RT Journal Article T1 EphrinA4 plays a critical role in α4 and αL mediated survival ofhuman CLL cells during extravasation A1 Flores, Miguel A. A1 Fortea Gordo, Paula A1 Trinidad, Eva M. A1 García, Dolores A1 Soler, Gloria A1 Ortuño, Francisco J. A1 Zapata González, Agustín A1 Alonso Colmenar, Luis Miguel AB 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. PB Impact journals SN 1949-2553 YR 2016 FD 2016-06 LK https://hdl.handle.net/20.500.14352/23128 UL https://hdl.handle.net/20.500.14352/23128 LA eng NO Ministerio de Economía y Competitividad (MINECO) NO Fundación Científica Eugenio Rodríguez Pascua (España) NO Asociación Española Contra el Cancer NO British Council School DS Docta Complutense RD 10 abr 2025