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Dissertations / Theses on the topic 'Acute Leukaemia'
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1
Bomken, Simon Nicholas. "Investigating leukaemic propagation in childhood acute lymphoblastic leukaemia." Thesis, University of Newcastle Upon Tyne, 2013. http://hdl.handle.net/10443/1865.
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Childhood acute lymphoblastic leukaemia (ALL) does not possess a propagating cell hierarchy, at least as defined by B-cell precursor immunophenotype. Indeed, many, or even all, leukaemic blasts may have the potential to propagate the disease. This unusual characteristic mirrors the substantial capacity for clonal expansion demonstrated by fully differentiated normal lymphoid cells. This Fellowship aimed to investigate the genetic programmes underlying the propagation of acute lymphoblastic leukaemia. An initial candidate approach confirmed the expression of PIWIL2, a gene critical to the maintenance of germline stem cells, in both cell line and primary ALL. Knockdown of PIWIL2 resulted in reduced cellular proliferation and significant prolongation of doubling time in two ALL cell lines, SEM (MLL/AF4) and 697 (E2A/PBX1). Unexpectedly, PIWIL2 was also found to be expressed in peripheral lymphoid cells from healthy donors, but not terminally differentiated cells of myeloid origin, suggesting that PIWIL2 may have a previously unidentified function in both normal and malignant lymphoid cells. A second project has developed an in vitro genome-wide RNAi screen to identify candidate genes involved in the clonal propagation of ALL. This project has assessed a serial re-plating assay using feeder cell co-culture to provide a surrogate niche environment. Initial results have demonstrated the feasibility of such an approach. The benefit of using a co-culture re-plating assay, as compared to a standard suspension culture approach, remains under investigation. ii Finally, this Fellowship developed a protocol for the lentiviral transduction of patient-derived leukaemic blasts and cloned and validated a novel lentiviral vector capable of in vitro analysis, in vivo disease monitoring and RNAi. With these, it will now be possible to validate candidate leukaemic propagation genes in vivo, using primary leukaemic material. The results of these studies will provide candidates for the development of novel therapeutic agents for children with ALL.
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Bradbury, Dawn Ann. "Factors regulating the autocrine growth of leukaemic cells in acute myeloblastic leukaemia." Thesis, Nottingham Trent University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.332817.
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Knapper, Steven. "FLT3 inhibitors in acute myeloid leukaemia." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432548.
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Smith, Matthew Liam Walker. "Mutation profiling in acute myeloid leukaemia." Thesis, Queen Mary, University of London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.416112.
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Quinn, M. F. "Homeobox gene expression in acute leukaemia." Thesis, Queen's University Belfast, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398094.
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Mannari, Deepak. "The genomics of acute myeloid leukaemia : an investigation into the molecular pathogenesis of acute myeloid leukaemia with t(8;21)." Thesis, Queen Mary, University of London, 2012. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8822.
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Acute myeloid leukaemia is a clonal disorder characterised by recurrent chromosomal translocations. One of the commonest, is the t(8;21) which results in part of the AML1 gene being juxtaposed to most of the ETO gene with the resultant chimeric protein, AML1-ETO, acting predominantly as a transcriptional repressor. Despite the extensive literature available, the exact mechanism by which the chimeric protein results in AML has not been fully elucidated. By using exon arrays and high throughput sequencing as tools it was hoped to gain further insights into the molecular basis of this disease. Gene expression profiling using the exon arrays highlighted molecular pathways and specific genes that play a key role in the pathogenesis in t(8;21). Exon arrays were also used to profile individual exon expression of the ETO gene. This demonstrated that the genomic breakpoint of ETO in the t(8;21) is variable between different patients. This technique also resulted in the discovery of a new exon in the ETO gene. This novel exon results in formation of alternative transcripts of AML1-ETO and was shown in mouse models to play a key role in leukaemogenesis. Chromatin immunoprecipitation followed by high throughput sequencing revealed novel aspects of AML1-ETO binding. A number of novel genes that bind AML1-ETO were recognized and in conjunction with the expression data, a number of hypothesis on how AML1-ETO binding effects gene expression are made.
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Swanepoel, Yolande. "A retrospective study of acute lymphoblastic leukaemia in Paediatric patients at Dr George Mukhari Hospital (2003-2007)." Thesis, University of Limpopo (Medunsa Campus), 2008. http://hdl.handle.net/10386/262.
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Thesis (M Med(Haematology))-- University of Limpopo (Medunsa Campus), 2008.Introduction: ALL (Acute Lymphoblastic Leukaemia) is the most common leukaemia in childhood. The two most important features predictive of outcome are age and presenting WBC at diagnosis. NCI risk criteria are applied to all children with precursor B-ALL, dividing them into NCI “high risk” (age < 1 year and ≥ 10 yrs, WBC > 50 x 10 9/ ) and NCI “standard risk” (age ≥ 1 year and < 10 yrs, WBC < 50 x 10 9/ ). Gender, immunophenotyping and genetic studies are other features that have been shown to be associated with outcome. Objectives: To determine the correlation between survival outcome of paediatric patients with ALL and different variables, e.g. biological, haematological, immunophenotypic and cytogenetic features at diagnosis, and to determine the duration of survival of a patient since the diagnosis of ALL, at Dr George Mukhari Hospital. Methods: This study was conducted over the period 2003-2007. Children diagnosed with ALL with ages ranging from 1-12 years, were identified. The hospital and laboratory records were analysed retrospectively. Early prognostic features were identified from patient data. Results: Descriptive statistical measures were used to summarize data. Twenty nine paediatric patients with ALL were identified of which 12 were female and 17 were male. The mean age of patients at diagnosis was 7,2 years. The presenting leucocyte count ranged from 2,5 to 325 x 10 9/ . Cytogenetic studies of three patients were available, all of which were unfavourable prognostic factors. Immunophenotyping revealed ten patients with T-cell ALL, 17 patients with B-cell ALL and two patients whose immunophenotype was unknown as recorded results were not available. Twenty one patients’ survival data were known. The longest duration of survival of a patient was 3,7 years. There were seven patients known to be alive at the end of the study period. Conclusion: The cases reported herein and those described in the literature demonstrate the importance of a careful and multidisciplinary approach in the diagnosis and evaluation of paediatric ALL.
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Taussig, David. "Characterisation of acute myeloid leukaemia stem cells." Thesis, Queen Mary, University of London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.424766.
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Cartwright, Cher Suzanne. "Thiopurine Metabolism in Childhood Acute Lymphoblastic Leukaemia." Thesis, University of Sheffield, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.500442.
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Olwill, Shane. "Annexin II expression in acute myeloid leukaemia." Thesis, University of Ulster, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274092.
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Armenteros-Monterroso, Elena. "Investigating reptin function in acute myeloid leukaemia." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/10038392/.
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Acute myeloid leukaemia (AML) is a disease characterized by the clonal expansion of immature white blood cells, which show increased proliferation, self-renewal and a block of differentiation. Despite recent advances in therapy, AML still causes over half of all leukaemia related paediatric deaths, as cytogenetically defined subgroups with poor prognosis are still prevalent. Chromosomal translocations, which encode abnormal fusion proteins, are common in patients with AML, and the MLL (Mixed Lineage Leukaemia) locus is the most frequently rearranged in paediatric AML. Previous studies in our laboratory used global gene expression analysis in conditionally immortalized MLL-rearranged mouse myeloid cells to demonstrate that Reptin was positively regulated by MLL-fusion genes. Reptin (also known as RUVBL2 or Tip48), functions as part of multi-protein complexes involved in chromatin remodelling, DNA repair, regulation of transcription and ribonucleoprotein assembly. Further work in our laboratory found Reptin to be essential for sustaining the hyperproliferative state and clonogenic potential, as well as suppressing apoptosis, of human AML cells, both MLL-rearranged and non-MLL rearranged. The aim of this study was to investigate the transcriptional pathways regulated by Reptin in human AML and to establish the efficacy of targeting Reptin in vivo. By using an inducible shRNA model to deplete Reptin expression we demonstrate that Reptin is essential for leukaemic progression in vivo, as Reptin knockdown in established human leukaemias resulted in increased survival and the cure of most xenotransplanted mice. Moreover, our analyses of global gene expression data in cells depleted for Reptin expression at different time points indicated that Reptin depletion is negatively correlated with the Leukaemic Stem Cell self-renewal signature. Furthermore, our gene expression results also indicated that Reptin modulates the expression signature of the transcription factors c-MYC and c-MYB, master regulators of survival and self-renewal pathways in AML. Additionally, immunoprecipitation assays identified a novel interaction between endogenous Reptin and c-MYB, and ChIP assays showed decreased binding of c-MYB and the epigenetic mark H3K27ac at the promoter region of the c-MYB target gene MPO after Reptin loss. Collectively, our data identify a new pathway modulated by Reptin and confirm that Reptin is a good therapeutic target for the treatment of AML.
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Stringaris, Katherine. "Natural killer cells and acute myeloid leukaemia." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/18014.
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Despite successful induction chemotherapy, most patients with acute myeloid leukemia (AML) will relapse. Immune surveillance by T cells or natural killer (NK) cells may play a role in preventing relapse. This thesis examines the potential of NK cells to control AML. Study 1 explored in 248 patients with haematological malignancies from the US National Institutes of Health, the genetic diversity of NK killer immunoglobulin receptor (KIR) genes in patients and their stem cell donors and their impact on outcome after stem cell transplantation (SCT) for haematological malignancy. Individuals with AML receiving SCT from donors inheriting 3 particular B-haplotype KIRs were 4 times less likely to relapse than those with donors without these favourable KIRs. Study 2 explored in samples obtained from 499 patients enrolled on UK MRC/NCRI AML trials, whether KIR genotype affects the risk of developing AML or the outcome of remission induction chemotherapy. While KIRs had no effect on the development or outcome of de novo AML, individuals with more activatory KIRs, in particular 2DS2, developed significantly less secondary AML, suggesting that activatory KIRs can protect against secondary AML. These studies support a role for NK-mediated immune surveillance in AML. Study 3 investigated the phenotype and function of AML NK cells. In 32 prospectively collected samples from AML patients undergoing remission induction chemotherapy at the Hammersmith Hospital, AML patients were found to have reduced NK activatory receptors, increased NK inhibitory receptors, and reduced cytotoxic function towards leukaemia, compared to healthy donors. These abnormalities corresponded with failure to achieve remission and can be induced in normal NK incubated with AML blasts. I conclude that KIR genetics have a limited influence on AML development and outcome but that AML itself can impair NK function, reducing the chance of achieving remission. These findings have implications for NK based immunotherapy for AML.
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Dokal, Arran D. "Investigating the heterogeneity of leukaemia kinase networks and the impact of the microenvironment on leukaemic cell signalling." Thesis, Queen Mary, University of London, 2018. http://qmro.qmul.ac.uk/xmlui/handle/123456789/36218.
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The tumour microenvironment plays a key role in tumour progression. In this thesis acute myeloid leukaemia (AML) was used as a model system to investigate the interplay between stromal and cancer cells. AML is a heterogeneous clonal disorder of haematopoietic undifferentiated progenitor cells or 'blast cells', which accumulate in the bone marrow and lead to the reduced output of crucial haematopoietic elements. Due to its heterogeneity (at least in part), treatment of the disease has not witnessed great innovation in the past 30 years. The bone marrow microenvironment (BMM) has a key role in the haematological malignancies contributing to the survival of leukaemic blasts. Relapse in AML occurs because of residual disease and evidence suggests that this resistance is facilitated through leukaemic cells ability to reside in BMM niches. To understand the precise role of the BMM in AML progression and therefore target any supportive mechanisms requires knowledge of how AML cells communicate with their microenvironment. In the work presented in this thesis I undertook a multi-proteomic approach that utilised liquid chromatography tandem mass spectrometry (LC-MS/MS) to assess the interplay between AML and BMM cell signalling. This thesis shows the results of a secretomic analysis of stromal cell lines, which identified a previously uncharacterized panel of six stromal secreted proteins (BMP-1, CSF-1, CTGF, HGF, S100-A4 and S100-A11) that support primary AML cell survival and proliferation in culture. Comparison of AML cell signalling (using global phosphoproteomic methods) following treatment with the newly identified growth factors revealed that these signalling proteins elicit multi-nodular activation of signalling networks with known anti-apoptotic activity. Consistent with the cell signalling proteomics data, cell viability studies as a function of pharmacological kinase inhibitor treatment determined that the sensitivity of AML to targeted kinase inhibitors was modulated by the supportive stromal conditioned media. To investigate heterotypic signalling between cell populations, AML/stromal cell co-cultures were designed, tested and optimised. These studies identified additional activated pathways in AML cells that were only present when AML cells had physical interaction with stroma. Complementary analysis of the stromal cells which had been first cultured with AML cells revealed that despite heterogeneity there is an emerging stromal phospho-proteomic signature that is different in BMM independent AML cells vs BMM interactive AML cells. Collectively these findings evidence the influence that the BMM can have on AML signalling. Although evidence for the influence of BMM in modulating AML resistance to standard chemotherapy exists, this study highlights specific BMM components that contribute to the ability of AML cells to circumvent current treatments based on kinase targeted drugs. These observations have implications for designing future therapies for AML.
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Carapeti, Melina. "Identification of acquired genetic changes in acute leukaemia." Thesis, Imperial College London, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287882.
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Morgan, Rhys. "Role of γ-catenin in acute myeloid leukaemia." Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/55145/.
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Acute myeloid leukaemia (AML) is a heterogeneous clonal disorder of haematopoietic cells that primarily affects the elderly. Previously, our laboratory identified y-catenin as significantly overexpressed in AML. y-Catenin shares close structural and functional homology with the more intensively studied /3-catenin. Both catenins have dual roles in cell adhesion complexes and in transcription. Their transcriptional role is regulated by Wnt signalling which is critical for normal development and is one of the most frequently dysregulated processes in AML. In spite of this, little is known regarding the specific role of y-catenin in normal haematopoiesis or AML pathology. This study devised an intracellular flow cytometric staining assay to characterise the expression of y-catenin in normal haematopoietic subsets. y-Catenin exhibited a similar expression profile to /3-catenin. Expression was relatively high in haematopoietic stem/progenitor cells (HSC/HPC) and showed increased expression in myeloid differentiated cells (granulocytes and monocytes) while expression was lower in lymphoid cells and undetectable in red blood cells. Studies of subcellular distribution by confocal imaging showed reciprocal localisation of catenins in CD34+ cells, with /3-catenin predominantly nuclear translocated and y-catenin nuclear excluded. Conversely, in granulocytic and monocytic cells nuclear y-catenin levels were relatively high whilst nuclear /3-catenin levels were reduced. A small subset of the CD14+ monocyte population exhibited heavily nuclear translocated y-catenin. Subsequent knock-down studies of y-catenin showed this protein to be required for normal haematopoietic development in vitro, evidenced by the inhibition of macrophage differentiation and apparent reprogramming of committed monocyte progenitors for granulocytic development. In AML patients, y- catenin mRNA expression conferred a reduced complete remission rate arising from resistant disease, however discordance was found between mRNA and protein level, implying post-translational control of y-catenin expression in AML. In primary AML blasts (undifferentiated) y-catenin was aberrantly localised to the nucleus suggesting a transcriptional role in AML pathology. A correlation was identified between y- and (3-catenin protein expression in primary AML blasts and an association between nuclear levels of these proteins. To determine whether this association was causal, y-catenin was ectopically expressed in normal human CD34+ haematopoietic progenitor cells but had no significant influence on /3-catenin expression or localisation even following subsequent differentiation. In contrast, overexpression of y-catenin in leukaemic cell lines stabilised /3-catenin protein and promoted its translocation to the nucleus suggesting that the influence of y-catenin on /5-catenin is a feature of leukaemic cells but not normal cells. Phenotypically, overexpression of y-catenin had little effect on normal progenitor cells but was able to block agonist-induced differentiation of AML cell lines, probably via stabilisation of jS-catenin. In summary, this study indicates a role for y-catenin in the regulation of normal haematopoietic development and that its nuclear translocation is strictly regulated independently of /3-catenin in normal haematopoiesis. In leukaemic cells, however, this control is dysfunctional allowing y-catenin to promote the stabilisation and translocation of /3-catenin. This relationship may represent a pathological mechanism active in AML blasts to block myeloid differentiation and promote a leukaemic phenotype.
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Elmantaser, Musab Elmabrouk M. "Bone health in children with acute lymphoblastic leukaemia." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4447/.
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In chapter 1, bone structure, bone growth and development, osteoporosis in children and skeletal morbidities in children with acute lymphoblastic leukaemia (ALL) are discussed. After that, the mechanostat and the effect of whole body vibration (WBV) on bone health are considered. Finally, I examine diagnostic approaches to assess the musculoskeletal system. In chapter 2, the incidence and risk factors for skeletal morbidity in ALL children are determined. The medical records of all (n,186, male,110) children presenting with ALL between 1997 and 2007 and treated on UKALL97, UKALL97/01 or UKALL2003 were studied. Skeletal morbidity included musculoskeletal pain (MSP), fractures and osteonecrosis (ON). MSP was classified as any event of limb pain, muscle pain, joint symptoms or back pain that required radiological examination. Fractures and ON were confirmed by X-rays and MRI respectively. We found that skeletal morbidity, presenting as MSP, fractures or ON were reported in 88(47%) children of whom 56(63%) were boys. Of 88 children, 49(55%), 27(30%) and 18(20%) had MSP, fracture(s) or ON, respectively. Six (7%) had both fractures and ON. The median(10th,90thcentiles) age at diagnosis of ALL children without skeletal morbidity was 3.9years(1.4,12), which was lower than in those with skeletal morbidity at 8.2years(2.2,14.3) (p<0.00001,95%CI:1.7,4.4). Children with ALL diagnosed over 8years of age were at increased risk of developing fracture(s) (p=0.01,odds ratio(OR)=2.9,95%CI:1.3,6.5), whereas the risk of ON was higher in those who were diagnosed after 9years of age (p<0.0001,OR=15,95%CI:4.1,54.4). There was no gender-difference in the incidence of skeletal morbidity. Children who received dexamethasone had a higher incidence of skeletal morbidity than those who were treated with prednisolone (p=0.027,OR=2.6,95%CI:1.1,5.9). We concluded that the occurrence of skeletal morbidity in ALL children may be influenced by age and the type of glucocorticoids (GCs). These findings may facilitate the development of effective bone protective intervention. In chapter 3, the aim is to investigate the influence of physical activity, age and mineral homeostasis over the first 12months of chemotherapy on subsequent skeletal morbidity. We reviewed 56 children who presented with ALL between 2003 and 2007 and treated only on iv UKALL2003. The number of in-patient days over the first 12months of chemotherapy was collected and used as a surrogate marker of inactivity and lack of well-being. Data for serum calcium (Ca), phosphate (Pho), magnesium (Mg) and albumin were also collected over this period. Skeletal morbidity was defined as any episode MSP or fractures. We found that the median duration of in-patient days over the first 12months of treatment in children with no skeletal morbidity was 58days(40,100), whereas the median number of in-patient days during the first 12months in those children with any skeletal morbidity, MSP only or fractures only was 83days(54,131), 81days(52,119) and 91days(59,158), respectively (p=0.003). Children with skeletal morbidity and fractures particularly had lower levels of serum Ca, Mg and Pho compared with those without skeletal morbidity over the first 12 months of chemotherapy. There was a higher risk of skeletal morbidity in those who were diagnosed after the age of 8years (p=0.001,OR=16,CI:3,80). Multiple regression analysis showed that the incidence of skeletal morbidity only had a significant independent association with age at diagnosis (p=0.001) and the number of inpatient days (p=0.03) over the first 12months (r=23). All children who were diagnosed after the age of 8years with an inpatient stay of greater than 75 days in the first 12 months of the chemotherapy (n,14) had some form of skeletal morbidity (OR=64). The conclusion was that the incidence of skeletal morbidity in children receiving chemotherapy for UKALL2003 is associated with a higher likelihood of being older and having longer periods of inpatient stay. The close link between age and changes in bone mineral status may be one explanation for the increased bone morbidity in ALL children In chapter 4, the effects of two WBV regimens on endocrine status, muscle function and markers of bone turnover are compared. We recruited 10adult men with a median age of 33years(29,49), who were randomly assigned to stand on the Galileo platform (GP) (frequency (f)=18-22Hz, peak to peak displacement (D)=4mm, peak acceleration (apeak) =2.6-3.8g) or Juvent1000 (f=32-37Hz, 0.085mm,0.3g) platform (JP) three times/week for a period of eight weeks. The measurements were performed at five time points (T0, T1, T2, T3, T4) and performed in a four week period of run-in (No WBV), eight weeks of WBV and a four-week period of washout (No WBV). The measurements included anthropometries, body composition measured by Tanita, muscle function measured by Leonardo mechanography and biochemical markers of endocrine status and bone turnover. The immediate term effect of WBV at 22Hz was associated with an increase in serum growth hormone (GH), increasing v from 0.07μg/l(0.04,0.69) to 0.52μg/l(0.06,2.4) (p=0.06),0.63μg/l(0.1,1.18)(p=0.03) ,0.21μg/l (0.07,0.65) (p=0.2) at 5minutes, 20minutes and 60minutes after WBV, respectively in the GP group. The immediate term effect of GP at 18Hz was associated with a reduction in serum cortisol from 316nmol/l (247,442) at 60minutes pre-WBV to 173nmol/l(123,245)(p=0.01), 165nmol/l(139,276)(p=0.02) and 198nmol/l(106,294)(p=0.04) at 5minutes, 20minutes and 60minutes post-WBV, respectively. At 22 Hz, GP was associated with a reduction in serum cortisol from 269nmol/l(115,323) at 60minutes before WBV to 214nmol/l(139,394)(p=0.5), 200nmol/l(125,337)(p=0.08) and 181nmol/l(104,306)(p=0.04) at 5minutes, 20minutes and 60minutes post-WBV, respectively. Median serum cortisol decreased after eight weeks of WBV from 333nmol/l(242,445) to 270nmol/l(115,323)(p=0.04). Median serum of the carboxy-terminal telopeptide (CTX, bore resorption marker) reduced significantly after eight weeks of WBV from 0.42ng/ml(0.29,0.90) to 0.29ng/ml(0.18,0.44)(p=0.03). None of these changes were observed in the JP group. Therefore, WBV at a certain magnitude can stimulate GH secretion, reduce circulating cortisol and reduce bone resorption. These effects are independent of clear changes in muscle function and depend on the type of WBV that is administered. In chapter 5, the effect of WBV using GP on the bone health of children receiving chemotherapy for ALL was assessed. We recruited 16children with ALL with a median age of 7.8years(5-13.8; 9males), who were randomized either to receive side-alternating WBV (f=16-20Hz,D=2mm, apeak =1-1.6g)(n,9) or to stand on a still platform as a control group (n,7) for 9minutes, once/week for four months. Measurements were performed at baseline, two-month and four-month assessing bone health (DXA and p.QCT), body composition and muscle function by imaging and biochemical assessment. DXA BMC data were corrected for bone area and presented as BMC z-score. We found that the median compliance rate measured as a ratio of actual completed minutes and expected minutes of WBV was 55%(17,100). The median percentage change of total body BMC z score in the WBV group from baseline to four months dropped by 10%(-25,10)(p=0.1), whereas it was 87%(-203,4)(p=0.07) in the control group. The median lumbar spine BMC z-score (L2-L4) in the WBV group was -0.4(-1.3,0.3) and -0.3(-1.4,1.5) at baseline and four months, whereas the respective data in the control group were 0.04(-0.6,2.4) and -0.1(-1.1,1), respectively. The median percentage change in LS-BMC z-score declined from baseline to four-month by19%(-349,365)(p=0.1) vi and 75%(-1016,178)(p=0.1) in the WBV and control groups, respectively. We concluded that WBV is tolerated by children receiving chemotherapy.
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Wilson, Kerrie Lauren. "Malignant stem cells in childhood acute lymphoblastic leukaemia." Thesis, University of Newcastle Upon Tyne, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.525030.
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Brown, Nicola Jane Marie. "Inactivation of P21(WAF1/CIP1) in acute leukaemia." Thesis, University of Newcastle Upon Tyne, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.446232.
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Sorour, Amani Fouad Abdel Halim. "Chromosome 6q16-21 deletions in acute lymphoblastic leukaemia." Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399158.
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Pyzer, Athalia Rachel. "Myeloid-derived suppressor cells in acute myeloid leukaemia." Thesis, Queen Mary, University of London, 2017. http://qmro.qmul.ac.uk/xmlui/handle/123456789/36704.
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The tumour microenvironment consists of an immunosuppressive niche created by the complex interactions between cancer cells and surrounding stromal cells. A critical component of this environment are myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells arrested at different stages of differentiation and expanded in response to a variety of tumour factors. MDSCs exert diverse effects in modulating the interactions between immune effector cells and malignant cells. An increased presence of MDSCs is associated with tumour progression, poorer outcomes, and decreased effectiveness of immunotherapeutic strategies. In this project, we sought to quantify and characterise MDSC populations in patients with Acute Myeloid Leukaemia (AML) and delineate the mechanisms underlying their expansion. We have demonstrated that immune suppressive MDSCs are expanded in the peripheral blood and bone marrow of patients with AML. Furthermore, AML cells secrete extra-cellular vesicles (EVs) that skew the tumour microenvironment from antigen-presentation to a tumour tolerogenic environment, through the expansion of MDSCs. We then demonstrated that MDSC expansion is dependent on tumour and EV expression of the oncoproteins MUC1 and c-Myc. Furthermore, we determined that MUC1 signalling promotes c-MYC expression in a microRNA (miRNA) dependent mechanism. This observation lead us to elucidate the critical role of MUC1 in suppressing microRNA-genesis in AML, via the down-regulation of the DICER protein, a key component of miRNA processing machinery. Finally, exploiting this critical pathway, we showed that MDSCs can be targeted by MUC1 inhibition or by the use of a novel hypomethylating agent SGI-110.
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Green, C. L. "Studies on CEBPA mutations in acute myeloid leukaemia." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1379542/.
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Acute myeloid leukaemia (AML) is a highly heterogeneous disease with regard to clinical outcome, and molecular markers with prognostic impact can be used to stratify patients for risk-adapted therapy. CEBPA mutations have been associated with a favourable prognosis, however several questions remained, in particular whether one (CEBPA-single) or two (CEBPA-double) mutations were necessary for this benefit, and their interaction with other molecular markers. A method of detecting CEBPA mutations in patient samples using denaturing HPLC was developed and the CEBPA status of 1427 young adult AML patients (median age 43 years, range 15-68 years) determined. Overall, 107 (7%) were CEBPA-mutant: 48 (45%) CEBPA-single and 59 (55%) CEBPA-double. The majority of CEBPA-double patients (83%) had an out-of-frame insertion/deletion in the N-terminus and a mutation in the C-terminal DNA-binding/leucine zipper domains (DBD/LZD) that were on different alleles as determined by cloning. By contrast, mutations in CEBPA-single cases were distributed across the gene. CEBPA-double patients were less likely to have a FLT3/ITD (P=.04) and highly unlikely to have an NPM1 mutation (P<.0001) compared to CEBPA-WT/CEBPA-single cases. Eight year overall survival (OS) was higher in CEBPA-double patients compared to CEBPA-WT and CEBPA-single cases (54%, 34%, 31%, respectively, P=.004). In multivariate analyses, CEBPA-double, but not CEBPA-single, was an independent favourable factor for OS (P=.004) and relapse (P=.02). However, this benefit was completely lost in the presence of a FLT3/ITD. The mutant level of 101 mutations was determined by fragment analysis and the majority were of a level consistent with a heterozygous mutation present in most cells. The impact of ten atypical CEBPA mutations on C/EBPα transactivation activity was explored by a luciferase reporter assay. Only mutations affecting the DBD or LZD functional domains had an impact on transactivation activity. This work provides insight into the biology of CEBPA mutations and their use as clinical markers.
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Putwain, Sarah Lucy. "The role of Sox4 in acute myeloid leukaemia." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648624.
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Mangolini, M. "Oncogenic signalling in t(12;21) Acute Lymphoblastic Leukaemia." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1415780/.
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The t(12;21)(p13;q22) translocation is present in up to 25% of children with pre-B cell Acute Lymphoblastic Leukaemia (ALL). This translocation involves two transcription factors, TEL (ETV6) and AML (RUNX1), both of which have crucial roles in regulating haematopoiesis. Clinically, TEL-AML1 positive patients have good prognoses. However, late relapses, additional genetic lesions affecting prognosis, and long-term side-effects of chemotherapy remain a cause for concern. In light of recent studies showing genetic and functional heterogeneities in cells responsible for cancer clone maintenance and propagation, targeting common deregulated pathways may be critical for the success of novel therapies. Using Affymetrix GeneChip global gene expression analysis our laboratory previously identified three genes: Tbx2, E2f5 and Lif-R, specifically expressed in TEL-AML1 transduced mouse foetal liver haematopoietic progenitor cells (HPC) cells compared with control cells. Over-expression of these genes was confirmed by real-time qPCR and the specificity of target gene expression was evaluated in human TEL-AML1 positive and negative leukaemia cells. Pathway analysis of TEL-AML1 transcriptional target genes also demonstrated deregulated expression of genes associated with STAT3 signalling, known to be one of the most important pathways required for proliferation and maintenance of multipotency in cancer stem cells. In this study we demonstrate the importance of STAT3 activity in a mouse model of TEL-AML1 overexpression, in human TEL-AML1 positive leukaemia cells and primary human leukaemic samples. Our data indicate a central role for TEL-AML1 in maintaining activated STAT3. This is mediated by transcriptional induction of the Guanine nucleotide exchange factor, ARHGEF4, leading to RAC1 activation and consequent stimulation of STAT3. The latter is necessary for survival, proliferation and self-renewal of TEL-AML1 positive leukaemia through transcriptional induction of MYC expression. In conclusion, we show a novel signalling pathway important for maintenance of t(12;21) leukaemia that constitutes a promising novel therapeutic target for the treatment of this disease.
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Jackson, Rosanna Katherine. "Personalisation of dexamethasone in childhood acute lymphoblastic leukaemia." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3940.
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Dexamethasone (dex) is a key treatment for childhood acute lymphoblastic leukaemia (ALL), but is associated with significant variability in terms of toxicity and efficacy. In this project, the following variables were assessed to better understand how dex personalisation may be achieved: pharmacokinetics, intracellular dex accumulation, glucocorticoid receptor (GR) posttranslational modifications and B-cell maturation state. For pharmacokinetic studies, samples were collected from 154 patients randomised to short (10mg/m2 x 14 days) or standard (6mg/m2 x 28 days) dex induction therapy, as part of the UKALL 2011 trial, and analysed using a validated LC/MS method. Wide pharmacokinetic variability was observed, with AUC0-12h and Cmax significantly higher on the short compared to standard arm. However there was substantial overlap between the two arms, with a number of patients on the standard arm exhibiting higher exposures than those on short therapy. The UKALL 2011 trial found no statistical difference in terms of steroid-related toxicity or MRD response between short and standard dosing. These data suggest that the considerable dex pharmacokinetic variation identified may be a more important factor than variation in dosing regimen. For cellular pharmacology experiments, cell lines, primagraft and primary patient samples were studied. Dex sensitivity was assessed using Alamar Blue assays and GI50 values ranged from 2-1000nM. Western blotting indicated wildtype GR in all samples. Dex accumulation was assessed by LC/MS and flow cytometric analysis of dex-FITC. While patient samples exhibited large variability, dex accumulation was not significantly different between sensitive and resistant cells. Differential dex sensitivity was not accounted for by differences in GR posttranslational modifications, assessed using capillary isoelectric focusing. However, assessment of B-cell maturation using mass cytometry revealed a relationship with dex resistance. Importantly, >50% of patient cell samples had dex GI50 values greater than plasma concentrations observed on either arm of the UKALL 2011 trial. A combined approach incorporating pharmacokinetic assessments and cellular response in ALL cells may allow a more comprehensive understanding of dex pharmacology to optimise its clinical utility.
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Austin, Stephen J. "The prognostic significance of the mixed lineage leukaemia partial tandem duplication in acute myeloid leukaemia." Thesis, Cardiff University, 2010. http://orca.cf.ac.uk/54154/.
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This study concerns a specific molecular genetic mutation, the mixed lineage leukaemia partial tandem duplication ( MLL PTD). MLL is a transcriptional regulator that known to be instrumental in both normal haematopoiesis and in leukaemogenesis. This study aimed to evaluate the prognostic importance of this abnormality through investigation of its influence on clinical outcome, its utility as a marker of minimal residual disease (MRD) and the downstream effects of its expression. A qualitative PCR assay was established and determined the frequency of MLL PTD to be 5.2% in
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Hussey, Damian J. "An investigation of the (4;11)(q21;p15) translocation in acute lymphocytic leukaemia /." Title page, contents and abstract only, 2000. http://web4.library.adelaide.edu.au/theses/09PH/09phh9725.pdf.
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Thesis (Ph.D.) -- University of Adelaide, Dept. of Medicine, 2000.Copies of author's previously published articles inserted. Errata pasted onto verso of back end-paper. Bibliography: leaves 163-189.
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Chim, Chor-sang James. "Study of gene promoter methylation in acute promyelocytic leukaemia." Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B25256725.
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Evans, Jane P. M. "Tyrosine protein kinases and their substrates in acute and chronic leukaemias and their leukaemia cell lines." Thesis, University of Oxford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235871.
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Grandage, V. L. "Investigation of aberrant signal transduction in acute myeloid leukaemia." Thesis, University College London (University of London), 2007. http://discovery.ucl.ac.uk/1445527/.
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Haematopoiesis is the result of tightly regulated signal transduction pathways mediated by cytokines and their receptors. Aberrations in these pathways are an underlying cause for diseases such as leukaemia and other myeloproliferative and lymphoproliferative disorders. The PI3-Kinase/Akt pathway is central to regulation of cell survival and proliferation. This study found that the PI3-Kinase pathway is activated in AML cells. This activation was reduced or abolished when the cells were incubated with the PI3-Kinase inhibitor, LY294002. Leukaemic cell survival appeared to be dependent on PI3-Kinase activation as incubation with LY294002 resulted in a reduction in cell number and an increase in apoptosis. This was also true for the CD34+/38- leukaemic stem cell population. Further work indicated that activation of Akt alone was sufficient to protect factor dependent cells from cytokine withdrawal induced apoptosis and also from the cytotoxic effects of Ara-C and Etoposide. The JAK/ STAT Pathway is important for many biological responses including differentiation and proliferation and its dysregulation has also been reported in many malignancies. It was shown that G66976, a selective PKC inhibitor, is a potent inhibitor of JAK 2 in in vitro kinase assays and in whole cell systems and inhibits signaling downstream of multiple JAK2 coupled cytokines including IL-3, GM-CSF and EPO. G66976 was also found to inhibit signalling downstream of disease-associated forms of JAK2 such as the TEL-JAK2 fusion and mutant JAK2 V617F. The majority of primary AML cells investigated had constitutive STAT activation which was reduced by incubation with G66976 in the majority of cases. This reduction was accompanied by a decrease in cell survival and proliferation. This work indicates that both the PI3-Kinase/Akt and the JAK/STAT pathways would be appropriate targets for the development of small molecule inhibitors for use in the treatment of AML.
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Ivey, Adam Stuart. "Molecular characterisation and tracking disease in acute myeloid leukaemia." Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/molecular-characterisation-and-tracking-disease-in-acute-myeloid-leukaemia(a3aac920-4bbe-4360-afbd-2bd1dbe5e738).html.
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Acute myeloid leukaemia (AML) is a highly heterogeneous disease in terms of genetics and at the clonal level. Despite improved understanding of the genetic landscape of AML, pathogenesis and cause of disease relapse remain poorly understood. To address these issues exome sequencing was carried out on 25 diagnostic and 12 relapse samples from 28 cytogenetic standard risk AML patients. More than 500 somatic mutations were identified, including recognised recurrent mutations, and novel variants with driver potential. Copy number variations were also investigated, identifying loss of heterozygosity of chromosome 13 involving the FLT3 locus as a common event acquired at disease relapse. The heterogeneity of disease relapse was also highlighted with the analysis of paired diagnostic and relapse samples. To further develop an understanding of AML clonal architecture and disease evolution, targeted deep sequencing was then carried out using a custom gene panel informed by exome sequencing results. Two cohorts were analysed including 223 diagnostic and 49 relapse samples from NPM1 mutant AML patients, followed by 43 unselected AML patients. In the NPM1 mutant cohort co-operating mutations were identified in 99% of patients, while at least one mutation was detected in 91% of the unselected cohort. Furthermore, quantification of variant allele frequencies allowed detailed analysis of mutational hierarchy and clonal evolution of relapse. The prevalence of mutations in candidate genes was also assessed, notably identifying mutations of MYC as recurring events in NPM1 mutant AML. Knowledge of AML genetics can also be applied post-treatment to track minimal residual disease (MRD) using molecular markers. Reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) assays were designed and optimised for rare fusion genes and NPM1 mutations. As a model, the NPM1 mutant RT-qPCR assays were used to track MRD in follow up samples from a large cohort of NPM1 mutant AML patients. These data identified a single MRD measurement in the blood following the second course of chemotherapy was the most informative outcome predictor, independent of mutational profile. It was also established that analysis of sequential samples could identify patients destined for relapse providing an opportunity for pre-emptive treatment. In the future a more personalised treatment approach, incorporating both mutational profiling and MRD monitoring, may improve patient outcome.
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Rehe, Klaus. "Diversity of cancer stem cells in acute lymphoblastic leukaemia." Thesis, University of Newcastle Upon Tyne, 2012. http://hdl.handle.net/10443/1777.
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For many cancers research led to controversial results regarding frequency and identity of cancer stem cells, cells that self-renew and are able to reconstitute the full phenotype of the original malignancy. In some malignancies such as acute myeloid leukaemia the hierarchical stem cell model that suggests that only rare and immunophenotypically immature blasts exhibit stem cell characteristics, resembling the normal physiological haematopoietic hierarchy, has been well established. In contrast to that, the stochastic model states that all or at least a substantial proportion of malignant cells has stem cell potential whereby this is supported by extrinsic stimuli. Initially, several studies suggested that acute lymphoblastic leukaemia (ALL) also is organised in a hierarchy. However, using more immunocompromised mouse strains and refined transplantation techniques for in vivo xenotransplantation models, previous findings regarding frequency and restriction of stem cells to very early B-precursor cell stages have been challenged in more recent studies. In order to address the questions of identity and frequency of stem cells in ALL, a robust orthotopic mouse model with the most immunocompromised mouse strain currently available (NOD/scid IL2Rγnull; NSG) was established. Primary diagnostic patient ALLs or blasts harvested from engrafted mouse bone marrow were sorted for B-cell lineage differentiation markers CD10, CD19, CD20 or CD34 to purify candidate stem cell populations of different maturity. All transplanted cell populations, from the most immature CD34+CD19low stage to the already more differentiated stage of CD19+CD20high cells were able to reconstitute the original ALL in mouse bone marrow and followed a typical dissemination pattern with infiltration of the spleen. Furthermore, this more mature CD19+CD20high subpopulation proved self-renewal ability in serial transplantation experiments. To investigate, whether stem cells in ALL are a rare entity or more abundant, unsorted bulk leukaemia blasts were transplanted in limiting dilutions from 1 x 104 to 10 cells per mouse. Cell numbers required for engraftment varied between leukaemias but the leukaemia engrafted in mice when only 10 to 1,000 cells were transplanted. The limiting dilution experiments were repeated with sorted blast populations according to the surface antigens CD10, CD20 and CD34. Stem cell frequencies in all sorted populations were comparable and as few as 10 to 100 cells were sufficient to reconstitute the leukaemia in mice. Stem cells do not seem to be restricted to immature blast populations as in the hierarchical model but a broad spectrum of different blast immunophenotypes display stem cell capabilities. Furthermore, the frequency of stemness among unsorted bulk ALL cells as well as subpopulations of different maturity according to the blast immunophenotype is high and similar. The results from this thesis provide strong evidence for the stochastic cancer stem cell model in B precursor ALL.
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Lim, Seah-Hooi. "Immunotherapy and recombinant interleukin-2 in acute myeloid leukaemia." Thesis, University of Aberdeen, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.484307.
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In this study 12 acute myeloid leukaemia (AML) patients (3 in 1st complete remission (CR), 3 in 2nd CR, 3 in early relapse or partial remission and 3 in frank relapse) were treated with continuous infusion of recombinant Interleukin-2 (rIL-2). Adverse reactions among these patients were common. In all patients, there were evidence of lymphocyte activation with subsequent upregulation of the cellular cytotoxic functions following the infusion of rIL-2. Despite this, clinical response among patients treated with active disease remains disappointing, with only 1 patient achieving a 3rd complete remission after being treated in early 2nd relapse (marrow blast counts of 10%). The other patients had brief periods of stable disease but died eventually of disease progression. No conclusion however can be drawn from patients treated in complete remission due to the small number of patients entered into the study. In vitro studies were performed in a different cohort of AML patients, at presentation and during complete remission. In all the patients, both the Natural Killer (NK) and Lectin-Dependent Cellular Cytotoxicity (LDCC) activities were significantly reduced when compared to normal healthy controls. Patients in complete remission however had higher values than those studied during active diseases. These findings would suggest a strong rationale for the use of immunotherapy capable of upregulating the NK and LDCC activities, e.g. rIL-2. Further rationale for the use of immunotherapy has been drawn from the findings that leukaemia blast cells of AML are immunogenic, as evidenced by data of T cell activation in these patients and the presence of complement-fixing antibodies for autologous myeloblasts. More importantly no stimulation of the myeloblast proliferation by IL-2 was observed in any of the myeloblasts studied. All these findings would point to a good and safe rationale for the use of rIL-2 in AML patients.
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Aldhafiri, Fahad Khalid. "Weight status during and after childhood acute lymphoblastic leukaemia." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4500/.
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Background: This thesis sits within the arena of weight status during and after childhood acute lymphoblastic leukaemia (ALL), with a particular focus on the prevalence of unhealthy weight status amongst (ALL), Saudi and UK populations. Each chapter in the thesis explores different aspects of unhealthy weight status in ALL which had been highlighted as gaps in the literature at a conference in Puebla, Mexico, at the end of 2006. A summary of each study is given below. Study 1: Background: This study estimated prevalence of unhealthy weight status and metabolic syndrome (MS) amongst Saudi survivors of standard risk ALL. Methods: We recruited 56 survivors, mean age 13.4 years (SD 4.1), a mean of 9.1 years (SD 4.1) post-diagnosis. The BMI for age was used to define weight status relative to national (Saudi) and international (Cole et al., International Obesity Task Force (IOTF), World Health Organisation (WHO), and Centre for Disease Control and Prevention (CDC)) reference data. We measured body composition by dual energy X-ray absorptiometry (DXA), waist circumference, blood pressure, lipid profile (HDL-C, Triglycerides), fasting glucose and insulin. Results: According to international definitions based on BMI for age, around half of the sample had unhealthy weight status. All of the approaches based on BMI for age underestimated over-fatness, present in 27/51 (53%) of the sample according to DXA. Prevalence of MS was 7.1% (3/42 of those over 9-years old) and 5.4% (3/56) by applying the International Diabetes Federation (IDF) definition and National Cholesterol Education Program Third Adult Treatment panel Guidelines (NCEP III), respectively. However, MS by the NCEP III definition was present in 19% of the overweight and obese survivors and 7.1% of the sample had at least two of the components of MS. Conclusions: Unhealthy body weight and over-fatness may be common amongst adolescent Saudi survivors of standard risk ALL, though overweight and obesity may be no more common than in the general Saudi adolescent population. Defining weight status using BMI underestimates over-fatness in this population, as in other populations. Study 2: Background: Underweight, overweight, and obesity at diagnosis may all worsen prognosis in childhood ALL, but no studies have estimated prevalence of unhealthy weight status at diagnosis in large representative samples using contemporary definitions of weight status based on BMI for age. Methods: Retrospective study which aimed to estimate prevalence of underweight, overweight, and obesity at diagnosis for patients with childhood ALL on three successive UK treatment trials: UKALL X (1985-1990, n 1033), UKALL XI (1990- 1997, n 2031), UKALL 97/97-99 (1997-2002, n 898) .The BMI for age was used to define weight status with both UK 1990 BMI for age reference data and the IOTF definitions. Results: Prevalence of underweight was 6% in the most recent trial for which data were available. Prevalence of overweight and obesity was 35% in the most recent trial when expressed using IOTF definitions; 41% when expressed relative to UK 1990 reference data. Conclusions: Even with highly conservative estimates >40% of all UK patients with ALL were underweight, overweight, or obese at diagnosis in the most recent trial for which UK data are available (UKALL 97/99, 1997-2002). Study 3: Background: This study tested the hypothesis that overweight/obesity at diagnosis of childhood ALL was related to risk of relapse. Methods and results: In a national cohort of 1033 patients from the UK there was no evidence that weight status at diagnosis was related significantly to risk of relapse: log ranks test (p value= 0.90) with overweight and obesity as the exposure (n 917); individual (p value= 0.42) and stepwise (p value= 0.96) proportional hazards models, with BMI z score as the exposure (n 1033). Conclusion: The study does not support the hypothesis that overweight/obesity at diagnosis impairs prognosis in childhood ALL in the UK. Study 4: Background: In the sample of Saudi patients recruited to study 1 we compared DXA whole body and lumbar spine bone mineral density (BMD) using manufacturers software with a body size correction which derived bone mineral content (BMC) for bone area and Apparent bone mineral density of lumbar spine (BMADLS). Methods and results: The survivors of ALL were from Saudi Arabia (n 51, mean age 13.5 years). With no corrections, 29 patients (57%) had lumbar spine BMD z score < -1.0 and 21 (41%) had whole body BMD z score < -2. After correction, by using BMC for bone area method only 6 (12%) had lumbar spine BMC z score <-1.0 and 4 (8%) had whole body BMC z score <-2. By using BMADLS method, 18 (35%) had BMC <-1.0 and 6 (11%) had BMC Z score <-2. Conclusions: Correction for body size seems essential to accurate interpretation of DXA bone health data in adolescent survivors of ALL. The three correction methods provided different conclusions, but bone health remains a concern after treatment for ALL.
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Chim, Chor-sang James, and 詹楚生. "Study of gene promoter methylation in acute promyelocytic leukaemia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2002. http://hub.hku.hk/bib/B25256725.
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卓大治 and Tai-chi Cheuk. "Childhood acute lymphoblastic leukaemia with TEL-AML1 gene fusion." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31969690.
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Kozlowski, Ryszard E. "Aspects of blast cell proliferation in acute myeloblastic leukaemia." Thesis, Nottingham Trent University, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293853.
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Sulong, Sarina. "Determination of allelic imbalance in childhood acute lymphoblastic leukaemia." Thesis, University of Newcastle Upon Tyne, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.445581.
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Le, Dieu Helen Rifca. "Characterisation of T cell defects in acute myeloid leukaemia." Thesis, Queen Mary, University of London, 2009. http://qmro.qmul.ac.uk/xmlui/handle/123456789/561.
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Understanding the immune system in patients with cancer and how it interacts with malignant cells is critical for the development of successful immunotherapeutic strategies at a time when novel cancer treatment approaches are required. Acute myeloid leukaemia (AML) results in widespread interaction between the malignant cells and T cells and as such, offers an opportunity to study these interactions. A flow cytometric analysis of T cells in the peripheral blood of patients presenting with AML illustrated that the absolute number of T cells is increased in AML compared with healthy controls. Furthermore, a large population of CD3+56+ cells was identified. These cells are not natural killer T cells but effector T cells that may represent a failing immunosurveillance mechanism. Two technical issues were explored: how to separate T cells from the peripheral blood of newly diagnosed AML patients and the impact of the method of immunomagnetic cell separation on the gene expression profile of healthy T cells. Gene expression profiling was subsequently performed on T cells from AML patients compared with healthy controls. Global differences in transcription were observed suggesting aberrant T cell activation patterns in AML. As differentially regulated genes involved in actin cytoskeletal formation were noted, a functional assessment of the ability of T cells from AML patients to form immunological synapses was performed. This illustrated that although T cells from AML patients can form conjugates with autologous blasts, their ability to form immune synapses and recruit phosphotyrosine signalling molecules to that signalling interface is impaired. Taken together, these findings demonstrate that numerically T cells are plentiful in AML however they are abnormal in terms of the genes they are transcribing and in their interactions with tumour cells. Targeting immunological synapse formation may represent an important means of improving T cell recognition of tumour cells across a range of cancers.
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Sundaresh, A. "Aberrant transcriptional pathways in t(12;21) Acute Lymphoblastic Leukaemia." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1522624/.
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The single most frequent chromosomal translocation associated with childhood Acute Lymphoblastic Leukaemia is the t(12;21) rearrangement, that creates a fusion gene between TEL (ETV6) and AML1 (RUNX1). Although TELAML1+ patients have a very good prognosis, relapses occur in up to 20% of cases and many patients face long-term side effects of chemotherapy. Our laboratory has previously shown that TEL-AML1 regulates Signal Transducer and Activator of Transcription 3 (STAT3) activation, which is critical for survival of the leukaemic cells. In this study, inhibition of STAT3 in TEL-AML1+ cells results in decreased SMAD7 gene expression. SMAD7 is an antagonist of TGF-β signalling, functioning through a negative feedback mechanism, but is also known to function in other biological pathways. In order to investigate the role of SMAD7 in TEL-AML1+ leukaemia, lentiviral mediated SMAD7 knockdown was performed in human TELAML1+ cell lines. SMAD7 silencing inhibited proliferation of TEL-AML1+ cell lines, eventually leading to growth arrest and apoptosis. Furthermore, our data showed that this effect is not mediated through TGF-β signalling, indicating that SMAD7 was functioning through an alternative pathway. We also observed growth arrest following SMAD7 knockdown in other ALL and AML subtypes. Furthermore, silencing of SMAD7 in TEL-AML1+ ALL cells transplanted into immunodeficient mice impaired disease progression in vivo, resulting in prolonged disease latency. To investigate the essential pathways regulated by SMAD7 in these leukaemic cells, we performed RNA-sequencing analysis on TEL-AML1+ cells following SMAD7 knockdown. Global gene expression analysis revealed SMAD7 to be a regulator of cholesterol biosynthesis, a pathway critical for leukaemia cell survival. Our 4 experiments establish a novel transcriptional pathway operating specifically in t(21;21) ALL, but regulating downstream pathways essential for ALL in general. This study highlights new therapeutic opportunities for ALL.
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El-Sharkawi, D. "Studies to investigate epigenetic factors in acute myeloid leukaemia." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1528735/.
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Acute myeloid leukaemia (AML) is a heterogeneous disease with numerous recurrent cytogenetic and molecular abnormalities. This heterogeneity is reflected in the variation in clinical outcome seen in patients. This disparity in outcome is also seen within groups of patients who have the same mutation or no known molecular abnormalities. To investigate whether the DNA methylation profile of samples can provide prognostic information, the methylome of forty cytogenetically normal AML samples that were wild-type for NPM1 and FLT3 was analysed, 20 were from patients with chemosensitive disease and 20 with chemoresistant disease. Unsupervised cluster analysis revealed the DNA methylation profile to be most associated with underlying CEBPA genotype hence a CEBPA signature was created using the 25 CpG sites that differed the most between wild-type (n=30) and classic CEBPADM (double mutant) samples (n=10). Two follow-up cohorts were analysed, validating the initial signature in differentiating classic CEBPADM samples from wild-type. CEBPASM (single mutant) samples had profiles more similar to the CEBPAWT (wild-type) signature. Non-classic CEBPADM samples with at least one mutation leading to loss of function of the C terminal were associated with a CEBPA mutant methylation profile. Methylation of the CEBPA promoter was not associated with a classic CEBPADM methylation profile in eight of the nine cases exhibiting hypermethylation. The ASXL1 gene, known to have a role in histone regulation, was screened in 371 patients using denaturing HPLC. The overall mutation rate was 9%. Overall survival was significantly lower in patients with an ASXL1 mutation, however the mutation was associated with secondary disease and older age, and thus in multivariate analysis mutations in ASX L1 lost significance. These studies indicate that epigenetic factors are closely linked to other prognostic traits such as age or underlying molecular status of the AML. Given this association, DNA methylation could play an important role in assessing the significance of different types of mutations.
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Shah, Niraj Mayank. "The role of NRF2 in acute myeloid leukaemia (AML)." Thesis, University of Liverpool, 2018. http://livrepository.liverpool.ac.uk/3022789/.
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Acute Myeloid Leukaemia refers to the excess proliferation of myeloid progenitor cells. Whilst the 5-year survival rate is 40% in younger patients, this falls to 5% in patients over 65 and resistance to front-line chemotherapy agents remain a problem. We previously identified NRF2, a regulator of anti-oxidant genes, to be constitutively activated in AML and this correlated with resistance to chemotherapy. Recent studies have also suggested NRF2 also plays a more oncogenic role. To further understand NRF2's role in both chemotherapy resistance and oncogenesis we looked at its ability to regulate miRNA in AML. Using a miRNA array, we identified several miRNAs, including miR-125b and miR-29b, whose expression correlated with that of NRF2 in both cell lines and AML patient samples. Both miRNAs exist as paralogs, in that they contain the same miRNA sequence but exist in different genomic locations and we used qPCR to identify miR-125b1 and miR-29b1 as paralogs regulated by NRF2. Using a reporter assay we confirmed the activity of putative NRF2-ARE binding sites in both miRNA promoters. To understand the function of both in AML we manipulated their expression using miRNA 'mimics' or antagomIRs. Individual manipulation of either miRNA resulted in a slight increase in apoptosis. However, the miRNAs appeared to act synergistically as when expressed simultaneously a significant increase in apoptosis was seen both in cell lines and patient blasts. Manipulation of both miRNA also resulted in the increased sensitivity of AML cells to chemotherapy agents. BAK1, STAT3 and AKT2 were shown to be targets of both miRNAs providing a novel mechanism by which NRF2 expression can affect AML cells. To further study the role of NRF2 in AML we used CRISPR-Cas9 to generate NRF2-deficient cells. CRISPR guide RNA were designed to target NRF2 Exons 1, 2 and genome editing validated in HEK293T cells. Leukaemic cell lines (K562 and THP-1) were virally transduced with guides targeting Exon 4 of NRF2. Once editing was verified clones were derived by growing selected cells in Methycellulose-containing medium. Putative clones were initially screened using MG-132 (to stabilise NRF2) and further confirmed by treatment with the NRF2 inducers CDDO-Me and Sulforaphane. Verified clones were characterised by Sanger Sequencing. In addition to CRISPR-Cas9 we also validated a number of other gene-editing methodologies including CRISPR-Cpf-1 and TALENs. Overall these methodologies represent powerful tools to further characterise the role of NRF2 in AML.
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Oram, Sarah Helen. "Cis-regulation of LM02 in T-acute lymphoblastic leukaemia." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609663.
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Mansour, M. R. "Role of the Notch signalling pathway in acute leukaemia." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1420122/.
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The Notch signalling pathway is important in development and differentiation of a diverse range of both embryonic and adult tissues. There is now strong evidence implicating aberrant Notch signalling in the pathogenesis of T-cell acute lymphoblastic leukaemia (T-ALL), with over 50% of paediatric patients having activating mutations in NOTCH-1. This thesis aims to explore several aspects of the Notch pathway in both T-ALL and acute myeloid leukaemia (AML). Chapter one summarises the published data on the Notch signalling pathway itself, addressing the basic understanding of Notch activation through cell-to-cell interaction, as well as the mechanisms through which it is regulated. The role that Notch signaling plays in normal haematopoiesis is also discussed. Chapter three addresses the incidence and characteristics of NOTCH-1 mutations in a cohort of adult patients with T-ALL in comparison to the published study of paediatric T-ALL, as well as in a cohort of patients with infantile leukaemia and AML. Secondly, the prognostic significance of NOTCH-1 and FBXW7 mutation status of adult T-ALL patients treated on the UKALLXII was investigated. Thirdly, a novel mutation affecting the LNR domain of NOTCH-1 is reported. Chapter four includes data quantifying NOTCH-1 mutation level in T-ALL patients, as well as the stability of NOTCH-1 mutations at presentation and relapse. These data indicate NOTCH-1 mutations commonly occur as secondary events in leukaemia pathogenesis, and suggest widespread clonal heterogeneity in T-ALL. Chapter five explores the functional and prognostic consequences of a novel alternatively spliced isoform of the CSL transcription factor in AML, which was termed CSL-TREX (for TRuncates Exon X). The functional consequences of expressing CSL-TREX in CD34+ cells, in luciferase reporter assays and co-immunoprecipitation experiments with NOTCH-1 is reported. Chapter six summarises the overall implications of these findings to T-ALL and AML, and the future directions of research in this area.
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Naiel, Abdulbasit. "Study of acute myeloid leukaemia with known chromosomal translocations." Thesis, Brunel University, 2014. http://bura.brunel.ac.uk/handle/2438/9303.
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Acute myeloid leukaemia (“AML”) is a clonal disease characterised by increased, uncontrolled abnormal white blood cells and the accumulation of leukaemia immature cells in the bone marrow and bloodstream. Chromosomal rearrangements have been detected in almost half of AML cases. It has been proven that the chromosomal rearrangements constitute a marker for the diagnosis and prognosis of AML and have therapeutic consequences. The discovery of these rearrangements has led to a new World Health Organization (“WHO”) classification system. However, small regions of cryptic chromosomal rearrangements have been identified among these cases. Such cryptic rearrangements can be explained by the identification of small regions which cannot be found by conventional chromosome banding techniques. Moreover, approximately 50% of AML cases have been found with normal karyotypes. The improvement of cytogenetic techniques, including fluorescence in situ hybridization (“FISH”) and single nucleotide polymorphism (“SNP”) platforms, have allowed the detection of small rearranged regions (such as copy number changes) both in normal and abnormal karyotype AML. This study identifies: (i) cryptic chromosomal translocations in leukaemia cells of AML patients; (ii) DNA copy number changes in patients with known chromosomal translocations; and (iii) the proliferating state of leukemic cells harbouring chromosomal abnormalities within a series of patients. In the initial study, the FISH technique was performed on 7 AML patient samples to validate a novel three colour probe for the detection of t(7; 12). The results demonstrated that the new three-colour FISH approach used in this study has enabled the detection of a cryptic t(7;12) translocation as part of a complex rearrangement in one patient previously been described as having t(7;16) and ETV6-HLXB9 fusion transcript at the molecular level. To date there are only two cases of a cryptic t(7; 12) translocation reported in the literature. Additionally, the new three-colour FISH approach also enabled identification of t(7; 12) in a new seven year-old AML patient (the first case of childhood leukaemia with an onset after infancy to be found positive for t(7; 12)). In the second study the FISH technique was used to validate three colour probe sets for the detection of 7(q22-q31) and 7(q22-q36.1) regions on several myeloid cell lines. The results indicate that the probes found chromosome 7 rearrangements in myeloid cell lines with complex rearrangements. The three colour probe sets enabled detection of a new rearrangement in the k562 cell line, described as a duplication of 7q36 region, followed by intrachromosomal insertion of long arm material into the short arm of chromosome 7. The intrachromosomal insertion identified in k562 cell line is an uncommon form of chromosomal rearrangement in myeloid leukaemia which has not been previously reported. In the third study, the Illumina BeadArray approach was used to assess copy number alterations (“CNAs”) and copy number loss of hertrozygosity (“CN-LOH”) regions in 22 AML patients samples with inv(16)(p13;q22) and t(8;21)(q22;q22) rearrangements. In order to distinguish between true CNAs and false-positive findings as well as to verify whether CNAs are present in the same clone harbouring inv (16), FISH was used on fixed chromosome and cell suspensions from the same patients. The results showed a low number of copy number losses and copy number gains in 17 (77.27%) out of 22 cases, with an average of 1.86 CNAs per case as well as copy neutral-LOH with an average of 6.7% per patient. Furthermore, interphase FISH was carried out on four cases showing a 7q36.1 deletion, 4q35.1 deletion, 16.13.11 deletion and 8q24.21-q24.3 gain identified by array. The FISH results confirmed CNAs in most cases while CNA was not confirmed in one patient. Moreover, the FISH data analysis showed that the CNAs were found in both cells without inv (16) and cells harbouring the inv (16) rearrangement. In the final study, indirect immunofluorescence (IF) was used to determine the ki67 staining patterns in 8 stimulated and unstimulated peripheral blood samples and k562 cell lines. The results showed a high percentage of ki67 positive staining in the stimulated samples in comparison with unstimulated samples, which showed a low percentage of ki67 positive staining. In addition, a high percentage of proliferating cells were detected in the k562 cell line. ImmunoFISH was performed on five different patient samples and leukaemia cell lines using specific probes in the regions of interest to detect the chromosomal abnormalities and using the ki67 antibody to assess the proliferation state of the cells. The results showed that the proliferation state of the cells carrying chromosomal abnormalities in two patients was higher than the proliferation state of the cells carrying abnormalities in three patients; in other words, most of the cells carrying abnormalities were proliferating in two cases and non-proliferating in three cases.
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Ede, Benjamin Christopher. "Improving therapies for childhood T cell acute lymphoblastic leukaemia." Thesis, University of Bristol, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.752757.
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RIBEIRO, Ana Rita Matias Rosa de Almeida. "Insights into Acute Myeloid Leukaemia metabolism using NMR Spectroscopy." Master's thesis, Instituto de Higiene e Medicina Tropical, 2017. http://hdl.handle.net/10362/22443.
Full textAbstract:
A Leucemia Mielóide Aguda (LMA) é o segundo tipo de leucemia mais
diagnosticado e o mais comum entre adultos. É uma condição hematológica caracterizada pela infiltração da medula óssea e do sangue por populações clonais de células mielóides imaturas, anormalmente diferenciadas e altamente proliferativas. É uma doença muito
heterogénea, originando-se a partir de uma grande variedade de linhagens hematopoiéticas, com perfis genéticos distintos.(2,3)
Uma das apresentações menos comuns desta doença é a acidose láctica
(acumulação de lactato no sangue), relacionada com um mau prognóstico de sobrevivência.(4) Esta condição está relacionada com elevadas taxas de glicólise aeróbica, o “efeito de Warburg”, resultando na produção de lactato que é excretado para o microambiente. Vários estudos demonstram que alguns tipos de células tumorais incorporam lactato e utilizam-no como base para o metabolismo oxidativo. (5,6)
Estudou-se o metabolismo de lactato e glucose de três linhagens de LMA (HL60, THP1 e HEL) através de RMN. Investigou-se também a influência do VEGF (importante no microambiente tumoral, estando envolvido no processo de angiogénese em LMA) nestas linhas celulares.(7)
Os resultados demonstraram que as linhas promielocítica e monocítica conseguem utilizar o lactato como base para a manutenção das suas necessidades energéticas e de biomassa, utilizando-o como substrato para o ciclo de Krebs e para a fosforilação oxidativa. Observámos que a linha monocítica metaboliza a glucose através da glicólise e da via das pentoses fosfato. A linha eritroleucémica depende da presença de glucose, sendo incapaz de suster o seu metabolismo usando o lactato como substrato. O VEGF parece ter um efeito positivo nas linhas HL60 e THP1, potenciando as taxas de glicólise e promovendo a produção de nucleótidos, o que sugere que o VEGF pode ter influência neste padrão metabólico alterado. Assim, as três linhagens de LMA apresentam diferentes graus de plasticidade metabólicas, tendo algumas se adaptado para tirar partido do microambiente, enquanto que outras parecem incapazes de se ajustar.
Também investigámos como a exposição a diferentes microambientes influencia o metabolismo da LMA. O microambiente natural dos blastos de LMA encontra-se na medula óssea mas as células podem espalhar-se e acumular-se noutras zonas do corpo onde, para sobreviver, têm de se adaptar a um microambiente diferente. Em alguns casos, a LMA resulta na infiltração do Sistema Nervoso Central, normalmente afectando as
meninges. (1)
Células HEL foram inoculados na medula e cérebro de ratinhos e, através de análise multivariada de espectros de RMN, foi possível fazer a distinção entre os perfis metabólicos das células expostas a cada um dos microambientes. Os resultados mostraram que esta linhagem está melhor adaptada para sobreviver no microambiente da medula do que no microambiente cerebral. Em ambos os microambientes observaram-se
alterações graduais no metabolismo resultantes de mais tempo de exposição, demonstrando que o metabolismo celular não é estático, sendo influenciado pelas características do meio envolvente.
Em conclusão, foi demonstrado que a elucidação do metabolismo de leucemia e da sua interacção com o microambiente é indispensável à caracterização desta doença e pode contribuir para esclarecer os mecanismos biológicos responsáveis pelo seu desenvolvimento e progressão.Acute Myeloid Leukemia (AML) is the second most diagnosed type of leukemia and the most common in adults. It is a haematological disorder characterized by the bone marrow and peripheral blood infiltration of clonal populations of abnormally differentiated and highly proliferative blasts. It is a very heterogenous disease, originating from a wide variety of haematopoietic lineages with a diverse genetic landscape.(2,3) One of the less typical presentations of AML involves lactic acidosis (the accumulation of lactate in the blood) which has been correlated with poor survival prognosis. (4) This condition is correlated with high rates of aerobic glycolysis, the “Warburg effect”, resulting in the production of lactate that is excreted to the microenvironment. Several studies have found that some cancer cells have can take up lactate and utilize it as a source for oxidative metabolism.(5,6) We studied the glucose and lactate metabolism of three different AML lineages (HL60, THP1 and HEL) through NMR spectroscopy. We also investigated the influence of VEGF (another key player in tumour microenvironment, known to be involved in tumour-related angiogenesis in AML) in these cell lines.(7) Our results showed that the promyelocytic and monocytic lines can rely on lactate to sustain their energy and biomass demands, utilizing it as substrate for the TCA cycle and oxidative phosphorylation. On the monocytic line we confirmed that glucose is mainly metabolized through glycolysis and pentose phosphate pathway. The erythroleukemic line was unable to sustain its metabolism on lactate consumption, being dependent on glucose to sustain the cells’ metabolism. VEGF seem to have a positive effect on the HL60 and THP1 lines, increasing glycolytic rates and promoting nucleotide production, which suggest that it may have a role in supporting the alternative metabolism exhibited by these cells. So, the three lineages of AML display very different metabolic plasticity, with some having adapted to take advantage of their environment, while others seeming unable to adjust. We also investigated how exposure to different microenvironments influences AML cell metabolism. The normal environment of AML is the bone marrow (BM), but the cells can spread and accumulate in other organs of the body, where they are required to adapt to a completely different environment. In some cases, AML can involve infiltration of the Central Nervous System, usually in the form of leptomeningeal disease.(1) We inoculated HEL cells into the brain and BM of mice and, through multivariate analysis of NMR data, were able to distinguish between the metabolic profiles of the cells exposed to the two environments. Our results showed that the HEL cell line is much better suited to survive in the BM microenvironment than in the brain microenvironment. In both microenvironments, there were gradual metabolic modifications as the result of increased exposure, indicating that cell metabolism is not static and is influenced by the characteristics of the surrounding microenvironment. In conclusion, we showed that understanding leukaemia metabolism and its interaction with the microenvironment is indispensable for disease characterization and can provide valuable insights into the biologic mechanisms that govern AML progression and survival.
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Yu, N. "Identifying and targeting dormant cells in acute myeloid leukaemia." Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/33679/.
Full textAbstract:
Relapse in AML is thought to arise from dormant leukaemic cells that are characterised by low RNA synthesis activity, protected by the bone marrow (BM) niche, and may evade the effects of chemotherapeutic drugs. Our aim was to investigate agents which might be able to overcome chemoprotection by targeting the intrinsic apoptosis pathway. We developed in vitro assays to identify and characterise the dormant AML cells using combinations of markers, including the cell-division marker PKH26, leukaemia-associated phenotypes (LAPs), and dormancy markers. In a dormancy model based on 12-day AML/stroma co-culture, we have shown that the expression of some aberrant phenotypes can persist for several days. Also, after 12 days, some of the CD34+, PKH26high (dormant), and LAP+ (leukaemic) cells maintained their primitiveness and were still clonogenic. Furthermore, our chemosensitivity data showed that novel agents TG02, and BH3 mimetics ABT-737 and ABT-199, which inhibit the B-cell lymphoma 2 (BCL-2) family of anti-apoptotic molecules, could efficiently target BM niche-mediated chemoresistance, which is thought to be one of the main obstacles to traditional chemotherapy. We explored various candidate dormancy markers based on the low RNA, non-proliferative profile of dormant cells. Among those tested, the RNA synthesis marker Pyronin Y (PY), and an antibody to the transferrin receptor CD71 were the most reproducible in terms of marker expression and stability. We endeavoured to characterise cell dormancy on the molecular level by investigating gene expression in the PYlow (dormant) and PYhigh (proliferating) subsets and have obtained limited results. In summary, this study has identified and partly characterised dormant AML cells by development of in vitro assays, and has shown chemosensitivity to novel agents TG02, ABT-737 and ABT-199 in dormant leukaemia cells.
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Robinson, Hazel M. "Acquired abnormalities of chromosome 21 in acute lymphoblastic leukaemia." Thesis, University of Southampton, 2008. https://eprints.soton.ac.uk/161483/.
Full textAbstract:
The intrachromosomal amplification of chromosome 21 (iAMP21) was identified as a novel and prognositically important acquired chromosomal abnormality in childhood acute lymphoblastic leukaemia (ALL). It is defined by multiple copies of the RUNX1 gene, as seen by fluorescence in situ hybridisation (FISH), localised to a single abnormal duplicated chromosome 21 [dup(21)]. The morphological form of this chromosome is highly variable between patients and currently the only reliable method of detection is FISH with probes to RUNX1. Studies of 48 iAMP21 patients using detailed FISH techniques and array-based comparative genomic hybridisation highlighted an extensive region of chromosome 21 involvement. A minimum common region of amplification, between 33.19 and 39.80Mb, including RUNX1 was identified, together with a minimum common region of deletion, between 46.54 and 46.92Mb, in 100% and 77% of patients, respectively. This study established that there were unique patterns of imbalance, with evidence of deletions, inversions and amplification, displayed on the dup(21), between individual patients. This provided evidence of an abnormality that may have arisen from a breakage-fusion-bridge mechanism, possibly initiated by loss of a telomere. Results indicated that iAMP21 represents a distinct genetic subgroup of childhood ALL and is not secondary to a cryptic abnormality of chromosome 21. Two possible variant cases were identified both involving chromosome 15. The abnormality can be distinguished from other numerical abnormalities of chromosome 21 by exploiting the unique pattern of gain, amplification and deletion seen in these patients. This allowed for the development of diagnostic tests based on copy number using either FISH or multiplex ligation dependent probe amplification (MLPA), both of which successfully identified iAMP21 patients.
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Krishnamurthy, Pramila. "Cellular and vaccination-based immunotherapy of acute myeloid leukaemia." Thesis, King's College London (University of London), 2014. http://kclpure.kcl.ac.uk/portal/en/theses/cellular-and-vaccinationbased-immunotherapy-of-acute-myeloid-leukaemia(ea5188b6-c807-4a99-8473-e99f55f19559).html.
Full textAbstract:
Approximately 50% of Acute Myeloid Leukaemia (AML) patients relapse within 5 years of diagnosis. Allogeneic haematopoietic stem cell transplantation (HSCT) has curative potential, partly mediated by a Graft-versus-Leukaemia (GvL) effect. GvL activity may be boosted by donor lymphocyte infusions (DLI) after HSCT, given pre-emptively (pDLI), to prevent relapse in mixed donor chimeric recipients, or therapeutically (tDLI) following disease recurrence. Few publications report efficacy of these approaches, therefore a retrospective analysis of outcomes after DLI at our institution, following lymphodepleted, reduced intensity conditioned HSCT for AML/myelodysplastic syndromes (MDS), was performed. Encouraging estimated 5-year overall survival rates following DLI of 80% for pDLI recipients and 40% for tDLI recipients were observed. Incidence of GvHD was only moderate, suggesting delayed add-back of immune cells can boost GvL reactions in AML/MDS patients without excessive toxicity. However, despite association of DLI with reduced relapse, leukaemia recurrence in a proportion of patients highlights that GvL activity is neither guaranteed nor universally sustained. Two forms of vaccination are described in this thesis, aiming to enhance priming and activity of leukaemia-reactive T-cells. Both offer broad applicability across all human leucocyte antigen (HLA)-types. T-cell responses to peptide vaccinations targeting the leukaemia-associated antigen Wilms’ Tumour protein (WT1) were enhanced by exploration of novel adjuvants for induction of cell-mediated immunity. Vaccinations comprising these adjuvants and single peptides or overlapping peptides spanning the whole WT1 protein, induced functional T-cell responses (antigen-specific in vivo cytolytic activity and interferon-gamma production) in C57BL/6 mice. Secondly, autologous AML blasts, genetically modified to express the immunostimulatory molecules CD80 and IL-2, were co-administered as a vaccine with tDLI in a Phase I clinical trial. Preliminary data supporting safety of this approach and possible induction of immune responses to vaccination, evidenced by development of a delayed-type hypersensitivity reaction in a subject, are presented. This thesis describes broad-based immunotherapeutic strategies in AML patients for prevention of disease recurrence by enhancement of anti-leukaemic immune responses.
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Cheuk, Tai-chi. "Childhood acute lymphoblastic leukaemia with TEL-AML1 gene fusion." Hong Kong : University of Hong Kong, 2000. http://sunzi.lib.hku.hk/hkuto/record.jsp?B22264619.
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