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

Abstract

Erythropoietin-producing hepatocellular carcinoma receptors (EPHs) represent the largest family of receptor tyrosine kinases (RTKs). EPH interaction with ephrins, their membrane-bound ligands, holds a pivotal role in embryonic development, while, though less active, it is also implicated in various physiological functions during adult life. In normal hematopoiesis, different patterns of EPH/ephrin expression have been correlated with hematopoietic stem cell (HSC) maintenance and lineage-committed hematopoietic progenitor cell (HPC) differentiation, as well as with the functional properties of their mature offspring. Research in the field of hematologic malignancies has unveiled a rather complex involvement of the EPH/ephrinsignaling pathway in the pathophysiology of these neoplasms. Aberrations in genetic, epigenetic, and protein levels have been identified as possible players implicated both in tumor progression and suppression, while correlations have also been highlighted regarding prognosis and response to treatment. Initial efforts to therapeutically target the EPH/ephrin axis have been undertaken in the setting of hematologic neoplasia but are mainly confined to the preclinical level. To this end, deciphering the complexity of this signaling pathway both in normal and malignant hematopoiesis is necessary.

Association of the rs1966265 and rs351855 FGFR4 Variants with Colorectal Cancer in a Mexican Population and Their Analysis In Silico

“…The EFNA4 gene encodes the protein epinephrine 4, which belongs to the epinephrine family of transmembrane proteins. Together with their receptors, these proteins act in the nervous system and during erythropoiesis, as well as in the proliferation and metastasis of various types of cancer through different signaling pathways [ 51 ]. The SLC3A2 (solute carrier family 3 member 2) gene encodes a transporter protein that is involved in the regulation of intracellular calcium levels and transports amino acids (e.g., leucine and glutamine) that are essential for metabolic activation and cellular function as facilitators of plasma membrane transport.…”

The Clinical Relevance of the EPH/Ephrin Signaling Pathway in Pediatric Solid and Hematologic Malignancies

“…Subsequent findings have reported its role in erythroid and monocyte differentiation, as well as B-cell maturation [129]. However, the exploration of EPH/ephrin signaling in the oncogenesis of the pediatric hematopoietic system remains limited, with existing data predominantly focusing on leukemia [129]. In this section, we will outline the reported role of EPH/ephrins in pediatric hematologic malignancies, primarily focusing on T-cell ALL (T-ALL), which presents relapse in most pediatric patients, despite the use of chemotherapeutic agents, novel agents targeting lymphocyte signaling pathways (i.e., Notch1, JAK, and BCL2 inhibitors), steroids, and allogeneic stem cell transplantation [130].…”

“…The pioneering identification of EPHB4's involvement in hematopoietic processes, specifically myeloid differentiation, marked the initiation of understanding the implication of EPH/ephrin signaling in the context of hematopoiesis [128]. Subsequent findings have reported its role in erythroid and monocyte differentiation, as well as B-cell maturation [129]. However, the exploration of EPH/ephrin signaling in the oncogenesis of the pediatric hematopoietic system remains limited, with existing data predominantly focusing on leukemia [129].…”

“…Thymic T-cell development [129] T-ALL High-level expression associated with sensitivity to chemotherapy [132] EPHB6-mediated preservation of Akt signaling increases chemosensitivity [132] Doxorubicin [132] High-level expression [133] Chemotherapy resistance via enhancement of self-proliferation processes (increased CCNB1 and KIF20A) [133] ephrin-B1…”