Research Specialty :
Molecular Mechanisms of Acute Leukemia, cell cycle control, and the action of tumor suppressors.
Acute leukemia, tumor suppressors, cell cycle, transcriptional repression, co-repressors,Cell cycle,Chromatin,Chromosome,Gene regulation,Malignancy,Mouse,Signal transduction,Stem cells,Transcription,Transcription factor
The study of acute leukemia has yielded the first demonstration of a genetic alteration in human cancer, the identification of the first oncogene in humans, the first demonstration of impairment of apoptosis in tumorigenesis, and the first demonstration of targeted therapeutics in cancer. Acute leukemia is characterized by chromosomal translocations, which affect master regulatory genes.
As such, only 1 or 2 additional mutations may be required to induce the tumor. Therefore, the study of chromosomal translocations not only yields important information for human disease, but also provides direct insights into the action of master regulators that control the cell cycle (cellular proliferation), apoptosis, and cellular differentiation.
The translocations that we study, the t(8;21), the t(12;21), and the inv(16), are the most frequent translocations associated with acute myeloid and childhood B-cell leukemia. Each of these translocations involves portions of two genes, which are fused at the chromosomal breakpoint, creating a new chimeric gene that causes the leukemia. Thus, to understand how these translocation fusion proteins cause cancer, we must understand the normal regulatory roles of each of the normal genes and then uncover how the fusion of parts of these two genes causes cancer. For example, we have found that mice lacking Mtg16, a target of the t(16;21), are viable, but have profound defects in the hematopoietic stem cell, T cell development, and erythropoiesis.
In addition, we are interested in studying factors that are closely related to these master regulatory genes that might have similar functions in other tissues (e.g., Mtgr1 is required for the formation of the secrectory cell lineage in the small intestine).
Finally, a major focus is to identify factors used by these chromosomal translocations that might be therapeutic targets. We have identified histone deacetylase 3 as one potential target. We engineered mice to conditionally delete this gene and found dramatic phenotypes in cultured cells, the liver, and in the hematopoietic system. This promises to a rich resource for further investigation.
We use multiple approaches including mouse genetics (gene knockout studies and mouse models of leukemia), molecular biology, protein biochemistry, cDNA microarrays, and proteomics. To date, we have identified functions for these master regulatory genes in the small intestines, colons, and hematopoietic stem cells and linked the Myeloid Translocation Gene family to Wnt and Notch signaling. We have also branched out to examine a key chromatin modifying enzyme, histone deacetylase 3 Hdac3), which is recruited by the chromosomal translocation proteins and may be a therapeutic target in acute leukemia. We are especially interested in how Hdac3 regulates genomic stability and hematopoietic stem cell functions.