title: 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 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.
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, Third Medical Department, Salzburg University Hospital, Salzburg, Austria. t.hartmann@salk.at
authors.forename: Tanja Nicole
authors.initials: TN
authors.lastname: Hartmann
authors.forename: Valentin
authors.initials: V
authors.lastname: Grabovsky
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Petra
authors.initials: P
authors.lastname: Desch
authors.forename: Gabriele
authors.initials: G
authors.lastname: Rubenzer
authors.forename: Stefan
authors.initials: S
authors.lastname: Wollner
authors.forename: Inbal
authors.initials: I
authors.lastname: Binsky
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vallon-Eberhard
authors.forename: Anita
authors.initials: A
authors.lastname: Sapoznikov
authors.forename: Meike
authors.initials: M
authors.lastname: Burger
authors.forename: Idit
authors.initials: I
authors.lastname: Shachar
authors.forename: Michal
authors.initials: M
authors.lastname: Haran
authors.forename: Marek
authors.initials: M
authors.lastname: Honczarenko
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement / Q000276:immunology*; D018925:Chemokines / Q000276:immunology; D042783:Endothelial Cells / Q000276:immunology / Q000473:pathology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000276:immunology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000276:immunology* / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009360:Neoplastic Cells, Circulating / Q000276:immunology* / Q000473:pathology; D013154:Spleen / Q000276:immunology
chemical_list: D018925:Chemokines; D039041:Integrin alpha4beta1; D016169:Lymphocyte Function-Associated Antigen-1