Core B

PROJECT SUMMARY Acute Myeloid Leukemia (AML) is a heterogeneous disease, with subtypes defined by a range of clinical, morphological, cytogenetic, and molecular characteristics. This Core provides the projects with the resources to study the human disease in various sub-types, allowing investigators to examine metabolic differences and varying sensitivity to anti-leukemic agents. Specific Aims: Aim 1) Expand, maintain, and characterize leukemia tissue banks at PSCI, UVA, and MSKCC. Banks provide cell samples from a broad variety of AMLs and normal controls. Samples cryopreserved in many aliquots allow repeated interrogation. Cases are categorized according to clinical data and genotyping. Core B will develop long-term culture propagation of primary hAML stem cells for programmatic assays. Aim 2) Assess the safety and the maximum tolerated dose (MTD) and pharmacokinetics (PK) of agents in vivo. Animal models for preclinical toxicity (dose escalation, MTD), and pharmacokinetics assessment are in place at PSCI. Results from this Aim are critical for the development of Program therapeutics. Aim 3) Develop and maintain animal models for testing Program-derived therapies. Our published studies demonstrate promising data in a number of such models. Aim 3A. Provide NRGS (NOD- Rag1null IL2rg null) cell line xenograft models for therapeutic studies (performed at PSCI). Transplantable luciferase labeled AML cell lines grown as NRGS xenografts yield in vivo tumor monitoring and rapid readout of efficacy (PSCI). Core B will provide and extend Standard of Care Models to compare to Program therapeutics. Aim 3B. Provide transplantable, genetically engineered mouse models (GEMMs) of AML to test novel therapeutics (performed at MSKCC and PSCI). Aim 3C. NRGS engraftment with Patient-Derived Xenografts (PDXs) for confirmation and extension of data from other models (performed at PSCI and MSKCC). This Core has developed an innovative technique for retroviral labeling primary AML which seems likely to expedite and expand the efficiency of study of PDXs greatly. These various services provided to all projects are essential to the success of the program.