Molecular 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 …

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 …

Molecular Functions Of Mll Phd3 Binding To Its Ligands Cyp33 And H3k4me3, Gayathree Raman

Dissertations

Mixed Lineage Leukemia protein (MLL) is required for proper embryonic development, and hematopoiesis. It is a SET domain containing histone methyl transferase that trimethylates histone H3 on lysine 4 (H3K4Me3), a histone modification that correlates with active transcription. The 3rd PHD finger of MLL binds to H3K4me3. Thus MLL is a "writer" with an embedded "reader" for H3K4Me3. Cyp33 is another known ligand of MLL PHD3. Over expression of Cyp33 results in transcriptional repression of MLL target genes.

The aim of this study is to determine the biological function of MLL PHD3 binding to H3K4Me3 or Cyp33. Cyp33 binding to …

Significance Of Protein Interactions In Mediating Af9 Function, Bhavna Malik

Dissertations

Rearrangements of the MLL gene at chromosome band 11q23 have been associated with a heterogeneous group of lymphoid, myeloid and mixed lineage leukemias. MLL rearrangements occur approximately in 70% of infant leukemias and are also common in therapy-related leukemias where patients were previously treated with topoisomerase II inhibitors. Unfortunately, these patients have a poor prognosis. MLL gene rearrangements give rise to chimeric proteins that contain the N-terminal portion of MLL fused to the C-terminal portion of over 50 different fusion partners. The chimeric proteins cause constitutive expression of some MLL target genes such as HOXA9 and MEIS1, and enhanced proliferation …

A Study Of The Therapeutic Potential Of Af4 Mimetic Peptides, Nisha N. Barretto

Dissertations

Mixed lineage leukemias (MLL) are a group of acute and aggressive leukemias. They account for over 70% of infant leukemias, and 10% of acute adult leukemias. Pediatric ALL and therapy related MLL leukemias carry poor prognosis in spite of several advancement in the field of leukemia research. Therefore, new therapies for MLL leukemias are needed.

Majority of MLL leukemias arise due to the balanced translocations of the MLL gene. As a result of these translocations, chimeric MLL fusion proteins are expressed. The most frequently occurring MLL fusion proteins are known to aberrantly recruit the super elongation complex (SEC) resulting in …

The Role Of Cyp33 In Mll Mediated Gene Repression, Steven D. Poppen

Dissertations

Mixed Lineage Leukemia (MLL) is a multidomain protein whose gene is translocated in a subset of AML leukemias. Translocation of the MLL gene is present in approximately five percent of adult acute leukemias and ten percent of pediatric leukemias (Daser, A 2004, Look, A 1997, Huret, J 2001) Patients presenting in the clinic at the time of diagnosis with an MLL fusion have been shown to respond poorly to treatment and have a worse prognosis than matched wild type MLL patients (Rubnitz, J 1994, Rubnitz, J 1999). Novel therapies therefore are needed in order to more effectively treat patients with …

Determination Of An Interaction Between Nipped B-Like Protein And Mll, Adam Robert Marek

Master's Theses

The Mixed Lineage Leukemia (MLL) protein serves as a positive transcriptional regulator during hematopoietic and embryonic development. The MLL gene can undergo chromosomal translocations producing leukemia-causing fusions that retain the MLL amino-terminus, including the repression domain. A recent yeast two-hybrid screening used the MLL repression domain as bait and yielded nine positive clones of Nipped B-like (NIPBL).

NIPBL is a crucial member of the cohesin complex, which functions in the segregation of sister chromatids during cell division. However, recent evidence suggests the cohesin complex can also function as a transcriptional regulator.

In this study, we wanted to confirm this interaction …

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 …