Section of Hematology / Oncology
Professor of Medicine
Referring Physician Access Line: 1-877-DOM-2730
|BA||1988||Harvard & Radcliffe Colleges||Biochemical Sciences
|PhD||1995||University of California, San Francisco||Biochemistry
|Residency||1999||The University of Chicago||Internal Medicine
|Fellowship||2003||The University of Chicago||Hematology/Oncology
Epigenetic changes, including DNA methylation and histone modifications, alter chromatin structure, thereby regulating gene transcription. Cancer cells are characterized by abnormal DNA methylation, and work in my laboratory focuses on elucidating mechanisms that control DNA methylation within cancer cells. Our laboratory has shown that cancer cells exhibit aberrant splicing of the DNMT3B gene, which encodes one of the three DNA methyltransferases. The aberrant splicing produces DNMT3B transcripts containing premature stop codons, which encode truncated proteins lacking the catalytic domain. We hypothesize that truncated DNMT3B proteins contribute to the abnormal DNA methylation observed in cancer cells, and we are currently testing this hypothesis in mouse and in several human tumor systems.
Transgenic mice expressing DNMT3B7, the truncated DNMT3B protein most frequently observed in cancer cells, exhibit disrupted embryonic development, including defects in craniofacial development, heart formation, and in the development of the skeletal and hematopoietic systems. Many of these phenotypes are also seen in human who have mutations of the DNMT3B gene. We observe changes in DNA methylation within organs that express the transgene, thus supporting our hypothesis. The DNMT3B7 transgenic animals provide a model by which we can study the molecular mechanism for the DNA methylation alterations seen in cancer cells. We have crossed them to the Emu-myc transgenic mice, which are predisposed to the development of B cell lymphomas, and we observe striking alterations to the kinetics of tumor formation in double transgenic animals.
We are also testing our hypothesis that truncated DNMT3B isoforms regulate DNA methylation within human cancers: neuroblastoma (in conjunction with Susan Cohn and her laboratory) and myeloid leukemias. We are currently correlating the complement of DNMT3B transcripts with the DNA methylation state of primary human tumors.
Leukemia, lymphoma, hematologic malignancies, bone marrow transplantation
- Rampal, R., Alkalin, A., Madzo, J., Vasanthakumar, A., Patel, J., Li, Y., Ahn, J., Abdel-Wahab, O., Shih, A., Lu, C., Ward, P.S., Tsai, J.J., HriÅTosello, V., Tallman, J.E., Zhao, X., Daniels, D., Dai, Q., Ciminio, L., Aifantis, I., He, C., F., Tallman, M.S., Ferrando, A., Carroll, M., Paietta, E., Thompson, C.B., Licht, J.D., Mason, C., Godley, L.A., Melnick, A., Figueroa, M.E., and Levine, R.L. DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia. Cell Rep. 9: 1841-1855 (2014).
- Mariani, C.J., Vasanthakumar, A., Madzo, J., Yesilkanal, A., Bhagat, T., Yu, Y., Bhattacharyya, S., Wenger, R.H., Cohn, S.L., Nanduri, J., Verma, A., Prabhakar, N.R., and Godley, L.A. TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma. Cell Rep. 7:1343-52 (2014).
- Zhang, M.Y., Churpek, J.E., Keel, S.B., Walsh, T., Lee, M.K., Loeb, K.R., Gulsuner, S., Pritchard, C.C., Sanchez-Bonilla, M., Delrow, J.J., Basom, R.S., Forouhar, M., Gyurkocza, B., Schwartz, B.S., Neistadt, B., Marquez, R., Mariani, C., Coats, S., Hofmann, I., Lindsley, R.C., Williams, D.A., Abkowitz, J.L., Horwitz, M.S., King, M.-C., Godley, L.A., and Shimamura, A. Germline ETV6 mutations in familial thrombocytopenia and hematologic malignancy. Nature Genetics 47: 180-185 (2015).
- Polprasert, C., Schulze, I., Sekeres, M.A., Makishima, H., Przychodzen, B., Hosono, N., Singh, J., Padgett, R.A., Gu, X., Phillips, J.G., Clemente, M., Parker, V., Lindner, D., Dienes, B., Du, Y., Oakley, K., Nguyen, N., Mukherjee, S., Pabst, C., Godley, L.A., Churpek, J.E., Pollyea, D.A., Krug, U., Klein, H.-U., Dugas, M., Berdel, W., Yoshida, K., Shiraishi, Y., Chiba, K., Tanaka, H., Miyano, S., Ogawa, S., Müller Tidow, C., and Maciejewski, J.P. Inherited and somatic defects in DDX41 in myeloid neoplasms. Cancer Cell 27: 658-670 (2015).
- Churpek, J.E., Pyrtel, K., Kanchi, K.L., Shao, J., Koboldt, D., Miller, C.A., Shen, D., Fulton, R., O’Laughlin, M., Fronick, C., Pusic, I., Uy, G.L., Braunstein, E.M., Levis, M., Ross, J., Elliott, K., Heath, S., Jiang, A., Westervelt, P., DiPersio, J.F., Link, D.C., Walter, M.J., Welch, J., Wilson, R., Ley, T.J., Godley, L.A., and Graubert, T.A. Genomic analysis of germline and somatic variants in familial myelodysplasia/acute myeloid leukemia. Blood 126: 2484-2490 (2015).