Expression and Function of the Eph Receptor Family in Leukemia and Hematopoietic Malignancies: Prospects for Targeted Therapies

Abstract

There has been considerable interest in recent years in the development of therapies, which target Eph receptors or their ephrin ligands. The Eph receptor tyrosine kinases and their membrane bound ephrin ligands are cell surface molecules involved in many biological functions and cell behaviors during embryogenesis and in adult life. However, they are also expressed in an aberrant fashion on many tumors and are re-expressed on normal cells in nonmalignant pathological states. Some of the eph/ephrins including EphA7 and EphA1 protein are thought to function as tumor suppressors in particular cancers. In tumors where Eph/ephrin proteins are expressed at high levels, being expressed on the cell surface these proteins are readily accessible to antibody-mediated therapies several of which are in advanced pre-clinical or early clinical evaluation, including antibodies specific for EphA2, EphA3, and EphB4 which are expressed on many different tumors. We will review the general features of the Eph/ephrin system and discuss the role of this system in normal hematopoiesis before focusing on the role of Eph proteins in leukemia and other hematological malignancies and possible avenues for therapy.of highly conserved tyrosine residues and a PDZ-binding motif. The conserved tyrosine residues have been shown to serve as a docking site for proteins, which mediate downstream ephrin signaling [2,9] Classification, Structure and Binding of Eph/ephrinThe Eph receptors and their membrane bound ephrin ligands represent the largest family of receptor tyrosine kinases (RTK's). The first member, EphA1, was originally termed Eph, as it was first identified in an Erythropoietin-Producing Hepatocellular (Eph Nomenclature committee, 1997) carcinoma cell line [1]. Fourteen members of the Eph family of RTK have been identified in mammals, which are divided into two groups, the EphA and EphB family. This is based on their sequence homology, ligand specificity and structural features. In mammals there are nine members of the EphA subgroup (EphA1-8 and EphA10) and five EphB receptors (EphB1-4 and EphB6) [2,3].Eph receptors are type I transmembrane proteins composed of extracellular region including a ligand binding domain with two distinct ligand-binding interfaces (N terminal β jelly roll domain) determining the ephrin binding, and a cysteine-rich region containing an epidermal growth factor (EGF)-like motif that is involved in receptor dimerization followed by two fibronectin type-III domains [4,5]. The intracellular region comprised of a conserved juxtamembrane domain, a tyrosine kinase domain and a sterile alpha motif (SAM) domain, the latter having a potential role in receptor clustering [6,7]. Most of the Eph receptors, possess a C-terminal PDZ (Postsynaptic density protein, Disc large, Zona occludens tight junction protein) binding motif that is involved in signaling at a sub-cellular level and in the assembly of large molecular complexes [3,5,8] (Figure 1a).The ephrin ligands of Eph receptors are also membrane bound proteins an...

EphA3 as a target for antibody immunotherapy in acute lymphoblastic leukemia

“…Expression of EphA3 in leukemia and the low expression on normal tissues led us to investigate the potential of EphA3 as a therapeutic target in ALL. 27 We showed that EphA3 was expressed in~1/3 of ALL cases and appears to be more significantly expressed in some subgroups, particularly cases having the t(1; 19) translocation. Although only four cases with MLL translocations were tested, taken together with our previous data, 28 it seems unlikely that EphA3 would be expressed in these leukemias as MLL transcriptionally induces expression of other Eph receptors with redundant function.…”

Targeted therapies in hematological malignancies using therapeutic monoclonal antibodies against Eph family receptors

“…Eph receptors acting alone or with ephrin ligands play an important role in many pathological conditions, including cancer, which makes them potential therapeutic targets in a range of diseases [27]. Eph/ ephrin bidirectional signaling affects many important oncogenic pathways, including cell adhesion, invasion, migration, proliferation, and angiogenesis, through activation or inhibition of various signaling networks, including SRC family kinases; RAS/RHO family GTPases; Wnt/β-catenin; focal adhesion kinase (FAK); and the phosphoinositide 3-kinase/AKT (PI3K/ AKT), mitogen-activated protein kinase (MAPK), and vascular endothelial growth factor (VEGF) pathways [27,28].…”

“…The expression of these genes has been implicated in mechanisms, including cell activation, adhesion, migration, and differentiation. Many studies have showed expression of the Eph/ephrin family of proteins on malignant hematopoietic cells [28,29]. Human EphA3 was first identified in a pre-B-ALL cell line and was subsequently shown to be expressed in a proportion of both lymphoid and myeloid leukemias [28][29][30][31][32].…”

“…Many studies have showed expression of the Eph/ephrin family of proteins on malignant hematopoietic cells [28,29]. Human EphA3 was first identified in a pre-B-ALL cell line and was subsequently shown to be expressed in a proportion of both lymphoid and myeloid leukemias [28][29][30][31][32]. EphA3 is the first Eph receptor to have been investigated successfully in clinical trials in hematological cancers [32,33].…”

A high affinity recombinant antibody to the human EphA3 receptor with enhanced ADCC activity

“…EphA3 expression has also been observed in multiple myeloma (De Vos et al, 2001) and can be induced by s-Thalidomide treatment in a myeloma cell line (Liu et al, 2004). Recently, EphA3 has been identified as a gene involved in survival of leukemic stem cells (Ashton et al, 2012) and therefore represents a new therapeutic target for hematologic malignancies (Charmsaz et al, 2013;Keane et al, 2012). Additionally, EphA3 expression in colorectal cancer (Xi, 2011), gastric cancer (Xi, 2012) glioblastoma (Day, 2013) and hepatocellular cancer (Lu et al, 2013) has been shown to correlate with poor prognosis.…”