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

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.

Role of LFA-1 and ICAM-1 in Cancer

“…Moreover, signaling by Rac1 and CDC42 GTPases which activates LFA-1 shows extensive degrees of alteration in CLL patients, so that some authors suggest that progression to CLL requires these GTPases to be bypassed [ 63 ]. Defective LFA-1-dependent endothelial transmigration could play a role in the survival of CLL cells [ 64 ]. Despite the necessity of B-CLL cells to home in on lymph nodes and bone marrow, it is not uncommon to observe a lower CD18 expression in B-CLL than in normal B cells in healthy individuals [ 60 ].…”

EPH/Ephrin Signaling in Normal Hematopoiesis and Hematologic Malignancies: Deciphering Their Intricate Role and Unraveling Possible New Therapeutic Targets

“…Additionally, soluble ephrinA4 isolated from the sera of patients led to an increase in the number and viability of CLL cells recovered from the LNs of adoptively transferred mice. Overall, these results indicate that ephrinA4-mediated survival during TEM could enhance the transcellular TEM route of the CLL cells [167].…”

Role of LFA-1 and ICAM-1 in Cancer

“…Moreover, signaling by Rac1 and CDC42 GTPases to activate LFA-1 shows extensive degrees of alteration in CLL patients, so that some authors suggested that progression to CLL requires bypassing these GTPases [38]. The defective LFA1-dependent endothelial transmigration could play a role in survival of CLL cells [39]. Despite the necessity of CLL B cells to home to lymph nodes and bone marrow, it is not uncommon to observe a lower CD18 expression in B-CLL than that of normal B cells in healthy individuals [35].…”