Circulating B-cell chronic lymphocytic leukemia cells display impaired migration to lymph nodes due to reduced LFA-1 expression

Homing to secondary lymphoid organs and re-entry to bone marrow (BM) are central aspects of leukemic pathophysiology. We investigated the roles of the two major lymphocyte integrins LFA-1 and VLA-4 on B-cell chronic lymphocytic leukaemia (CLL) cells in these processes. We found that CLL cells expressed significantly reduced LFA-1 due to low beta2 integrin transcripts and displayed diminished adhesiveness to ICAM-1-expressing endothelium in vitro. VLA-4 expression was heterogenous but underwent rapid activation by the BM chemokine CXCL12. Nevertheless, CLL cells failed to transmigrate across VCAM-1, ICAM-1 and CXCL12 expressing endothelium due to their deficient LFA-1 expression. Furthermore, when injected into tail veins of immunodeficient mice, normal B cells rapidly homed to lymph nodes (LNs) in a LFA-1 dependent manner whereas CLL cells did not. CLL alike normal B lymphocytes used VLA-4 rather than LFA-1 to reenter the BM. In contrast, both normal and CLL B cells homed to mice spleen in an LFA-1- and VLA-4-independent manner. Our results suggest that CLL cells are deficient in LFA-1-dependent trafficking to LNs but residual subsets can still re-enter the BM. Integrin blocking could be therefore an efficient strategy to prevent circulating CLL cells from reaching prosurvival niches in LNs and BM and directing these cells to the spleen.