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

Tanja Nicole Hartmann,Anita Sapoznikov,Idit Shachar,Petra Desch,Alexandra Vallon-Eberhard,Richard Greil,Valentin Grabovsky,Marek Honczarenko,Gabriele Rubenzer,Ronen Alon,Stefan Wollner,Meike Burger,Michal Haran,Wei Wang,Inbal Binsky

doi:10.1158/0008-5472.can-08-4136

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 beta2 integrin transcripts. VLA-4 expression was heterogeneous 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.

Highlights

B-cell chronic lymphocytic leukemia (CLL) is marked by the accumulation of CD5+ B lymphocytes within the blood, bone marrow (BM), and secondary lymphoid tissues but the molecular signals that determine CLL trafficking to these organs are largely unknown
When LFA-1 expression on peripheral blood (PB) CLL cells derived from 105 patients was compared with that on B lymphocytes of 11 healthy age-matched persons, highly significantly reduced LFA-1 expression was observed on CLL cells (Fig. 1A)
Dissecting LFA-1 expression on healthy BM B-cell types, we found lowest LFA-1 levels on pro-B and pre-B cells, comparable with those found in CLL cells, whereas at later maturation stages of normal B lymphocytes LFA-1 expression was very high (Supplementary Fig. S1)

Summary

Introduction

B-cell chronic lymphocytic leukemia (CLL) is marked by the accumulation of CD5+ B lymphocytes within the blood, bone marrow (BM), and secondary lymphoid tissues but the molecular signals that determine CLL trafficking to these organs are largely unknown. Doi:10.1158/0008-5472.CAN-08-4136 hematopoietic cells in the BM and lymphoid organs To enter these organs, circulating cells need to arrest on specific endothelial barriers, to locomote over the endothelial surface toward interendothelial junctions, and to cross these junctions while resisting disruptive shear forces [3, 4]. Both firm adhesion and ability to locomote and transmigrate across endothelial barriers depend on the ability of circulating cells to establish dynamic adhesive interactions through their a4 integrins VLA-4 (a4h1) and a4h7 and the h2 integrins LFA-1 (aLh2) and Mac-1 The integrins undergo reversible activation by endothelial-presented chemokines [6]

Methods

Results

Conclusion