| Description |
Despite the extensive study of acute myeloid leukemia (AML), patient outcome has not significantly improved in the past 30 years. An improved understanding of the development and progression of this disease is necessary to develop new and more effective treatment strategies. This dissertation presents results that reveal an important role for the transcription factor Oct1 and its cofactor OCA-B in AML. An MLL-AF9 driven AML mouse model is used in conjunction with transgenic Oct1 and Ocab mice to study the role of these proteins in vivo. Oct1 knockout in mice given MLL-AF9 protects the mice from developing AML. These mice live significantly longer than control mice with Oct1; however, these Oct1 knockout mice die from hematopoietic failure. Oct1 knockout in the bone marrow of adult mice does not show a phenotype until the mice are injected with 5-FU, after which the mice without Oct1 die rapidly, likely from bone marrow failure. These results together indicate a role for Oct1 in promoting AML and for responding to hematopoietic stress responses. ChIP results in human samples suggest that Oct1 could contribute to AML through facilitating the activation of Cdx2. Cdx2 is a homeodomain transcription factor aberrantly expressed in almost all AML cases. We observe that Oct1 binds to an octamer motif in the Cdx2 promoter in both healthy and leukemic human patient samples, but that Oct1 associates with repressive cofactors in healthy patient samples and with activating cofactors in leukemic patient samples. OCA-B has been experimentally detected in some cases of AML. Using the same MLL-AF9 driven mouse AML model as with Oct1, we find that mice with Ocab-/- bone marrow are protected from AML development. However, when Ocab is acutely deleted after AML is already established, mice are not protected from AML progression. These results suggest that OCA-B is important for the initiation of MLL-AF9 driven AML, but not in the maintenance of the disease. The results presented in this dissertation with Oct1 and OCA-B in promoting leukemia indicate an avenue for future leukemia research that will hopefully contribute to furthering the understanding of and improved treatment strategies for AML. |
