Xiaobing; Munoz-Sagredo, Leonel; Streule, Karolin; Muschong, Patricia; Bayer, Elisabeth; Walter, Romina J.; Gutjahr, Julia C.; Greil, Richard; Concha, Miguel L.; Müller-Tidow, Carsten; Hartmann, Tanja N. & Orian-Rousseau, Véronique
