Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular Biology

Abstract

Mixed lineage leukemias have a relatively poor prognosis and arise as a result of translocations between the MLL gene and one of multiple partner genes. Downstream targets of MLL are aberrantly upregulated and include the developmentally important HOX genes and MEIS1, as well as multiple miRNAs, including the miR-17-92 cluster and miR-196b. Here I utilize custom anti-miRNA oligonucleotides to examine the contribution of specific miRNAs to MLL leukemias both as individual miRNAs and in cooperation with other miRNAs. Combinatorial treatment with antagomirs against miR-17 and miR-19a of the miR-17-92 cluster dramatically reduces colony forming ability of MLL-fusion containing cell lines but not non-MLL AML controls.

Further, I validated PKNOX1 as a target of both miR-17 and miR-19a. MEIS1 and PKNOX1 are TALE domain proteins that participate in ternary complexes with HOX and PBX proteins. Here I examine the competitive relationship between PKNOX1 and MEIS1 in PBX-containing complex formation and determine the antagonistic role of PKNOX1 to leukemia in a murine MLL-AF9 model. Collectively, these data implicate the miR-17-92 cluster as part of a regulatory mechanism necessary to maintain MEIS1/HOXA9 -mediated transformation in MLL leukemia. This approach represents a paradigm where targeting multiple non-homologous miRNAs may be utilized as a novel therapeutic regimen.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

Download

Share

COinS