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

SIMPLE SUMMARY: The EPH/ephrin signaling axis holds a pivotal role in a plethora of physiologic processes during embryonic development and adult life, while more recent studies highlight its implication in the pathogenesis of multiple types of solid tumors. Different patterns of EPH/ephrin expression have been identified in normal hematopoiesis concerning the maintenance, differentiation, and function of hematopoietic stem cells and their mature offspring. Emerging data suggest that EPH/ephrin aberrations contribute to the pathogenesis of various hematologic malignancies, exerting both tumor-promoting and tumor-suppressive functions. Thus, unraveling the intricate role of EPH/ephrin signaling in the setting of hematologic neoplasia can contribute to the development of promising therapeutic targets to overcome unmet needs. 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.