PROJECT SUMMARY

A primary obstacle in the successful treatment of MDS is the resilience of MDS stem cells (MDS-SCs). These cells exhibit profound genetic and molecular heterogeneity, enabling them to evade conventional therapeutic regimens. Several studies including research from our group have uncovered multiple cell surface proteins to prospectively identify MDS-SCs; yet, there is still substantial heterogeneity within these populations. Achieving durable clinical remission necessitates the development of precision strategies specifically designed to identify, understand, and eliminate the MDS-SC reservoir. In this study, I propose to employ heparan sulfate (HS) glycotyping to resolve functional heterogeneity within MDS-SCs. HS glycotypes are essentially extremely diverse molecular signatures of sugars on cell surface. Using a library of specialized antibodies recognizing distinct HS glycotypes, I will investigate the extent of HS glycotype diversity within MDS-SCs and how that facilitates MDS pathogenesis. Using complementary genetic and antibody-based approaches, I will also delineate the functional roles of HS pathways during MDS pathogenesis. These efforts would not only help us understand MDS pathogenesis at a stem cell level but also uncover novel strategies for MDS-SC directed therapies. This work is a blend of discovery science and potential translational application, taking us one step closer to developing treatments that specifically target the roots of MDS.