Expression profile of Eph receptors and ephrin ligands in healthy human B lymphocytes and chronic lymphocytic leukemia B-cells

Alonso-C, Luis M; Trinidad, Eva M.; Garcillán, Beatriz; Ballesteros, Mónica; Castellanos, Milagros; Cotillo, Ignacio; Múñoz, Juan José; Zapata, A.

doi:10.1016/j.leukres.2008.08.010

Cited by 29 publications

(25 citation statements)

References 34 publications

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“…As determined by flow cytometry, ephrinA4 expression was significantly higher in LAneg than LApos samples (Figure 3A-i) while no significant differences were found according to ZAP-70, IGVH or CD38 parameters (Figure 3A-i) confirming its association with the LA condition of patients previously found by us [16, 18]. Remarkably, ephrinA4 expression levels were low in most trisomy 12 (tris12) cases (4 out of 5) and, to a lower extent, del11q positive samples (3 out of 4) (Figure 3A-i) which could be in concert with the increased risk to suffer lymphadenopathy in these patients.…”

Section: Resultssupporting

confidence: 77%

“…We showed that this can be in part linked to overexpression of ephrinA4, a GPI-membrane-linked ligand of the Eph receptor family of tyrosine kinases which is found as a membrane bound and a soluble isoforms in CLL and normal B cells [17, 18]. Reverse signaling through the cell surface expressed isoform inhibits integrin mediated adhesions of CLL cells to endothelium through binding to EphA2 receptor on the surface of endothelial cells [16, 19] likely impairing extravasation.…”

Section: Introductionmentioning

confidence: 99%

“…This process could be coupled to enhanced diapedesis through sequestration and internalization of ICAM-1 and VCAM-1 [16] rather than through increased vascular permeability of the altered endothelial junctions found after ephrinA1 treatment [20]. Moreover patients having lymphadenopathy show increased serum levels of ephrinA4 in addition to decreased expression of ephrinA4 on the surface of CLL cells [18]. Together these findings pointed to soluble isoform as a likely mechanism contributing to nodal dissemination of CLL cells which needed further confirmation in a more physiological in vivo setting [21–23].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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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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Section: Resultssupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…Both HUVEC and B cells can express other Eph/ephrin members that bind to the corresponding recombinant homodimer such as EphA4, in the case of TNF-a activated HUVECs, 24 and several EFNA ligands, in the case of CLL or normal B cells. 31 Binding assays demonstrated signaling) and the EFN-expressing cells (reverse signaling) [21][22][23] and the occurrence of cell and non-cell autonomous roles. 20 …”

Section: Disclosing Epha2-efna4 Bidirectional Signaling Within the Momentioning

confidence: 99%

“…24 Co-expression of receptors and ligands within the same cell and/or cell subpopulation should be taken into consideration. Thus, the differential expression of some members within a given cell population, mainly B-cell subpopulations, 31 could have side effects in the overall population response. Co-expression of different Eph/EFN members is commonly observed and some of them have been referred as a mechanism of regulation of Eph/EFNs signaling.…”

Section: Contextualizing Epha2-efna4 Interactions As Possible Guidingmentioning

confidence: 99%

Eph-ephrin bidirectional signaling comes into the context of lymphocyte transendothelial migration

Trinidad

Zapata

Alonso-Colmenar

2010

Cell Adhesion & Migration

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A better knowledge of the molecular mechanisms that govern leukocyte trafficking is of major relevance for the clinics. Both normal and pathologic extravasation of lymphocytes are a fine-tuned spatio-temporal event of migratory path-finding, likely regulated by molecular guidance cues underlying cell movements in other systems. We have recently reported that members of the Eph family of receptor tyrosine kinases, namely EphA2 and one of its ligands, ephrin-A4 (EFNA4) can mediate in the traffic of chronic lymphocytic leukemia (CLL) cells and presumably of normal B cells between the blood and the tissues. The importance of EphA2-EFNA4 interactions at the endotheliumlymphocyte interface during TEM could rely on their attractive/repulsive properties. In the present work, we expand on those results by including additional insights and new suggestions for future studies that discuss the relevance of these molecules in overall cell adhesion dynamic events.

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EphB4 Expressing Stromal Cells Exhibit an Enhanced Capacity for Hematopoietic Stem Cell Maintenance

et al. 2015

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The tyrosine kinase receptor, EphB4, mediates cross-talk between stromal and hematopoietic populations during bone remodeling, fracture repair and arthritis, through its interactions with the ligand, ephrin-B2. This study demonstrated that transgenic EphB4 mice (EphB4 Tg), overexpressing EphB4 under the control of collagen type-1 promoter, exhibited higher frequencies of osteogenic cells and hematopoietic stem/progenitor cells (HSC), correlating with a higher frequency of long-term culture-initiating cells (LTC-IC), compared with wild type (WT) mice. EphB4 Tg stromal feeder layers displayed a greater capacity to support LTC-IC in vitro, where blocking EphB4/ephrin-B2 interactions decreased LTC-IC output. Similarly, short hairpin RNA-mediated EphB4 knockdown in human bone marrow stromal cells reduced their ability to support high ephrin-B2 expressing CD34 1 HSC in LTC-IC cultures. Notably, irradiated EphB4 Tg mouse recipients displayed enhanced bone marrow reconstitution capacity and enhanced homing efficiency of transplanted donor hematopoietic stem/progenitor cells relative to WT controls. Studies examining the expression of hematopoietic supportive factors produced by stromal cells indicated that CXCL12, Angiopoietin-1, IL-6, FLT-3 ligand, and osteopontin expression were more highly expressed in EphB4 Tg stromal cells compared with WT controls. These findings indicate that EphB4 facilitates stromal-mediated support of hematopoiesis, and constitute a novel component of the HSC niche. STEM CELLS 2015;33:2838-2849 SIGNIFICANCE STATEMENTThe tyrosine kinase receptor, EphB4, mediates cross-talk between stromal and hematopoietic populations during bone remodelling, fracture repair and arthritis, through its interactions with the ligand, ephrin-B2. The present study demonstrated a functional role for EphB4 in osteogenic cell-mediated support of hematopoiesis and constitute a novel component of the HSC niche for the regulation of blood cell production.

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Expression profile of Eph receptors and ephrin ligands in healthy human B lymphocytes and chronic lymphocytic leukemia B-cells

Cited by 29 publications

References 34 publications

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

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

Eph-ephrin bidirectional signaling comes into the context of lymphocyte transendothelial migration

EphB4 Expressing Stromal Cells Exhibit an Enhanced Capacity for Hematopoietic Stem Cell Maintenance

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