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Circulating B-cell chronic lymphocytic leukemia cells display impaired migration to lymph nodes and bone marrow.

Hartmann, Tanja Nicole, Grabovsky, Valentin, Wang, Wei, Desch, Petra, Rubenzer, Gabriele, Wollner, Stefan, Binsky, Inbal, Vallon-Eberhard, Alexandra, Sapoznikov, Anita, Burger, Meike, Shachar, Idit, Haran, Michal, Honczarenko, Marek, Greil, Richard, Alon, Ronen·2009·Cancer Research
DOI 10.1158/0008-5472.can-08-4136

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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 β2 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):OF3121–30]

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Metadata

Authors
Hartmann, T. N., Grabovsky, V., Wang, W., Desch, P., Rubenzer, G., Wollner, S., Binsky, I., Vallon-Eberhard, A., Sapoznikov, A., Burger, M., Shachar, I., Haran, M., Honczarenko, M., Greil, R., & Alon, R.
Affiliations
  • 1Laboratory for Immunological and Molecular Cancer Research, Third Medical Department, Salzburg University Hospital, Salzburg, Austria;
  • 2Department of Immunology, Weizmann Institute of Science;
  • 4Department of Internal Medicine, Freiburg University Clinic, Freiburg, Germany; and
  • 3Hematology Institute, Kaplan Medical Center, Rehovot, Israel;
  • 5Biogen Idec, Inc., Cambridge, Massachusetts
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2009-04-01
Volume
69
Issue
7
Pages
3121-3130
ISSN
  • 0008-5472
  • 1538-7445
DOI
10.1158/0008-5472.can-08-4136
Cited by
75
References
1
Language
en

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