Erythropoietin Enriches Specific iNOS Producing Myeloid Cells within the Spleen Tumor Microenvironment Capable of Inhibiting Leukemogenesis

It is well established that the tumor microenvironment plays a critical role in the induction and progression of hemopoietic malignancies. We have previously demonstrated that the spleen provides a “tumor-promoting niche” that supports leukemic growth. Specific treatments, such as cytokine therapy and genetic manipulation, can lead to dramatic changes in the splenic microenvironment and reverse a tumor-promoting outcome to an inhibitory effect. For example, we were first to demonstrate that two-fold overexpression of systemic levels VEGF levels in mice heterozygous for a VEGF-A hypermorphic allele, markedly decelerates the progression of Friend virus-induced leukemia. Moreover, in a unique mouse model of familiar polycythemia, in which erythropoietin is constitutively activated, we have identified the abnormal expansion of unique hematopoietic progenitors capable of leukemia inhibition through the secretion of iNOS and additional factors. These results implicate the tumor microenvironment as a pivotal factor in the control of cancer growth and progression. In a recent study, we have shown that treatment of normal mice with Epo resulted in a polycytemic phenotype associated with enrichment of iNOS-producing myeloid cells. Moreover, treatment of leukemic mice with Epo delayed cancer progression associated with enrichment of specific c-Kit-/ Sca1+ myeloid cells within the spleen, expressing high levels of iNOS. Further characterization suggested that these cells may be identical to the previously identified Myeloid derived, suppressor M1 macrophages cells with potent tumor inhibitory activity. Overall, this study demonstrates for the first time that Epo can enrich specific myeloid suppressor cells capable of inhibiting cancer progression. Thus, Epo could be a candidate for microenvironmental therapy of leukemia as well as other cancers.