The major goals of Core 3 are to provide the SPORE with the infrastructure and professional expertise needed to develop, validate, and implement molecular biomarker tests on patient samples and xenografted human leukemias. These tests will be used to characterize the response of myeloid neoplasms obtained from patients and preclinical models to targeted therapies being tested in each of the projects. The Core is led by Dr. Jon C. Aster, a senior leukemia investigator and practicing hematopathologist. Tests will be carried out in the Core will include assays that gauge NPM1 and DNMT3A mutational status (Project 1), SYK activation (Project 2), mutational status of genes encoding spliceasome components and SF3B1 inhibition (Project 3), and the expression of immune checkpoint proteins (Project 4). The Core will also perform serial NextGen Sequencing to determine the effect of targeted therapy on clonal dynamics, and develop new tests that assess the sensitivity of tumor cells to apoptosis (BH3 profiling/mitochondrial priming), or that predict and gauge the response of neoplastic cells to SYK inhibitors, Menin/MLL inhibitors, and other targeted therapeutics. The specific aims of the Core are: 1) To use a clinically validated amplicon-based NextGen sequencing test to identify mutations, define clonal heterogeneity, and follow the clonal evolution of myeloid neoplasms during therapy 2) To develop, validate, and implement tests for phospho-SYK, immune checkpoint proteins, lineage- specific host immune cell markers, and other protein biomarkers 3) To develop, validate, and implement RNA profiling-based tests that identify signatures of effective targeting of leukemogenic signaling pathways with novel therapeutic agents, including spliceasome inhibitors, and Menin/MLL inhibitors 4) To develop, validate, and implement a BH3 profiling/mitochondrial priming assay to predict the response of myeloid neoplasms to targeted therapeutics