Circulating B-Cell Chronic Lymphocytic Leukemia Cells Display Impaired Migration to Lymph Nodes and Bone Marrow

Abstract

Homing to secondary lymphoid organs and bone marrow (BM) is a central aspect of leukemic pathophysiology. We investigated the roles of the two major lymphocyte integrins LFA-1 and VLA-4 on B-cell chronic lymphocytic leukemia (CLL) cells in these processes. We found that the majority of CLL cells expressed significantly reduced LFA-1 due to low B2 integrin transcripts. VLA-4 expression was heterogenous but underwent rapid activation by the BM chemokine CXCL12. CLL cells failed to transmigrate across VCAM-1-expressing, ICAM-1-expressing, and CXCL12-expressing endothelium, whereas when LFA-1 expression was regained in subsets of CLL cells, these lymphocytes rapidly transmigrated the endothelium. Furthermore, when injected into tail veins of immunodeficient mice, normal B cells rapidly homed to lymph nodes (LN) in a LFA-1-dependent manner, whereas CLL cells did not. Nevertheless, only residual CLL subsets could reenter BM, whereas both normal and CLL cells homed to the mice spleen in an LFA-1-independent and VLA-4-independent manner. Our results suggest that CLL cells have a reduced capacity to adhere and transmigrate through multiple vascular endothelial beds and poorly home to lymphoid organs other than spleen. Integrin blocking could thus be an efficient strategy to prevent circulating CLL cells from reaching prosurvival niches in LNs and BM but not in spleen.

An impaired transendothelial migration potential of chronic lymphocytic leukemia (CLL) cells can be linked to ephrin-A4 expression

“…5,6,8 Finally, several lines of evidence have suggested that CLL cells could have an altered capacity to migrate into the different tissue compartments. [10][11][12][13] Hence, further work is necessary to unravel the mechanisms of CLL-cell extravasation into tissues through the definition of new molecular players. 14 CLL cells differentially express some members of the Eph receptor tyrosine kinase family, partially correlating with clinical features.…”

Small B-cell lymphomas of the spleen: how to tell them apart

“…This may be related in part to the expression of cell surface adhesion molecules on neoplastic B cells that allow preferential homing to the spleen over other lymphoid organs [19,20]. Although CLL is the most common small B-cell neoplasm to involve the spleen, the degree of splenomegaly may be less than that seen with other B-cell lymphomas [21].…”

Eph-ephrin bidirectional signaling comes into the context of lymphocyte transendothelial migration

“…[49][50][51][52] In accordance with our study, 24 several lines of evidence support the notion that CLL cells have an impaired migration into tissues that can be linked to an adhesion deficiency to HEV. [53][54][55][56][57][58] CLL cells form proliferation centers or "pseudofollicles" within the infiltrated lymphoid tissues that can contribute to their survival and/or expansion 59,60 and also to the enlargement of lymph nodes or clinical lymphadenopathy observed in some patients. 61 A defective egress of the CLL cell population leading to their retention within tissues has also been proposed but not firmly demonstrated.…”