While much has been learned about the genetic origins of the myelodysplastic syndromes (MDS), relatively little is known about the factors that determine responses to one of the mainstays of MDS therapy –the hypomethylating agents (HMAs) – and it remains extremely difficult to predict which patients will respond to HMA therapy. Since response rates are modest and all MDS patients will eventually become refractory to HMA therapy, it is extremely important to better understand how these agents work in order to develop more effective therapeutic strategies. Our studies have identified hypoxia-inducible factor 1 alpha (HIF1a) as a critical regulator of HMA therapy resistance. We have investigated how HIF1a induces therapy resistance, and worked to identify the best HIF1a inhibitors to use in combination with HMAs to treat MDS patients. In the past year we have made significant progress with respect to these goals. In addition to identifying a list of candidate genes responsible for the effects of HIF1a, we have shown that MDS and AML patient cells are more sensitive to the combination of HMA and HIF1a inhibitor treatment than either alone. In addition, we have shown generated data indicating that in contrast to conventional thinking, the two major types of HMAs used to treat MDS patients work via unique molecular mechanisms. We also have generated data that the combination of HMAs with HIF1a inhibitors show promise as a therapeutic strategy based on their ability to eliminate leukemia cells in mice transplanted with human cells. Overall, these studies shed light on how HMA therapies induce their effects and demonstrate that HIF1a inhibition in combination with HMA therapy may be a viable and improved therapeutic strategy to treat MDS patients.