Biochemistry, Biophysics, and Structural Biology Commons^™

The Mir-17-92 Cluster Contributes To Mll Leukemia Development Through The Repression Of The Meis1 Competitor Pknox1, Yousaf Anwar Mian

Dissertations

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 …

Eliminating Acute Myeloid Leukemia Stem Cells By Targeting The Niche Microenviromnent: Co-Inhibition Of Tnf/Il1- Jnk And Nf-Κb, Andrew Volk

Dissertations

Leukemia Stem Cells (LSCs) from Acute Myeloid Leukemia (AML) require the activity of the transcription factor NF-kB to maintain stemness and drive tumor formation. Blocking NF-kB can preferentially eliminate LSCs in vitro with minimal effects on healthy Hematopoietic Stem and Progenitor Cells (HSPCs), making NF-kB a compelling target for anti-leukemia therapies. However, blocking NF-kB in vivo can only extend survival for a short period of time before transplanted mice succumb to the disease. I propose this is due to components of the in vivo niche supporting LSC survival and compensating for the inhibition of NF-kB.

I observed patients with partially …

The Role Of Af9 And Af9-Mediated Protein Interactions In Hematopoiesis And Leukemogenesis, Alyson Anne Lokken

Dissertations

The AF9 protein is one of the most common chromosomal translocation partners of the MLL gene in MLL leukemia. Wild-type AF9 is a member of the pTEFb transcription elongation complex, and interacts with gene regulatory proteins such as AF4/AF5q31, DOT1L, Pc3/CBX8 and BCoR. These interactions are retained in the oncogenic MLL-AF9 fusion protein, and may be required for leukemic transformation.

Using bone marrow progenitor cells isolated from conditional Af9 knockout mice, we examined in vitro differentiation of hematopoietic progenitor cells to the erythroid, myeloid and megakaryocytic lineages in the presence or absence of Af9. Based on previously published studies, we …

Critical Functions Specified By The Mll Cxxc Domain Determine Leukemogenic Capacity, Noah Warren Birch

Dissertations

TheMixed Lineage Leukemia(MLL) gene can participate in chromosomal translocations which generate a fusion protein leading to acute leukemia. A better understanding of how MLL fusion proteins contribute to leukemia is necessary in order to develop more effective treatments. In my dissertation project, I investigated the functional role of amino acids within the MLL CXXC domain to determine how specific residues contribute to leukemogenic capacity.

MLL fusion proteins retain the amino-terminal portion of MLL including the CXXC DNA-binding domain while the carboxy-terminal portion is comprised of a fusion partner. The closest homolog of MLL, MLL2 (alternatively named MLL4), also contains a …

The Specific Role Of The Mll Cxxc Domain In Mll Fusion Protein Function, Laurie Ellen Risner

Dissertations

The MLL gene was first identified because it is involved in chromosome translocations which produce novel fusion proteins that cause leukemia. The CXXC domain of MLL is a cysteine rich DNA binding domain with specificity for binding unmethylated CpG-containing DNA. The CXXC domain is retained in oncogenic MLL fusions, and is absolutely required for the fusions to cause leukemia. This project explored the role of the CXXC domain by introducing structure-informed point mutations within the MLL CXXC domain that disrupt DNA binding, and by performing domain swap experiments in which different CXXC domains from other proteins, including DNMT1, CGBP and …