ZAP70 expression enhances chemokine-driven chronic lymphocytic leukemia cell migration and arrest by valency regulation of integrins

What is it about?

B cell chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia. A hallmark of the pathophysiology of CLL is that blood circulating leukemia cells are mainly in a cell cycle arrested phase, whereas CLL cells within lymph nodes are proliferating and hence promote disease progression. Notably, the non-receptor tyrosine kinase ZAP70 is primarily expressed in the aggressive form of CLL carrying unmutated IgVH genes, which also express high levels of the integrin VLA-4. In the present study, we describe novel molecular insights in CLL dissemination. We identify a critical role of ZAP70 in chemokine driven human CLL cell migration and inside-out signaling to integrins. We found that ZAP70-positive CLL cells migrated significantly better towards ligands of the lymph node homing chemokine receptors CCR7 and CXCR4. Moreover, ZAP70 expressing CLL cells adhered more efficiently to integrin ligands. Mechanistically, we discovered that ZAP70 expression controls chemokine driven clustering of the integrins VLA-4 and LFA-1 on CLL. Consequently, ZAP70-expressing CLL cells arrested on immobilized integrin ligands or endothelial cells in a chemokine dependent manner. Hence, we describe a novel mechanism how ZAP70 controls chemokine driven valency regulation of integrins and arrest of CLL cells on endothelial cells. As this process is central for homing to lymph organs, we think that our study represents an important advance in understanding the molecular mechanism of increased ZAP70-positive CLL homing and disease progression.

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