ABSTRACT The mission of the Biospecimen/Pathology Core will be to assist investigators with the development of preclinical models that accurately reflect the genomic landscape of human acute myeloid leukemia (AML), and their use in preclinical efficacy studies. The Core will play a central role in annotating, distributing, and tracking biospecimens from AML patients enrolled in biospecimen banking and therapeutic research protocols. Detailed biospecimen annotation, including documentation of pre-analytic processing variables, pathology findings, and patient clinical history will be recorded in robust relational databases. The Core will be composed of two highly integrated units: The Tissue Collection and PDX Modeling Unit will be responsible for providing access to human tissues and PDX models. The Mouse Hospital Unit will provide an integrated infrastructure to support pre- and co-clinical trials exploring efficacy of single agent and/or combinatorial treatments in relevant models using standardized protocols that mimic those used in patients. The MSK Mouse Hospital houses the only academic GLP-compliant facility in the region, providing investigators with the unique opportunity to perform GLP-compliant, IND-enabling safety toxicology studies for novel compounds and biologics in-house. The specific aims of the core are: Aim 1. To maintain and expand a model AML resource designed to annotate and distribute biospecimens for translational AML research. Aim 2: To assist in the generation of AML PDX models and access to human tissues banked at MSK along with their clinical and genomic annotation. Aim 3: To design and execute toxicity and therapeutic studies exploring tolerability and efficacy of single agent and combination therapies against xenograft, primary transplant, and genetically engineered mouse leukemia models (GEMMs). Each of the research projects relies extensively on the Biospecimen/Pathology Core to achieve their translational research objectives. For RP 1, the core will help with delineating molecular predictors of sensitivity and resistance to IDH inhibitors, and testing novel combination therapeutic approaches to increase therapeutic efficacy in IDH1/2-mutant AML. For RP 2, the core will provide materials for complex karyotype (CK) AML genetic studies, aid in the generation of models that accurately recapitulate CK AML-specific features, and use these models to test the tolerability and efficacy of novel OGDH inhibitors. For RP 3, the core will help with co-clinical trials of PRMT5 inhibitors in PDX models and help perform preclinical in vivo studies of PRMT and other splicing inhibitors. For RP 4, the Core will support the group in establishing PDX models of AML to test the efficacy of autologous CD371-targeted IL18-secreting CAR T cells.