Mouse Models for Acute Myeloid Leukemia
Patients with myelodysplastic syndrome (MDS) are at increased risk of developing acute myeloid leukemia (AML). Little is known about the cellular and molecular events that underlie this association. We propose to develop a robust animal model for the human disease that will be invaluable in defining these events and for identifying potential therapeutic targets to interrupt disease progression from MDS to AML. Animal models have been previously difficult to generate because the MDS patient bone marrow cells fail to grow when engrafted in earlier models of mice lacking an immune system, the standard method of generating mouse models of human cancer.
To overcome this problem we will use novel strains of "NSG" mice that we have developed that are uniquely able to accept and sustain engrafted human bone marrow cells and human leukemias. We will accomplish this goal in two aims. The first aim will focus on genetically optimizing the NSG mice and the methods of MDS cell engraftment into the mice so that the MDS cells grow and progress to AML. The second aim will analyze changes in gene expression that signal the progression of MDS bone marrow cells to AML allowing us to identify the cells that initiate AML. This model will provide novel insights into the development of AML in patients with MDS, lead to the identification of new therapeutic targets, and permit the testing of novel therapeutics for halting the progression of MDS to AML without putting patients at risk.
We propose to develop a new paradigm for the in vivo study of the progression of human MDS to AML using technology not previously available. We will use the novel immunodeficient NSG mouse strains we developed which transgenically expresses human growth factors critical for the engraftment and function of human HSC and human AML. These "next generation" humanized mice will provide a new in vivo platform for study of this disease without putting patients at risk. We will also investigate the genomic changes that accompany transition from MDS to AML using state of the art sequencing technology and bioinformatic expertise available at The Jackson Laboratory.
Our study will be the first to characterize the molecular events that occur during the transition of MDS to AML. The project proposed here represents a close collaboration between our basic science laboratory that has expertise in cancer models of humanized mice, experts in bioinformatic analyses of genome scale data, long standing (>30 years) collaborators at the University of Massachusetts Medical School, and clinical oncologists at Eastern Maine Medical Center and Weill-Cornell Medical College. The team encompassing expertise assembled to address this problem is innovative, and exemplifies the "team science" approach required for understanding and developing new approaches to prevent and cure this disease.