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Transcriptional Silencing Of Foxd3 Is An Early Event Mediating Epigenetic Silencing In Tcl1 Positive Chronic Lymphocytic Leukemia

Chen, Shih-Shih
http://rave.ohiolink.edu/etdc/view?acc_num=osu1214923446

Abstract Details

2008, Doctor of Philosophy, Ohio State University, Molecular Genetics.
Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in adults; recent findings in CLL diagnosis, mechanism of pathogenesis and therapy options are reviewed in in the introductory Chapter 1. Early stages in the development of CLL have not been explored mainly due to the inability to study normal B-cells in route to transformation. Over-expression of human TCL1, a known CLL oncogene, in murine B-cells leads to the development of mature CD19+/CD5+/IgM+ clonal leukemia with a similar disease phenotype seen in human CLL. In Chapter 2, we used this TCL1 murine model of CLL and corresponding human CLL samples in a cross-species Epigenomics approach to address the timing and relevance of epigenetic events occurring during leukemogenesis. In the TCL1 positive B-cells, aberrant DNA methylation of CpG islands occurred progressively more frequently with age. We found a high concordance of methylated genes in the TCL1 mouse and human CLL. Increased methylation at 9 to 14 months correlated with progressively decreasing levels of microRNAs miR29b/miR29c and increased protein levels of their targets DNMT3A/3B. While the increased protein levels of de novo DNMT transferases can not explain methylated targets in TCL1 mice, in Chapter 3, a predicted Foxd3 binding sequence was much more frequently found in methylated genes (70%) as compared to unmethylated genes (29%). Specifically, Foxd3 promoter methylation is noted at five months, and its expression is silenced within one month as a consequence of a TCL1 activated NFκB repressor complex. Similar silencing of FOXD3 was also found in human CLL. Loss of the FOXD3 transcription factor leads to silencing of downstream targets, chromosome remodeling, promoter specific DNA methylation and thus manifesting its role in early leukemogenesis. During the disease development, one of the Foxd3 target genes, inhibitor of DNA binding protein 4 (Id4) is found methylated at a late stage of leukemogenesis in TCL1 mice. While Id4 has been suggested as a tumor suppressor gene in many types of leukemia including CLL, double or hetero knockout Id4 mice do not develop leukemia. To elucidate the role of late-stage methylated genes in CLL development, in Chapter 4, the outcome of loss of Id4 was further investigated using genetically modified mice. In the presence of the heterozygous TCL1 transgene, the mice with haploid loss of Id4 exhibited elevated white blood cells counts, accelerated death accompanied with enlarged spleens and B cells infiltrated secondary organs; while the same background TCL1 mice tend to have slower disease progression. Non-transformed B-lymphocytes from wild-type as opposed to Id4 haplotype deficiency were more resistant to dexamethasone therapy. Overall, our findings suggest aberrant DNA methylation as an early and accumulated event during CLL disease development, the loss of targets might be required for disease progression in both mouse and human CLL-cells. Finally, in Chapter 5 we discuss the relevance of the findings in the preceding chapters and the future direction of this body of work to understanding the pathogenesis of CLL.
John Byrd, C (Advisor)
Christoph Plass (Advisor)
Michael Ostrowski (Committee Member)
Susan Cole (Committee Member)
Natarajan Muthusamy (Committee Member)
146 p.
Biomedical Research
TCL1; CLL; FOXD3; DNA methylation

Recommended Citations

Citations

  • Chen, S.-S. (2008). Transcriptional Silencing Of Foxd3 Is An Early Event Mediating Epigenetic Silencing In Tcl1 Positive Chronic Lymphocytic Leukemia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1214923446

    APA Style (7th edition)

  • Chen, Shih-Shih. Transcriptional Silencing Of Foxd3 Is An Early Event Mediating Epigenetic Silencing In Tcl1 Positive Chronic Lymphocytic Leukemia. 2008. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1214923446.

    MLA Style (8th edition)

  • Chen, Shih-Shih. "Transcriptional Silencing Of Foxd3 Is An Early Event Mediating Epigenetic Silencing In Tcl1 Positive Chronic Lymphocytic Leukemia." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1214923446

    Chicago Manual of Style (17th edition)

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© 2008, some rights reserved.Creative Commons License Transcriptional Silencing Of Foxd3 Is An Early Event Mediating Epigenetic Silencing In Tcl1 Positive Chronic Lymphocytic Leukemia by Shih-Shih Chen is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by The Ohio State University and OhioLINK.