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

¹Laboratory for Immunological and Molecular Cancer Research, Third Medical Department, Salzburg University Hospital, Salzburg, Austria; ²Department of Immunology, Weizmann Institute of Science; ³Hematology Institute, Kaplan Medical Center, Rehovot, Israel; ⁴Department of Internal Medicine, Freiburg University Clinic, Freiburg, Germany; and ⁵Biogen Idec, Inc., Cambridge, Massachusetts

^* To whom correspondence should be addressed. E-mail: t.hartmann{at}salk.at.

	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 2 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. [Cancer Res 2009;69(7):OF1–10]

Key Words: Integrins, adhesion, trafficking, homing, shear flow