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.
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