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.

 

 

Organization: 
The Jackson Laboratory
Researcher: 
Leonard Shultz, Ph.D
Grant Amount Given: 
$169,834
Year Issued: 
2014
Period: 
Annual
Grant Category: 
Research
Types of Cancer: 
Cellular
Leukemia
Molecular
Grant Duration: 
2 Year Accelerator Grant

Maine Cancer Foundation Grants to this Organization:

Year Program Amount Category Organization
2014 A Slice of Life: The Search for Variation in Brain Tumors $50,000 Research The Jackson Laboratory
2014 Genetic Testing for Primary Care Providers: Case-based Web Modules $49,220 Education The Jackson Laboratory
2014 A Secondary Syndrome: Acute Myeloid Leukemia $50,000 Research The Jackson Laboratory
2014 Are Micro RNAs the Key to Stopping Lung Cancer? $50,000 Research The Jackson Laboratory
2014 Mouse Models for Acute Myeloid Leukemia $169,834 Research The Jackson Laboratory
2013 Development of Optimized Ex Vivo Organotypic Slice Culture Systems $164,686 Research The Jackson Laboratory
2013 Defining Susceptibility To Transformation By Epigenetic Landscape $49,999 Research The Jackson Laboratory
2013 Assessing Therapeutic Potential of a New Drug ICG-001 in Glioblastoma $50,000 Research The Jackson Laboratory
2013 The Maine Triple-Negative Breast Cancer Study $212,601 Research The Jackson Laboratory
2012 FoxC2 Function in glioma stem cells and Vasculature $84,000 Research The Jackson Laboratory
2012 New Models for Lung Cancer Research $199,036 Research The Jackson Laboratory
2012 Online CME Course $27,600 Education The Jackson Laboratory
2011 Imaging Glicoma Stem Cell Dynamics in Vivo $90,000 Research The Jackson Laboratory
2010 MicroRNA Expression during Lung Tumor Progression $90,000 Research The Jackson Laboratory
2010 Genetic Chemotherapy: Inducing Leukemia and Lymphoma Cell Self Destruction $67,500 Research The Jackson Laboratory
2010 Notch Signaling in Medulloblastoma Initiation and Cancer Stem Cell Maintenance $90,000 Research The Jackson Laboratory
2009 Validating S100A6 as a Novel Marker and Potential Therapeutic Target of Brain Cancer Stem Cells $80,000 Research The Jackson Laboratory
2008 Development Genomics of Lung Cancer $79,524 Research The Jackson Laboratory
2008 Homologous Recombination Factor XRCC2 in B-Cell Genome Stability and Tumor Supression $79,696 Research The Jackson Laboratory
2006 The Role of Src Kinases in Regulation of Stem Cell Survival in CML $75,000 Research The Jackson Laboratory
2006 Chromatin Reorganization in Pro-B Cell Lymphoma Nuclei $74,180 Research The Jackson Laboratory
2005 A Gene Expression Study for the Hormone Independent Growth Transition of Ovarian Cancer Cells in vivo $20,000 Research The Jackson Laboratory
2004 Malignant Ovarian Granulose Cell Teumorigenesis $37,165 Research The Jackson Laboratory
2003 Parent-of-Origin Genetics in a Model of Ovarian Ganulosa Cell Tumorigenesis $35,500 Research The Jackson Laboratory