The Role of Dot1l in Normal Hematopoiesis and MLL Translocation Leukemia.
dc.contributor.author | Jo, Stephanie Youngyoon | en_US |
dc.date.accessioned | 2013-06-12T14:16:24Z | |
dc.date.available | NO_RESTRICTION | en_US |
dc.date.available | 2013-06-12T14:16:24Z | |
dc.date.issued | 2013 | en_US |
dc.date.submitted | 2013 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/97932 | |
dc.description.abstract | Disruptor of telomeric silencing 1-like (Dot1l) is a histone 3 lysine 79 methyltransferase. Studies of constitutive Dot1l knockout mice show that Dot1l is essential for embryonic development and prenatal hematopoiesis. Dot1l also interacts with fusion partners of Mixed Lineage Leukemia (MLL) gene, which is commonly translocated in human leukemia. However, the requirement of Dot1l in postnatal hematopoiesis and leukemogenesis of MLL translocation proteins have not been conclusively shown. With conditional Dot1l knockout mouse model, we examined the consequences of Dot1l loss in postnatal hematopoiesis and MLL translocation leukemia. Deletion of Dot1l led to pancytopenia and failure of hematopoietic homeostasis, and Dot1l-deficient cells minimally reconstituted recipient bone marrow in competitive transplantation experiments. In addition, MLL-AF9 cells required Dot1l for oncogenic transformation, while cells with other leukemic oncogenes such as Hoxa9/Meis1 and E2A-HLF did not. Furthermore, both histone methyltransferase activity of Dot1l and interaction with MLL fusion partner are required for transformation by MLL-AF9. In addition, loss of Dot1l affected histone modification at select loci instead of leading to global changes. These findings illustrate a crucial role of Dot1l in normal hematopoiesis, leukemogenesis of specific oncogenes, and histone cross-talk. | en_US |
dc.language.iso | en_US | en_US |
dc.subject | Dot1l | en_US |
dc.subject | MLL | en_US |
dc.subject | Hematopoiesis | en_US |
dc.subject | Leukemia | en_US |
dc.subject | Histone Modifications | en_US |
dc.title | The Role of Dot1l in Normal Hematopoiesis and MLL Translocation Leukemia. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Molecular & Cellular Pathology | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.contributor.committeemember | Hess, Jay L. | en_US |
dc.contributor.committeemember | Koenig, Ronald Jay | en_US |
dc.contributor.committeemember | Trievel, Raymond C. | en_US |
dc.contributor.committeemember | Kunkel, Steven L. | en_US |
dc.contributor.committeemember | Maillard, Ivan Patrick | en_US |
dc.contributor.committeemember | Nesvizhskii, Alexey | en_US |
dc.subject.hlbsecondlevel | Molecular, Cellular and Developmental Biology | en_US |
dc.subject.hlbsecondlevel | Pathology | en_US |
dc.subject.hlbtoplevel | Health Sciences | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/97932/1/josteph_1.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
Files in this item
Remediation of Harmful Language
The University of Michigan Library aims to describe library materials in a way that respects the people and communities who create, use, and are represented in our collections. Report harmful or offensive language in catalog records, finding aids, or elsewhere in our collections anonymously through our metadata feedback form. More information at Remediation of Harmful Language.
Accessibility
If you are unable to use this file in its current format, please select the Contact Us link and we can modify it to make it more accessible to you.