LAUSR

Simple Summary Anticancer nucleoside analogs are promising treatments that often result in damaging toxicities and therefore ineffective treatment. Mechanisms of this are not well-researched, but cellular nucleoside transport research in mice might provide additional insight given transport’s role in mammalian hematopoiesis. Cellular nucleoside transport is a notable component of mammalian hematopoiesis due to how mutations within it relate to hematological abnormities. This review encompasses nucleoside transporters, focusing on their inherent properties, hematopoietic role, and their interplay in nucleoside drug treatment side effects. We then propose potential mechanisms to explain nucleoside transport involvement in blood disorders. Finally, we point out and advocate for future research areas that would improve therapeutic outcomes for patients taking nucleoside analog therapies. Abstract Anticancer nucleoside analogs produce adverse, and at times, dose-limiting hematological toxicities that can compromise treatment efficacy, yet the mechanisms of such toxicities are poorly understood. Recently, cellular nucleoside transport has been implicated in normal blood cell formation with studies from nucleoside transporter-deficient mice providing additional insights into the regulation of mammalian hematopoiesis. Furthermore, several idiopathic human genetic disorders have revealed nucleoside transport as an important component of mammalian hematopoiesis because mutations in individual nucleoside transporter genes are linked to various hematological abnormalities, including anemia. Here, we review recent developments in nucleoside transporters, including their transport characteristics, their role in the regulation of hematopoiesis, and their potential involvement in the occurrence of adverse hematological side effects due to nucleoside drug treatment. Furthermore, we discuss the putative mechanisms by which aberrant nucleoside transport may contribute to hematological abnormalities and identify the knowledge gaps where future research may positively impact treatment outcomes for patients undergoing various nucleoside analog therapies.