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EphrinA4 plays a critical role in α4 and αL mediated survival ofhuman CLL cells during extravasation

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Flores, Miguel A. and Fortea Gordo, Paula and Trinidad, Eva M. and García, Dolores and Soler, Gloria and Ortuño, Francisco J. and Zapata González, Agustín and Alonso Colmenar, Luis Miguel (2016) EphrinA4 plays a critical role in α4 and αL mediated survival ofhuman CLL cells during extravasation. Oncotarget, 7 (30). pp. 48481-48500. ISSN 1949-2553

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Official URL: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5b%5d=10311



Abstract

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.


Item Type:Article
Uncontrolled Keywords:Leukemia, Extravasation, Apoptosis, integrin, Ephrin
Subjects:Medical sciences > Medicine > Hematology
Medical sciences > Medicine > Immunology
Medical sciences > Biology > Cytology
ID Code:41276
Deposited On:13 Feb 2017 16:19
Last Modified:14 Feb 2017 09:22

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