DukeSpace will be down for maintenance at 9:15 AM EDT on Tuesday, July 29. Expected downtime is 20 minutes or less.

Show simple item record

dc.contributor.advisor Kondo, Motonari en_US
dc.contributor.author Chung, Eva en_US
dc.date.accessioned 2012-05-29T16:43:42Z
dc.date.available 2014-05-19T04:30:05Z
dc.date.issued 2011 en_US
dc.identifier.uri http://hdl.handle.net/10161/5684
dc.description Dissertation en_US
dc.description.abstract <p>Hematopoiesis is the continual process of blood cell generation that primarily occurs in the bone marrow of adult animals. Hematologic neoplasms can also occur in the bone marrow and often result from dysregulation of signal transduction pathways. One example is the activation of the Ras oncogene, which has been linked to a variety of different cancers, including hematologic neoplasms. Ras is located proximal to the cell membrane and can activate many downstream effector pathways, thus it is difficult to determine which downstream pathway is mediating oncogenic Ras function. My thesis work focused on the effect of inappropriate activation of MEK/ERK, a downstream Ras effector pathway, in the hematopoietic system.</p><p>Using a retroviral transduction system, we expressed a constitutively active form of MEK1 in hematopoietic stem cells (HSCs). Mice transplanted with HSCs expressing active MEK developed a lethal myelodysplastic syndrome/myeloproliferative disease (MDS/MPN) characterized by the expansion of granulocytes/macrophages (GM) at the expense of lymphoid cell development. Transplantation of active MEK-induced MDS/MPNs into naïve mice did not result in further disease, suggesting that the MDS/MPN is not a frank leukemia.</p><p>Bcl-2 is an anti-apoptotic molecule that has been shown to play a role in leukemia development and maintenance. Coupling expression of active MEK and Bcl-2 resulted in MDS/MPNs that were phenotypically identical and had very similar disease onset compared to active MEK-induced MDS/MPNs. However, transplantation of Bcl-2/active MEK-induced MDS/MPNs did not result in a myeloid disease; rather, it resulted in the development of T-acute lymphoblastic leukemia (T-ALL) that was marked by activated Notch signaling. </p><p>These results led us to conclude that activation of MEK/ERK was sufficient to cause a pre-leukemic myeloid disease; however, additional oncogenic factors, such as Bcl-2 and Notch, were necessary for frank leukemia development. Moreover, additional oncogenic factors can alter the disease phenotype and disease course. Future analysis of the interplay between oncogenic factors will help shed light on disease development and aid in the development of more effective cancer treatments.</p> en_US
dc.subject Immunology en_US
dc.subject Oncology en_US
dc.subject Bcl-2 en_US
dc.subject MAP kinase en_US
dc.subject myelodysplastic syndrome (MDS) en_US
dc.subject myeloproliferative neoplasm (MPN) en_US
dc.subject T-actue lymphoblastic leukemia (T-ALL) en_US
dc.title The Role of MEK in Leukemogenesis en_US
dc.type Dissertation en_US
dc.department Immunology en_US
duke.embargo.months 24 en_US

Files in this item

This item appears in the following Collection(s)

Show simple item record