Leukemia Program Project Summary / Abstract The mission of the Leukemia Program is to improve patient outcomes through innovative translational research on acute and chronic leukemias, myelodysplastic syndromes, myeloproliferative neoplasms, and antecedent premalignant states. Our longstanding objectives are to (a) discover cell-intrinsic and microenvironmental drivers of these conditions, and (b) translate laboratory discoveries into investigator-initiated early-phase clinical trials. To develop novel therapeutics, Program members leverage effective and fruitful collaborations between leukemia biologists, chemists, immunologists, and clinicians. These interactions depend critically on the Cancer Center’s collaborative infrastructure, shared resources, outstanding systems for clinical trial review and conduct, and the deep culture of bench-to-bedside investigation across the consortium. Community outreach and training in cancer research are deeply embedded in the Program’s laboratory, translational, and clinical efforts. The Program’s 89 members (69 primary and 20 secondary) represent six DF/HCC institutions and 10 academic departments. In 2019, peer-reviewed grant funding attributed to the Program was $8.9 million in direct costs from the NCI and $8.3 million from other sponsors. During the current funding period, primary Program members published 1,129 cancer-relevant papers. Of these, 27% were inter-institutional, 26% were intra-programmatic, and 41% were inter-programmatic collaborations between two or more DF/HCC members. For the next CCSG funding period, we propose the following two Specific Aims: 1) Identify novel mechanisms that contribute to the pathogenesis of acute leukemias, myelodysplastic syndromes, myeloproliferative neoplasms and premalignant states, and 2) Advance therapeutics that target vulnerabilities in these diseases.