Alumna Speaker at the 2006 MSTP Retreat

Lucy Godley , M.D., Ph.D.

I graduated from the Medical Scientist Training Program at Northwestern University in 1997. Currently I am an Assistant Professor of Medicine in the Section of Hematology-Oncology at the University of Chicago.

Research Interests

My laboratory focuses on elucidating molecular mechanisms of tumorigenesis. Specifically, we work in two general areas: (1) understanding how cancer cells develop altered DNA methylation and exploring the consequences of the disturbed methylation; and (2) determining the secondary events that occur during leukemogenesis. In project 1, cancer cells exhibit abnormal DNA methylation, although the precise mechanism(s) by which this occurs is not clear. Repetitive sequences are hypomethylated relative to normal cells, and the promoters of particular genes are hypermethylated, causing gene silencing. Both of these aberrations in DNA methylation contribute to the phenotype of cancer cells. Cancer cells are characterized by numerous abnormalities in chromosomal stability, growth control, and apoptosis. The hypomethylated repetitive sequences seen in cancer cells are thought to contribute to the formation of the chromosomal rearrangements found in virtually all cancer cells. Understanding the molecular mechanisms through which DNA methylation is established and maintained in cancer cells is likely to provide important insights that may lead to novel diagnostic strategies and therapeutic interventions.

My laboratory has made the initial observation that cancer cells exhibit aberrant splicing of DNMT3b, encoding one of the de novo methylases. We observed over 20 abnormal splicing events in cancer cells, both in solid as well as in hematopoietic tumors. All of these splicing forms are predicted to encode truncated versions of DNMT3B. We have studied one transcript in particular, DNMT3B7, because it is expressed in virtually all of the tumor cells that we have examined as well as in primary tumor cells from patients with acute myeloid leukemia. We are currently studying how truncated DNMT3B proteins affect the DNA methylation state of cancer cells.

In project 2, leukemia's, like all cancers, develop from multiple abnormal processes within cells. I am particularly interested in making observations about leukemia that ultimately can be directly translated from the laboratory back to the clinic. I have studied two patients with mast cell leukemia and has demonstrated that they express novel C-KIT transcripts. Her investigations are currently focused on understanding the effects of the abnormal C-KIT proteins produced by these transcripts and determining if these transcripts are seen in any other forms of leukemia. She is also interested in examining unusual cases of bone marrow malignancies by molecular analyses.

Project 1. 

Cancer cells exhibit abnormal DNA methylation, although the precise mechanism(s) by which this occurs is not clear.  Repetitive sequences are hypomethylated relative to normal cells, and the promoters of particular genes are hypermethylated, causing gene silencing.  Both of these aberrations in DNA methylation contribute to the phenotype of cancer cells. Cancer cells are characterized by numerous abnormalities in chromosomal stability, growth control, and apoptosis.  The hypomethylated repetitive sequences seen in cancer cells are thought to contribute to the formation of the chromosomal rearrangements found in virtually all cancer cells.  Understanding the molecular mechanisms through which DNA methylation is established and maintained in cancer cells is likely to provide important insights that may lead to novel diagnostic strategies and therapeutic interventions. 

We have made the initial observation that cancer cells exhibit aberrant splicing of DNMT3b, encoding one of the de novo methylases.  I have observed over 20 abnormal splicing events in cancer cells, both in solid as well as in hematopoietic tumors.  All of these splicing forms are predicted to encode truncated versions of DNMT3B.  We have studied one transcript in particular, DNMT3B7, because it is expressed in virtually all of the tumor cells that we have examined as well as in primary tumor cells from patients with acute myeloid leukemia.  We are currently studying how truncated DNMT3B proteins affect the DNA methylation state of cancer cells.

Project 2.

Leukemias, like all cancers, develop from multiple abnormal processes within cells.  We are particularly interested in making observations about leukemia that ultimately can be directly translated from the laboratory back to the clinic.  We have studied two patients with mast cell leukemia and have demonstrated that they express novel C-KIT transcripts.  We are currently focused on understanding the effects of the abnormal C-KIT proteins produced by these transcripts and determining if these transcripts are seen in any other forms of leukemia.  We are also interested in examining unusual cases of bone marrow malignancies by molecular analyses.

Clinical Interests:

Leukemia, lymphoma, hematologic malignancies, bone marrow transplantation.

Awards

2005 Kimmel Scholars' Award, from the Sidney Kimmel Foundation for Cancer Research, "The Role Of DNMT3B in Mediating The Abnormal DNA Methylation Patterns in Cancer Cells"

2004 Schweppe Foundation Career Development Award, "Deciphering the Mechanism of Abnormal DNA Methylation in Cancer Cells

Representative Publications:

1. Godley, L. A., Pfeifer, J., Steinhauer, D., Ely, B., Shaw, G., Kaufmann, R., Suchanek, E., Pabo, C., Skehel, J. J., and Wiley, D. C. Introduction of intersubunit disulfide bonds in the membrane-distal region of the influenza hemagglutinin abolishes membrane fusion activity. Cell 68: 635-645 (1992).

2. Donehower, L. A., Godley, L. A., Aldaz, C. M., Pyle, R., Shi, Y.-P., Pinkel, D., Gray, J., Bradley, A., Medina, D., and Varmus, H. E. Deficiency of p53 accelerates mammary tumorigenesis in Wnt-1 transgenic mice and promotes chromosomal instability. Genes and Development 9: 882-895 (1995).

3. Godley, L. A., Kopp, J. B., Eckhaus, M., Paglino, J. J., Owens, J., and Varmus, H. E. Wild-type p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes and Development 10: 836-850 (1996).

4. Godley, L. A., Lai, F., Liu, J., Zhao, N., and Le Beau, M. M. TTID: A novel gene at 5q31 encoding a protein with titin-like features. Genomics. 60: 226-233 (1999).

5. Lai, F., Godley, L. A., Joslin, J., Fernald, A. A., Liu, J., Espinosa III, R., Zhao, N., Pamintuan, L., Till, B. G., Larson, R. A., Qian, Z., and Le Beau, M. M. Transcript map and comparative analysis of the 1.5 Mb commonly deleted segment of human 5q31 in malignant myeloid diseases with a del(5q). Genomics. 71: 235-245 (2001).