CD44-hyaluronan interactions in the pathophysiology of CLL

B-cell chronic lymphocytic leukemia (CLL), the most prevalent leukemia in Western societies, is characterized by the progressive accumulation of CD5+ malignant B lymphocytes within the blood, the bone marrow (BM) and the lymph nodes (LNs). The proliferation and survival of CLL cells is highly dependent on their interactions with the tumor microenvironment. While the peripheral blood pool consists of mainly cell cycle arrested CLL cells, the LNs and to a lesser extent also the BM contain specialized proliferative areas, the so-called pseudofollicles. These areas are interspersed with CD4+ CD40L+ subsets of T lymphocytes suggesting that CLL activation by T cells may support the outgrowth of the malignant clone. The adhesion receptor CD44 participates in lymphocyte cell activation, migration and tissue retention via interaction with the extracellular matrix component hyaluronic acid (HA). CD44-HA interactions have been implicated in a variety of tumors. In CLL, elevated CD44 serum levels and CD44 variant (CD44v) isoform expression have been suggested as markers for disease progression but the although the underlying biological mechanisms remain elusive. This proposal aims to dissect how CD44(v) and HA contribute to the appropriate localization of CLL cells in lymphoid proliferation centers and the physiological consequences arising therefrom, with a particular focus on CD40L-mediated regulation of CD44. By using in vivo short-term adoptive transfer assays of human CLL cells to NOD/SCID mice and in vitro shear flow assays, we will dissect the contribution of CD44-HA interactions in CLL cell homing to lymphoid organs. Second, we will study the impact of CD40L-mediated CLL activation on CD44(v)-mediated adhesion on HA substrates and its consequences on survival and proliferation signaling. Finally, the results will be validated in vivo in a murine CLL model with a conditional CD44 knockout in the malignant B cells. Consequences of this CD44 deletion on leukemic dissemination, tumor cell survival and proliferation and on the development of chemoresistance of the animals will be assessed. Collectively, our data will contribute to a better understanding how the microenvironment induces tumor cell proliferation and chemoresistance in CLL via modulation of adhesive interactions. Therapeutic interference with highly affine CD44(v)-HA interactions may release the tumor cells from their protective niches, prevent their proliferation, and eventually provide strong synergism with conventional therapies.

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