PROJECT SUMMARY

Myelodysplastic syndrome (MDS) is a lethal hematopoietic malignancy. Peripheral blood cytopenias resulting from progressive bone marrow failure are a major manifestation of MDS and are predictive of poor prognosis (1-3). Clinically, curative therapeutic options for MDS are limited and even in the treatment of anemia in MDS. Only ~20% of MDS patients benefit from standard erythropoietin treatment, and many of the initial responders do not have long-term response (2, 3). One of the major progresses in MDS treatment in recent years is the development of lenalidomide as a new drug to specifically treat a subgroup of MDS patients with chromosome 5q deletion, which only counts for ~5% of total MDS population (4, 5). The only option for patients who do not respond to erythropoietin and lenalidomide is red blood cell (RBC) transfusion, but the problem is that transfusion exposes patients to insufficient correction of anemia, alloimmunization, and organ failure secondary to iron overload (6-9). Therefore, there is an unmet and urgent demand for patients and clinicians to have novel therapeutics to treat these refractory MDS (10).

The proposed project focuses on small molecular drugs and provides solution to treatment refractory MDS through boosting the expansion and differentiation of the therapeutically important hematopoietic progenitor cell type, the early erythroid progenitor, whose insufficiency contributes to resistance of MDS patients to current therapies. Early erythroid progenitor cell levels predict responsiveness of MDS patients to erythropoietin treatment. MDS patients with early erythroid progenitor numbers similar to normal individuals respond to erythropoietin, while patients with inadequate early erythroid progenitor fail to respond. My laboratory has recently established novel cell sorting protocols to purify early erythroid progenitor, allowing us to identify drug targets and small chemical compounds that boost their expansion and differentiation.

We have employed a combined chemical and CRISPR/Cas genomic approaches and identified a G protein-coupled receptor (GPCR) as an effective drug target. We have demonstrated that injection of GPCR antagonists completely corrects anemia of MDS with sustainable and longterm efficacy in genetically engineered MDS mouse model, the conditional knock-in Cre-Mx1 Srsf2 P95H/WT MDS model that faithfully recapitulates essential features of human MDS. To reduce potential side effects of GPCR antagonists, we performed medicinal chemistry modifications to reduce their distribution in brain tissues. We further tested therapeutic efficacy and performed drug pharmacology and toxicology studies on these new derivatives. The proposed small chemical drugs target MDS patients who do not respond to erythropoietin and lenalidomide and who lose their initial responses to become refractory. The drug will significantly improve current treatments of MDS, and the preclinical long-term efficacies strongly support these expected benefits.