EphrinA4 plays a critical role in α4 and αL mediated survival of human CLL cells during extravasation
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Miguel A. Flores1,3,*, Paula Fortea1,3,*, Eva M. Trinidad4, Dolores García2, Gloria Soler2, Francisco J. Ortuño2, Agustín G. Zapata1,3, Luis M. Alonso-Colmenar1,3
1Cytometry and Fluorescence Microscopy Research Center, Universidad Complutense de Madrid, 28040 Madrid, Spain
2Hematology and Medical Oncology Department, HGU Morales Meseguer, Marqués de los Velez, 30008 Murcia, Spain
3Department of Cell Biology, Faculty of Biology, Universidad Complutense de Madrid, José Antonio Nováis, 2, 28040 Madrid, Spain
4Transformation and Metastasis Group, Cancer Epigenetic and Molecular Biology Program (PEBC), IDIBELL, 08908 Barcelona, Spain
*These authors have contributed equally to this work
Luis M. Alonso-Colmenar, email: [email protected]
Keywords: leukemia, extravasation, apoptosis, integrin, ephrin
Received: March 04, 2016 Accepted: June 08, 2016 Published: June 27, 2016
A role of endothelial cells in the survival of CLL cells during extravasation is presently unknown. Herein we show that CLL cells but not normal B cells can receive apoptotic signals through physical contact with TNF-α activated endothelium impairing survival in transendothelial migration (TEM) assays. In addition, the CLL cells of patients having lymphadenopathy (LApos) show a survival advantage during TEM that can be linked to increased expression of α4 and αL integrin chains. Within this context, ephrinA4 expressed on the surface of CLL cells sequestrates integrins and inactivates them resulting in reduced adhesion and inhibition of apoptotic/survival signals through them. In agreement, ephrinA4 silencing resulted in increased survival of CLL cells of LApos patients but not LA neg patients. Similarly was observed when a soluble ephrinA4 isoform was added to TEM assays strongly suggesting that accumulation of this isoform in the serum of LApos patients could contribute to CLL cells dissemination and survival in vivo. In supporting, CLL lymphadenopathies showed a preferential accumulation of apoptotic CLL cells around high endothelial venules lacking ephrinA4. Moreover, soluble ephrinA4 isolated from sera of patients increased the number and viability of CLL cells recovered from the lymph nodes of adoptively transferred mice. Finally, we present evidence suggesting that soluble ephrinA4 mediated survival during TEM could enhance a transcellular TEM route of the CLL cells. Together these findings point to an important role of ephrinA4 in the nodal dissemination of CLL cells governing extravasation and survival.
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