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Global and Gene-Specific DNA Methylation Analysis in Human Leukemia

Rush, Laura J
http://rave.ohiolink.edu/etdc/view?acc_num=osu1046352386

Abstract Details

2003, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
Aberrant DNA methylation of CpG islands is important in tumorigenesis due to its inhibitory influence on gene transcription. We used a two dimensional gel electrophoretic technique called restriction landmark genomic scanning (RLGS) to interrogate genomes of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) samples for aberrant DNA methylation. In both diseases, we found the extent of methylation to be much greater than previously known. AML samples obtained at the time of diagnosis varied greatly in the degree of methylation. Some patients exhibited little to no methylation, while others had methylation of up to 8.3% of the RLGS profile. Similar results were found in CLL, except that all patients exhibited methylation of at least 2.5% of the RLGS profile. Importantly, methylation occurred in a non-random pattern (p < 0.0001), indicating that genes involved in the methylation process may play some role in the pathogenesis of these diseases. Our RLGS analysis of sixteen AML patients showed an over-representation of methylation events on chromosome 11. Chromosome 11 harbors several imprinted genes that are methylated in an allele-specific pattern in normal tissues, and these methylated domains may be responsible for spreading of methylation into normally unmethylated cancer-related genes. In both AML and CLL, we identified a large panel of genes that warrant further investigation to establish any relationship to pathogenesis and/or clinical outcome. One such gene, cytochrome P450 1B1 (CYP1B1) was identified in the AML study and investigated in further detail. Expression of this gene in cell culture is regulated, at least in part, by DNA methylation. Expression was restored by treatment with a demethylating agent, which also had a synergistic effect when used with a histone deacetylase inhibitor. Furthermore, the methylation state of CYP1B1 at the time of initial diagnosis with AML was highly predictive for probability of survival in males. Males with an unmethylated CYP1B1 locus on the RLGS profile had a worse survival than males who were methylated, or any females (p < 0.0001). Together, these data support our hypothesis that aberrant methylation patterns can be used for molecular classification and identification of novel methylated genes in leukemia.
Michael Caligiuri Christoph Plass (Advisor)
130 p.
DNA methylation; cancer; leukemia; epigenetics; CYP1B1

Recommended Citations

Citations

  • Rush, L. J. (2003). Global and Gene-Specific DNA Methylation Analysis in Human Leukemia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1046352386

    APA Style (7th edition)

  • Rush, Laura. Global and Gene-Specific DNA Methylation Analysis in Human Leukemia. 2003. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1046352386.

    MLA Style (8th edition)

  • Rush, Laura. "Global and Gene-Specific DNA Methylation Analysis in Human Leukemia." Doctoral dissertation, Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=osu1046352386

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.