Human acute myelogenous leukemia (AML) is highly heterogeneous and, as demonstrated by this group, exhibits significant variability in sphingoiipid metabolism. Current therapy of AML is highly toxic, yielding ultimately inadequate outcomes for the vast majority of patients. Cell lines are limited in their representation of primary AML subtypes and manifest clonal evolution in culture, suggesting limitations in their relationship to the primary case material. The systematic study of these diseases thus requires access to primary samples representing a substantial pool of cases, and correlation of these samples to clinical data including treatment outcomes. Animal models of various kinds are available, but models representing direct leukemogenesis via expression of relevant oncogenic proteins and immunodeficient xenografts propagating primary AML, provide relevant platforms for studying developing therapies. In this Core, materials and models will be provided to each Project to allow completion of proposed objectives. The following specific aims will be pursued:
Specific Aim 1 : Expand and maintain the PSHCI leukemia cell bank to provide programmatic access to cell and plasma samples from a broad variety of AML patients and normal hematopoietic controls. Samples will be cryopreserved in multiple aliquots to allow repeated interrogation via developing technologies. Clinical data will be collected and available to provide biologically meaningful categorization of AMLs.
Specific Aim 2 : Develop and maintain a menu of animal models in which to test promising program-derived therapies. Two such models are available.
Sub aim 2 A: Xenograft models of primary human leukemia have been developed in N0D/SCID/IL2ry (NSG) murine hosts and used as platforms for testing novel therapies. Multiple lines (originating from multiple AMLs of differing subtypes) will be passaged in NSG animals to provide in vivo validation of therapeutics. Human cord blood will be expanded in NSG mice to provide normal controls for in vivo toxicity studies.
Sub aim 2 B: Murine syngeneic models of AML using retroviral transduction of murine bone marrow cells with fusion protein oncogenes. We have established a MLL-AF9 retroviral transduction model, which develops a stem cell derived leukemia shown to be inhibited by Project-derived therapeutics. This Core is essential to the overall Program, each project of which uses primary, cells and in vivo models as provided here. These materials and testing platforms will allow development of novel therapies for these lethal diseases.

Public Health Relevance

The overall goals of the present project are to study sphingoiipid metabolism in AML, and to design novel sphingolipid-based therapeutics for the treatment of AML. This Core will serve an essential role for all projects by maintaining a repository of human AML samples with defined clinical outcomes, as well as by developing robust murine models to test the efficacy of the project's sphingolipid-based AML therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA171983-04
Application #
9146305
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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