Epigenetic drugs in overcoming the effects of bone marrow microenvironment-induced chemoprotection in pediatric AML
| Author(s) | Weber, Samantha J. | |
| Date Accessioned | 2018-12-20T13:04:54Z | |
| Date Available | 2018-12-20T13:04:54Z | |
| Publication Date | 2018 | |
| SWORD Update | 2018-10-18T16:03:16Z | |
| Abstract | Pediatric acute myeloid leukemia (AML) is a type of blood cancer, accounting for 18% of childhood leukemia, in which mutated immature myeloid cells are present in the bone marrow. The most common treatment option is induction chemotherapy, however this treatment is associated with high relapse rates contributed by chemotherapeutic resistance provided by the bone marrow microenvironment. New treatment options are needed for pediatric AML in order to improve survival and remission rates. AML is characterized by aberrant epigenetic landscape. Epigenetic changes such as DNA methylation and histone methylation and acetylation can promote leukemia development by altering gene expression at the level of transcription. Azacitidine, a DNA methyltransferase inhibitor, is currently used as treatment for relapsed and refractory AML in adults. Panobinostat, a histone deacetylase inhibitor, is in phase I clinical trials for AML in adults. Our lab previously demonstrated that azacitidine and panobinostat can induce complete remission in a mouse model of KMT2A (MLL) rearranged AML. However, assimilation of these drugs in the chemotherapy regimen is not well described. This research will focus on the use of epigenetic drugs used in combination with chemotherapy to treat pediatric AML. I hypothesize that the epigenetic drug combination will overcome chemoprotection mediated through cell-to-cell contact between the cellular adhesion molecules on AML cells and bone marrow cells. HS5 cells, human bone marrow stromal cells, provided maximum chemoprotection to AML cells in co-culture. This chemoprotection was not evident when AML cells were treated with HS5 cell conditioned media or separated from HS5 cells by a transwell filter. Azacitidine-panobinostat treatment significantly reduced adhesion of AML cells to HS5 cells. Taken together, these data support the hypothesis that cell-to-cell contact is needed for chemoprotection. I found that the epigenetic drugs, azacitidine and panobinostat, used in combination sensitized pediatric AML cell line and patient samples, to chemotherapeutic drugs (cytarabine or daunorubicin), overcoming the chemoprotection provided by HS5 cells. We also found that using azacitidine-panobinostat treatment in disseminated xenograft models of AML mobilized leukemic cells to the peripheral blood. This treatment in combination with chemotherapeutics is an effective treatment in increasing the overall survival in mice with AML. The data shown here supports my hypothesis that epigenetic drugs can overcome the bone marrow micro environmental chemo protection and that this protection is due to cell interactions within this environment. | en_US |
| Advisor | Duncan, Randall L. | |
| Advisor | Barwe, Sonali | |
| Degree | M.S. | |
| Department | University of Delaware, Department of Biological Sciences | |
| Unique Identifier | 1079758440 | |
| URL | http://udspace.udel.edu/handle/19716/24018 | |
| Language | en | |
| Publisher | University of Delaware | en_US |
| URI | https://search.proquest.com/docview/2131368050?accountid=10457 | |
| Keywords | Biological sciences | en_US |
| Title | Epigenetic drugs in overcoming the effects of bone marrow microenvironment-induced chemoprotection in pediatric AML | en_US |
| Type | Thesis | en_US |