Research Abstract:
My laboratory studies the molecular pathogenesis of myeloid leukemias. We are interested in defining inherited genetic susceptibility factors and somatically acquired mutations important for disease initiation and progression. Specific diseases of interest to our group include: the myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and MDS/AML arising as a consequence of prior chemotherapy (t-MDS/AML). Both mouse models and correlative studies using human samples are utilized.
Current projects include:
Genomics of myelodysplastic syndromes. A large panel of primary human MDS and patient-matched normal (germline) samples have been obtained. Samples are screened for acquired DNA lesions by high-throughput gene resequencing, array-based comparative genomic hybridization, and array-based mRNA/miRNA profiling. Novel mutations are further characterized using tissue culture and mouse model systems.
Susceptibility to therapy-related MDS/AML (t-MDS/AML). This project addresses the hypothesis that the risk of iatrogenic secondary leukemias is influenced by inherited genetic susceptibility factors. We are testing this hypothesis in human populations by candidate gene and genome-wide association studies. In addition, we have identified inbred mouse strains that are susceptible or resistant to t-MDS/AML. Intercross strategies are utilized to define the underlying genetic basis of t-MDS/AML susceptibility in mice.
Identification of copy number variants. In addition to single nucleotide polymorphisms (SNPs), large scale DNA copy number gains and losses are an important source of germline genetic variation in mammalian genomes. We are using array-based comparative genomic hybridization to measure copy number variation in mouse and human genomes. We have developed novel bioinformatic tools to identify copy number variants, define their boundaries, and relate these gains and losses to phenotypic variation in mice and humans.
Selected Publications:
Cahan P, Li Y, Izumi M, Graubert TA. The impact of copy number variation on local gene expression in mouse hematopoietic stem and progenitor cells. Nat Genet 2009 PMID:19270704.
Graubert T, Payton M, Shao J, Walgren R, Monahan R, Frater J, Walshauser M, Martin M, Kasai Y, Walter M. Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndrome pathogenesis. PLoS ONE 2009 4:e4583.
Funk R, Maxwell T, Izumi M, Edwin D, Kreisel F, Ley T, Cheverud J, Graubert T. Quantitative Trait Loci Associated with Susceptibility to Therapy-Related Acute Murine Promyelocytic Leukemia in hCG-PML-RARa Transgenic Mice. Blood 2008 112(4):1434-42.
Graubert T, Cahan P, Edwin D, et al. A high resolution map of segmental DNA copy number variation in the mouse genome. PloS Genetics 2007 3:e3.
Fenske TS, Minn M, Mathews V, et al. Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice. Cancer Research 2006 66:5029-5038.
Last Updated: 11/03/2009 |