Diss. (sammanfattning) Uppsala : Univ., 2007. / Härtill 4 uppsatser.

Thesis (Ph. D.)--Ohio State University, 2007.

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [48]-59).

Thesis (MD.) - University of Glasgow, 2009. / MD. thesis submitted to the Faculty of Medicine, Division of Cancer Sciences and Molecular Pathology, University of Glasgow, 2009. Includes bibliographical references. Print version also available.

Thesis (M. Med. Sc.)--University of Hong Kong, 2005.

The inherited bone marrow failure syndrome Fanconi Anaemia (FA) is caused by mutations in any one of the multiple FANC genes, which encode proteins that collaborate in the FA/BRCA DNA damage response pathway. FA is characterised by extreme predisposition to acute myeloid leukaemia (AML). AML in FA is associated with typical chromosomal aberrations involving gains of the long arm of chromosome 3 (3q gains). These are linked to overexpression of the oncogene ecotropic viral integration site 1 (EVI1). Based on this clinical observation, the hypothesis that EVI1 confers leukaemic transformation, in particular in the context of FA, was tested. Mouse embryonic stem cells with either functional or disrupted FA/BRCA-pathway were used to model normal and FA-associated embryonic haematopoiesis, and the effect of EVI1 overexpression was assessed in this model. EVI1 functions were also investigated with respect to protein interactions, focusing on the interaction with the co-repressor C-terminal binding protein 1 (CtBP1), in the context of genotoxic stress. To study this, in vitro haematopoietic differentiation assays, flow cytometry, mass spectrometry, immunoprecipitations and immunofluorescence were employed. In vitro haematopoietic differentiation using mouse embryonic stem cells with defective Fanca was successfully developed and applied. The analysis revealed that EVI1 overexpression in haemangioblast-like cells prevented the generation of haematopoietic precursors through endothelial to haematopoietic transition. Studies into EVI1 protein interaction dynamics showed that DNA damage-induced phosphorylation of EVI1 modifies interaction with the co-repressor CtBP1. This interaction was demonstrated to be partially required for the EVI1-induced block of the development of haematopoietic precursors using the mESC-based model. An EVI1-mediated modulation of the FA phenotype characteristic G2-arrest and of the FA-associated embryonic haematopoiesis was not demonstrated. This study contributes to the understanding of the function of the EVI1 oncogene in normal and FA-associated haematopoiesis and the DNA damage response. FA-associated haematopoiesis and leukaemogenesis can be further studied using the embryonic haematopoiesis model developed here, and further studies can build on the data generated with respect to EVI1.

Class of 2014 Abstract / Specific Aims: Evaluate serum posaconazole concentrations following dose adjustment in response to subtherapeutic serum concentrations. Determine optimal dose adjustment schema and identify toxicity with doses above 600 mg daily (e.g.: 200 mg per os three times daily). Methods: The health records were reviewed for 29 patients ≥ 18 years with acute myeloid leukemia over a four-year period. Participants initially received posaconazole 200 mg per os three times daily as prophylaxis and required at least one dose adjustment secondary to a subtherapeutic posaconazole serum concentration. Patients were stratified by posaconazole dosing following dose adjustment (A=200mg QID, B=300mg TID, C=400 mg TID, D=400 QID). Main Results: There was a statistically significant increase in posaconazole serum concentration in each group compared to baseline serum concentration, aside from group C (group A and B P<0.001, group C P=0.236, and group D P=0.0076). The majority of participants in 3 of the 4 groups reached therapeutic serum concentration (A=0.87, B=0.76, D=0.80) whereas group C had a serum posaconazole concentration on average below therapeutic range (0.51). There was no significant difference between the four groups in regards to renal function (p=0.35) or hepatic function (AST p=0.676, ALT p=0.877, total bilirubin p=0.097). Conclusion: A dose increase led to an increase in posaconazole serum concentration except for the dosing regimen of 400 mg three times daily. However, the study is limited by a small patient population, an unequal number of patients in each group, and potentially by poor absorption of posaconazole suspension. Further research is required to expand on these findings.

Human acute nonlymphoblastic or myelogenous leukemia (ANLL or AML) is a malignant disease of the bone marrow involving hemopoietic (blood-forming) cells of the myeloid lineage. ANLL is a complex neoplastic disease, whose fundamental nature is only partially understood despite intensive research. The disease is complicated by its apparent heterogeneity in terms of the degree of differentiation of hemopoietic stem cell involvement in different patients and the cellular expression of immunologically defined surface markers. The presence of a common antigen in myelogenous leukemia (CAMAL) has been previously identified. This thesis examines the expression of the CAMAL marker in or on bone marrow (BM) and peripheral blood (PB) cells using a monoclonal antibody-based indirect immunoperoxidase slide test. Increased numbers of CAMAL-positive cells were found in or on BM and PB of myeloid leukemia patients (with acute or chronic forms of the disease) compared with those found in normals or most lymphoid malignancies. Results presented herein have demonstrated that fluctuations in CAMAL BM values (% positive cells) correlated with survival time prior to relapse. In a blind study, ANLL patients Whose CAMAL BM values decreased post-chemotherapy had significantly (p < 0.025) longer first remission times (x = 19.2 months) than patients with increasing or static CAMAL BM values (x = 6.8 months). CAMAL BM values were often observed to increase during remission, prior to relapse, suggesting the presence of residual subclinical disease. Addition of excess purified leukemia-derived CAMAL to an in vitro myeloid progenitor cell assay caused profound inhibition of normal CFU-c growth but had no inhibitory effect on CFU-c growth from myeloid leukemia patients in active disease states. Depletion of CAHAL from normal plasma and conditioned media (sources of numerous hemopoietic growth regulatory factors) caused significant inhibition of normal, but not myeloid leukemic, CFU-c growth. These results indicated that myeloid leukemic cells possessed apparent differences in responsiveness to CAMAL-mediated hemopoietic regulation compared to normal cells. Lack of responsiveness to inhibition by leukemia-derived CAMAL may facilitate dominance of the malignant clone over normal cells. / Science, Faculty of / Microbiology and Immunology, Department of / Graduate

Acute Myeloid Leukemia (AML) is a type of cancer that affects the process of hematopoiesis. In individuals affected with AML, normal blood cells do not develop into red blood cells, white blood cells, and platelets, leading to symptoms such as anemia, neutropenia, and thrombocytopenia. The prognosis of AML is affected by multiple factors including: the genetic make-up of the leukemic cells, age of the affected individual, and underlying blood disorders such as myelodysplastic syndrome (MDS). MDS affects the development of stem cells into red blood cells, white blood cells, and platelets. Due to their clinical heterogeneity, AML and MDS continue to be a challenge that should be investigated in the community hospital setting. Remission rates between patients diagnosed with de-novo AML and patients diagnosed with AML with MDS were compared in a community hospital setting following induction therapy using a retrospective study design. Length of stay between patients diagnosed with de-novo AML and patients diagnosed with AML with MDS was compared during induction therapy. The association of age at diagnosis and number of chromosomal abnormalities to remission status was evaluated in each disease group. The association of blood transfusion requirements and neutropenic fever to length of stay was evaluated in each disease group. There were no statistically significant differences found between disease groups with respect to remission rates and length of stay. There were no statistically significant associations found between blood transfusion requirements and neutropenic fever in each disease group. There was an association found between age at diagnosis and remission status in patients diagnosed with AML with MDS. This indicates that older patients with AML with MDS are less likely to benefit from therapy and achieve complete remission. It is important to consider the small sample size, rare nature of the disease, and other variables that could have contributed to trends seen in the study population. The impact of predictors such as growth factor use and incidence of fungal infections should be investigated in future studies with AML patients. Considering these factors will allow for the development of targeted therapies and mechanisms against drug resistance for affected individuals.

Acute myeloid leukemia (AML) is a subset of leukemia that is characterized by the clonal expansion of cytogenetically and molecularly abnormal myeloid blasts. These blasts are highly proliferative accumulating in bone marrow and blood which leads to severe infections, anemia, and bone marrow failure. The poor prognosis of AML patients caused by the low tolerance to intensive chemotherapy has encouraged the pursuit of alternative therapeutic approaches. Differentiation therapy which involves the use of agents that can release the differentiation block in these leukemic blasts has emerged as a promising therapeutic approach. The use of All-trans retinoic acid (ATRA) represents a successful example of such an approach, nonetheless its efficacy is restricted to one subtype of AML. Efforts have been focused on finding differentiation agents which are effective for the other more common AML subtypes. Anti-CD44 targeted antibodies that activate the CD44 cell surface antigen are a promising candidate. Previous studies have shown that anti-CD44 treatment has been able to release the differentiation block in AML1 through AML5 subtypes. The exact mechanism by which anti-CD44 treatment is able to induce its effects has not been fully elucidated. Recent studies highlight the role that epigenetic mechanisms play during haematopoiesis and leukemogenesis and therefore, in this work we investigated the epigenetic mechanisms associated with anti-CD44 induced differentiation. Using AML cell lines from different subtypes, we demonstrated that anti-CD44-induced differentiation results in an extensive change of histone modification levels. We found that inhibiting enzymes responsible for the H3K9ac, H3K4me, H3K9me, and H3K27me modifications, attenuated the anti-proliferative and differentiation promoting effects of antic-CD44 treatment. Taken together, these data highlight the promising potential of using anti-CD44 as a therapeutic agent across multiple subtypes in AML