Broadly, my research aims to understand bone marrow malignancies on a molecular basis, specifically: (1) how covalent cytosine modifications control gene expression in hematopoiesis and the pathways that lead to altered patterns of DNA methylation/hydroxymethylation in human bone marrow cancers;…
more and (2) the molecular basis for inherited predisposition to leukemia. Cancer cells are characterized by abnormal patterns of DNA methylation/hydroxymethylation. My laboratory discovered that cancer cells exhibit aberrant splicing of DNMT3B, producing transcripts containing premature stop codons that encode truncated proteins lacking the catalytic domain. We developed transgenic mice that express DNMT3B7, one of the truncated DNMT3B isoforms expressed most commonly in human cancers, and these mice display disrupted embryonic development similar to the Dnmt3b knock-out animals, suggesting that DNMT3B7 acts as a dominant negative protein. Crossing these DNMT3B7 transgenic mice to the lymphoma-prone Myc-transgenic mice showed that DNMT3B7 accelerates tumorigenesis. We are now studying how DNMT3B7 and other truncated DNMT3B isoforms influence human tumors. We are also studying how DNA hydroxymethylation controls gene expression during normal and malignant hematopoiesis using mass spectrometry and a chemical labeling assay that specifically detects 5-hydroxymethylation. We hope that this work will lead to a deeper understanding of how DNA hydroxymethylation distribution is altered in hematopoietic malignancies, allowing us to develop rationale therapies that will be more effective and less toxic for patients. In additional translational work, we are identifying patients and families with a strong family history of hematopoietic malignancies and are studying the mutations within those individuals that predispose them to cancer.
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