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The effects of a methionine aminopepitdase inhibitor fumagillin on leukemia cell growth in-vitroMak, Wan-ling, Justina Crystaline, 麥允齡 January 2013 (has links)
Acute Myeloid Leukaemia (AML) is a disease normally found in elderly patients, with the median age of presentation at about 68 years. At this age, many of the patients are frail and unlikely to respond well to intensive chemotherapy treatments. Conventional chemotherapy eradicates the proliferating leukaemic progenitors while leaving the quiescent leukaemic stem cells undisturbed. These quiescent LSCs are able to then bring about leukaemic relapse. Fumagillin is a natural metabolite from Asperigillus fumigatus that is generally used as an anti-microbial agent but it is also known to bind to intracellular MetAP-II and inhibit endothelial cell growth. Many cancers are found to have an over expression of MetAP-II.
In the past, MetAP-II inhibitors have been tested and shown success in angiogenesis inhibition and tumor reduction. The aim of this study is to observe whether methionine aminopeptidase-2 inhibitors can be used in the treatment of acute myeloid leukemia. The investigation included a dose response comparison of various AML cell lines to fumagillin treatment, cell proliferation assay, a colony forming unit assay, and cell cycle analysis of KG-1 cells following three days of fumagillin treatment. I have determined that fumagillin does indeed decrease the cellular proliferation of KG-1 in vivo and at 10μM, prevents colony formation in methylcellulose plating. There is an increase in cells found in the sub-G1 phase with fumagillin treatment, as analyzed by flow cytometry. It is interpolated that fumagillin treatment increases AML cell apoptosis, in addition to hindering its ability to grow in culture. / published_or_final_version / Medicine / Master / Master of Medical Sciences
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Studies of histone demethylase JARID1B in hematopoiesis and leukemogenesisZhang, Jingxuan, 張璟璇 January 2014 (has links)
Post-translational modifications of histone proteins serve as one of the key epigenetic regulatory mechanisms in the development of organisms. It is well-known that methylation on histone lysine residues is an important epigenetic modification for the transcriptional regulation of normal hematopoiesis and leukemogenesis. JARID1B, a member of the JARID1 histone H3 lysine 4 (H3K4) demethylases, was found essential for the self-renewal of both embryonic stem cell and melanoma stem-like cell, and was involved in regulating genes, such as Egr1, Bmi-1 and p27, during embryo development. In addition, JARID1B is involved in the differentiation of neural cells and macrophages. Although JARID1B is believed to have important functions in stem cell biology, its role in hematopoiesis and leukemogenesis has not been systematically studied.
We therefore examined the expression profile of JARID1B in different hematopoietic lineage cells. We observed an up-regulation of JARID1B in differentiated hematopoietic cells by comparing with hematopoietic stem cells and progenitor cells, suggesting that the enhanced cellular level of JARID1B is associated with hematopoietic lineage commitment. Interestingly, JARID1B expression is generally low in human leukemia cell lines and in CML (Chronic Myeloid leukemia) patient samples compared to 〖CD34〗^+ cord blood cells and normal peripheral white blood cells, which indicates the down-regulation of JARID1B is associated with leukemia development. We further modulated the expression of JARID1B in human leukemia cell lines, K562 and SEM, and in mouse hematopoietic stem/progenitor cells (〖Lin〗^-/〖Sca〗^(-1+)/c-〖Kit〗^+, LSK cells). We found that knockdown of Jarid1b in LSK cells did not alter their cell-cycle pattern. However, total colony formation number was reduced in serial re-plating assays, suggesting Jarid1b is required for the maintenance of colony-forming ability and self-renewal property. Knockdown of JARID1B in K562 cells did not change their cell proliferation and cell-cycle pattern, but did consistently inhibit their colony-forming ability during serial re-plating assays. On the other hand, overexpression of JARID1B in K562 and SEM leukemic cells inhibited cell proliferation and colony formation, but with no significant changes on cell-cycle patterns. Furthermore, apoptosis staining did not show any correlations between JARID1B overexpression and apoptosis.
Previously, JARID1A, another JARID1 family member, was found as a fusion partner in AML (Acute Myeloid Leukemia); its third PHD domain, which locates at C-terminus, is associated with leukemogenesis. By amino acid sequence alignment, the differences between JARID1A and JARID1B protein are mainly occurred at their C-terminal regions, after the second PHD domain. Therefore, GST fusion protein pull-down experiments for this region was performed. Preliminary results showed that the C-terminus of JARID1B protein interacts with proteins of RNA transcriptional machinery complex. However, further investigation is needed to demonstrate these interactions are directly associated with JARID1B inhibitory effects on gene expression. To conclude, our results suggest that JARID1B plays an essential role in the biology of hematopoietic stem cells and leukemic cells. Investigation on its interacting partners and downstream target genes would lead us a detailed understanding of JARID1B function in hematopoietic cells. / published_or_final_version / Pathology / Doctoral / Doctor of Philosophy
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Distinctive functions of the polycomb group protein BMI-1 in hematopoiesis and leukemogenesisLam, Yuk-man, 林旭文 January 2014 (has links)
abstract / Pathology / Doctoral / Doctor of Philosophy
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CD56-positive: natural killer cell lymphoma/leukaemia黃傑煇, Wong, Kit-fai. January 2001 (has links)
published_or_final_version / Medicine / Master / Doctor of Medicine
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Substituted mitosenes: synthesis and antineoplastic activityHodges, John Cooke January 1981 (has links)
No description available.
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THE EFFECT OF 7,12-DIMETHYLBENZ(A)ANTHRACENE ON THE HEMOPOIETIC AND RETICULOENDOTHELIAL SYSTEMS IN FRIEND VIRUS LEUKEMIAElliott, Stephen C., 1939- January 1968 (has links)
No description available.
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Using Proteomics To Elucidate Critical Signaling PathwaysAhmed, Heba 11 1900 (has links)
Despite important advances in the therapy of acute myeloid leukemia
(AML) the majority of patients will die from their disease (Appelbaum,
Rowe, Radich, & Dick, 2001). Characterization of the aberrant molecular
pathways responsible for this malignancy provides a platform to discover
alternative treatments to help alter the fate of patients.
AML is characterized by a blockage in the differentiation of myeloid cells
resulting in the accumulation of highly proliferating immature
hematopoietic cells. Since treatments such as chemotherapy rarely destroy
the leukemic cells entirely, differentiation induction therapy has become a
very attractive treatment option. Interestingly, previous experiments have
shown that ligation of CD44, a cell surface glycoprotein strongly expressed
on all AML cells, with anti-CD44 monoclonal antibodies (mAbs) could
reverse this block in differentiation of leukemic blasts regardless of the AML subtype. To expand the understanding of the cellular regulation and circuitry involved, we aim to apply quantitative phosphoproteomics to monitor dynamic changes in phosphorylation state in response to anti-CD44 treatment.
Protein phosphorylation and dephosphorylation is a highly controlled biochemical process that responds to various intracellular and extracellular stimuli. As phosphorylation is a dynamic process, quantification of these
phosphorylation events would be vastly insightful.
The main objective of this project is to determine the differentiation-dependent
phosphoproteome of AML cells upon treatment of cells with the anti-CD44 mAb.In these experiments, optimization of protein extraction,
phosphopeptide enrichment and data processing and analysis has been achieved. The primary results show successful phosphoproteome extraction complemented with efficient phosphopeptide enrichment and informative data processing. Further quantification with stable isotope
labeling techniques is anticipated to provide candidates for targeted therapy.
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Integrated epigenetic and genetic analysis of transcriptional dysregulation in acute myeloid leukaemiaGudgin, Emma-Jane January 2013 (has links)
No description available.
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Cis-regulation of LM02 in T-acute lymphoblastic leukaemiaOram, Sarah Helen January 2011 (has links)
No description available.
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Activation of Chloride Channels with the Anti-parasitic Agent Ivermectin Induces Membrane Hyperpolarization and Cell Death in Leukemia CellsSharmeen, Sumaiya 28 July 2010 (has links)
FDA-approved drugs with previously unrecognized anti-cancer activity could be rapidly repurposed for this new indication. We compiled a library of such off-patent drugs to screen four leukemia cell lines and identified the anti-parasitic agent ivermectin that induced cell death at low micromolar concentrations. In cell death and clonogenic growth assays, low micromolar concentration of ivermectin significantly reduced viability of leukemia cell lines and patient samples compared to normal peripheral blood stem cells. In xenograft mouse models of leukemia, ivermectin decreased tumor volume and weight by up to 72% when compared to control without observable toxicity at pharmacologically achievable dosage. In this study, we further demonstrate that ivermectin activates chloride channels in leukemia cells leading to membrane hyperpolarization and increased reactive oxygen species generation. In addition, it demonstrated synergistic interaction when used in combination with Daunorubicin and Cytarabine. Therefore, this study highlights a potential new therapeutic strategy in repurposing ivermectin for the treatment of AML.
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