The primary focus of my lab is to understand the molecular mechanisms that govern myeloid blood cancers, with particular emphasis on myeloproliferative neoplasms (MPNs). The long-term vision for my research program is to elucidate molecular dependencies specific to MPN stem cells (MPN-SCs) that can be targeted for therapeutic intervention with the ultimate goal of eradicating MPN-SCs, sparing normal HSCs, and curing the disease. The focus of my research program during the first five years of my independent career was to identify differential molecular dependencies in type 1 versus type 2 calreticulin (CALR) mutated MPNs. As a postdoctoral fellow, I identified the shared gain-of-function mechanism by which both type 1 and type 2 mutant CALR proteins transform cells to drive disease. This work served as a foundation to subsequently understand how these two mutation types differ in their disease driving mechanisms. To this end, we identified the unfolded protein response (UPR) as differentially exploited by type 1 and type 2 CALR mutant cells, and that the UPR arm preferentially activated by each mutation type is dependent on specific losses-of-function (LOFs) engendered by type 1 versus type 2 CALR mutations. We found that type 1 CALR mutations cause loss of calcium (Ca2+) binding function, leading to depletion of ER Ca2+ and activation of and dependency on the IRE1a/XBP1 pathway of the UPR, while type 2 CALR mutations cause loss of chaperone function leading to activation of and dependency on the ATF6 pathway of the UPR. These discoveries led us to investigate how these LOFs affect other cellular processes, and found that loss of Ca2+ binding by type 1 CALR mutations leads to metabolic reprogramming and a dependency on glycolytic metabolism via increased cytosolic and mitochondrial Ca2+, while loss of chaperone function leads to impaired MHC-I processing and dysregulation of natural killer cell-based immune surveillance of type 2 CALR mutant cells. We are currently seeking to understand how these observations affect MPN-SC fitness and cell fate in primary human cell and mouse models, and whether these pathways represent novel therapeutic targets that can eradicate MPN-SCs to cure the disease.