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

The Role of DNMT3B in Mediating the Abnormal Methylation Patterns of Cancer Cells; Defining the Molecular Events that Accompany Unusual Cases of Hematopoietic Malignancies

Research Summary

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.

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.

Selected Papers

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

Varmus HE, Godley LA, Roy S, Taylor ICA, Yuschenkoff L, Shi Y-P, Pinkel D, Gray J, Pyle R, Aldaz CM, Bradley A, Medina D and Donehower LA. (1994). Defining the steps in a multistep mouse model for mammary carcinogenesis. Cold Spring Harbor Symposium on Quantitative Biology Volume LIX, 491-499.

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

Donehower LA, Godley LA, Aldaz CM, Pyle R, Shi Y-P, Pinkel D, Gray J, Bradley A, Medina D and Varmus HE. (1996). The role of p53 loss in genomic instability and tumor progression in a murine mammary cancer model. Prog. Clin. Biol. Res. 395: 1-11.

Godley LA, Kopp JB, Eckhaus M, Paglino JJ, Owens J and Varmus HE. (1996). Wild-type p53 transgenic mice exhibit altered differentiation of the ureteric bud and possess small kidneys. Genes and Development 10: 836-850.

Broccoli D, Godley LA, Donehower LA, Varmus HE and de Lange T. (1996). Telomerase activation in mouse mammary tumors: Lack of detectable telomere shortening and evidence for regulation of telomerase RNA with cell proliferation. Mol. Cell. Biol. 16: 3765-3772.

Jones JM, Attardi L, Godley LA, Laucirica R, Medina D, Jacks T, Varmus HE and Donehower LA. (1997). Absence of p53 in a mouse mammary tumor model promotes tumor cell proliferation without affecting apoptosis. Cell Growth and Diff. 8: 829-838.

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

Lai F, Orelli BJ, Till BG, Godley LA, Fernald AA, Pamintuan L and Le Beau MM. (2000). Molecular characterization of HsKELCH, a human homologue of the Drosophila kelch gene. Genomics. 66: 65-75.

Lai F, Godley LA, Fernald AA, Orelli BJ, Pamintuan L, Zhao N and Le Beau MM. (2000). cDNA cloning and genomic structure of three genes localized to human chromosome band 5q31 encoding novel nuclear proteins. Genomics. 70: 123-130.

Lai F, Godley LA, Joslin J, Fernald AA, Liu J, Espinosa R III, Zhao N, Pamintuan L, Till BG, Larson RA, Qian Z and Le Beau MM. (2000). 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.

Qian Z, Fernald AA, Godley LA, Larson RA and Le Beau MM. (2002). Expression profiling of CD34+ hematopoietic stem/progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia. Proc. Natl. Acad. Sci. USA, 99: 14925-14930.