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Murton, R. A. "Mechanisms associated with ethacrynic acid-induced Na'+, K'+ pump upregulation in Epstein-Barr virus-transformed lymphocytes." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.244775.
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Wright, Adrienne M. P. "A role for nucleoside transport processes in the cytotoxicity of 2-chlorodeoxyadenosine in leukemic lymphoblasts from children with acute lymphoblastic leukemia." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq23091.pdf.
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Antia, Irina J. "The turnover of sodium/potassium pumps in human lymphocytes during upregulation in response to lithium." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297074.
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Teyssou, Elisa. "Analyses génétiques et fonctionnelles de nouveaux gènes incriminés dans la Sclérose Latérale Amyotrophique (SLA) Genetic analysis of matrin 3 gene in French amyotrophic lateral sclerosis patients and frontotemporal lobar degeneration with amyotrophic lateral sclerosis patients Genetic analysis of CHCHD10 in French familial amyotrophic lateral sclerosis patients." Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066738.
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La Sclérose Latérale Amyotrophique (SLA) est une maladie neurodégénérative fatale caractérisée par la dégénérescence des motoneurones centraux et périphériques. Elle est le plus souvent sporadique (SALS, 90% des cas), tandis que les formes familiales (FALS) représentent 10% des patients. Une vingtaine de gènes liés à la SLA ont été identifiés et sont responsables de 70% des FALS et 10% des SALS. Le but de ce projet était d’étudier la contribution de 6 gènes rares dans une large cohorte de patients français atteints de SLA et d’étudier les conséquences fonctionnelles de certains variants identifiés. La première partie de ce projet a consisté à réaliser l’analyse génétique des gènes MATR3, CHCHD10, SS18L1, SQSTM1, UBQLN2 et PFN1. Aucun variant causal ne fut identifié pour les 2 premiers gènes alors que 2 nouveaux variants possiblement pathogènes ont été identifiés dans le gène SS18L1, 4 mutations pour SQSTM1, 5 dans UBQLN2 et 2 mutations déjà répertoriées dans le gène PFN1. Cette analyse génétique a permis de souligner un chevauchement génétique entre SLA et maladie de Paget pour SQSTM1 et entre SLA et Paraplégie Spastique pour UBQLN2. La deuxième partie de ce projet a consisté en l’étude de la pathogénicité de certains variants que nous avons identifiés dans les gènes SQSTM1, UBQLN2 et PFN1, par l’analyse (i) des inclusions dans les tissus post mortem de patients, (ii) de l’expression et de la dégradation protéique dans des lymphoblastes issus de patients SLA et/ou (iii) des conséquences cellulaires après surexpression in vitro et in vivo. Ces analyses ont montré, concernant SQSTM1, qui est impliquée dans la formation des autophagosomes, que les mutations perturbaient l’agrégation protéique, que les mutations dans le gène UBQLN2 altéraient la dégradation lysosomale et la liaison de la protéine avec HSP70 et que celles dans PFN1 dérégulaient la voie de l’autophagie alternative et la mitophagie. Notre travail a permis (i) d’évaluer la contribution chez les patients français atteints de SLA de plusieurs gènes incriminés dans la SLA, (i) d’élargir le spectre génétique commun à la SLA et à d’autres pathologies et (iii) de mettre en avant la pertinence de l’implication des voies de dégradation protéique, notamment l’autophagie, dans la pathogénèse de la maladieThe fatal Amyotrophic Lateral Sclerosis (ALS) motor neuron disease is characterized by the degeneration of upper and lower motor neurons. Most ALS cases are sporadic (SALS) whereas ~10% are familial (FALS). A growing number of genes has been identified in ALS and represent 70% of FALS and 10% of SALS. The aims of this project were to analyze the contribution of 6 rare genes in a large population of French ALS patients and to study the pathogenic impact of some identified variants.The first part of this work was dedicated to the genetic analysis of MATR3, CHCHD10, SS18L1, SQSTM1, UBQLN2 and PFN1 genes. No causing variants were identified for MATR3 and CHCHD10 while 2 new variants, probably pathogenic, were identified for SS18L1, as well as 4 mutations for SQSTM1, 5 for UBQLN2 and 2 already reported mutations for PFN1. These analyses also highlighted a genetic overlap between ALS and other diseases: the Paget disease of bone for SQSTM1 and spastic paraplegia for UBQLN2. The second part of this work was to study the pathogenicity of some of the mutations identified in SQSTM1, UBQLN2 and PFN1 genes using analyses of (i) inclusions in ALS patient post-mortem tissue, (ii) protein expression and degradation pathways in patient lymphoblasts and/or (iii) cellular consequences after in vitro and in vivo overexpression. Our results showed prominent aggregation of mutant SQSTM1 (involved in autophagosomes formation), impaired lysosomal degradation and disrupted protein binding to HSP70 for mutant UBQLN2 and deregulated alternative autophagy and mitophagy pathways for mutant PFN1. Our results (i) precised the contribution of several genes in French ALS patients, (i) documented the genetic overlap between ALS and other diseases and (iii) highlighted the role of protein degradation pathways, especially autophagy, in the pathogenesis of ALS
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Zborovszky, Camila Carolina. "Mitochondrial complex I functionality and protein oxidative damage in lymphoblasts from lithium responsive patients with bipolar disorder, affected and unaffected relatives." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/33274.
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Background: Evidence has demonstrated that mitochondria underline the neurobiology of bipolar disorder (BD). Investigating complex I functionality in transformed lymphoblasts from lithium responsive patients with BD, its relation with increased oxidative damage, and the response to stress induced by low glucose treatment, will aid in the search for peripheral biomarkers for this debilitating disorder.
Objective: Confirm the alterations in complex I activity as well as levels of its subunit, NDUFS7, in addition to oxidative damage to mitochondrial proteins, by increased levels of protein carbonyls and 3-nitrotyrosine content, in lymphoblasts . The response to low glucose stress will be evaluated by measuring complex I activity, NDUFS7 levels, and protein oxidative damage.
Design: Complex I activity was measured by spectrophotometry and tyrosine-nitration induced damage was assessed using a competitive enzyme immunoassay. Immunoblotting was used to measure NDUFS7 levels and protein carbonyl levels. All assays were carried out in cell pellet fractions, except for complex I activity which was carried out in mitochondrial fractions.
Patients: We studied lymphoblasts from patients (14 with BD, and 14 relatives of BD patients affected with a psychiatric illness) and from non-psychiatric comparison controls (N=15) as well as 16 relatives of BD patients unaffected by a psychiatric illness.
Results: Our results showed that levels of complex I activity in lymphoblasts differed significantly between the groups, with the lowest values for control subjects, and highest in unaffected and affected relatives, under normal glucose conditions. We did not find significant differences between the groups in NDUFS7, protein carbonyl, and 3-nitrotyrosine levels, nor did we find any correlation between complex I activity and NDUFS7, protein carbonyl, and 3-nitrotyrosine levels, for both treatment conditions (normal and low glucose).
Conclusions: These findings suggest an up-regulation of peripheral complex I activity in patients with BD and their relatives, as a potential compensatory mechanism preventing protein oxidative damage induced by complex I dysfunctionality . Future studies, evaluating the potential role of lithium in peripheral cells targeting sites such as complex I, are necessary in order to gain insight into the mechanisms in which cells can prevent the oxidative damage characteristic of the disorder.
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Kuchinskaya, Ekaterina. "Genetic studies of acute lymphoblastic leukemia /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-337-5/.
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Pettit, Andrew I. "Oxygen radical generation by lymphoblast NADPH oxidase in hypertension." Thesis, University of Leicester, 2006. http://hdl.handle.net/2381/29519.
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Objectives. The aim of this thesis was to investigate increased reactive oxygen species production originating from NADPH oxidase in lymphoblasts from hypertensive subjects. Results. Combined intra and extracellular stimulated reactive oxygen species production was increased in hypertensive cell lines. The ROS production was abolished by Diphenyleneiodonium chloride but not by rotenone, indicating that a non-mitochondrial flavoprotein, such as NADPH oxidase, was involved. Analysis of NADPH oxidase subcomponents revealed an increase in p22phox in lymphoblasts from hypertensive subjects, accounting for some of the increased reactive oxygen species production. There was increased basal Tyr/Thr phosphorylation of p44/p42 MAPK in the hypertensive lymphoblasts, but the difference was lost on stimulation. The various kinase inhibitors had no effect on basal reactive oxygen species production. Tyrosine kinase inhibition produced up to 70% reduction in stimulated reactive oxygen species production in both cell lines. Inhibition of p44/p42 MAPK kinase, P13K, and PLA2 produced a small reduction in stimulated ROS production. There was no differential reduction in ROS production from the hypertensive group with these inhibitors, suggesting no role of these pathways in priming of NADPH oxidase. Conclusions. We have shown there is increased reactive oxygen species production in lymphoblasts from hypertensive subjects probably originating from NADPH oxidase. Increased expression of p22phox in hypertension lymphoblasts accounts for approximately a third of the increased reactive oxygen species production. We could not demonstrate tyrosine kinase, p38 MAPK, p44/p42 MAPK, P13K or PLA2 priming of reactive oxygen species production.
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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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Lo, Tony Chung Tung. "Inactivation of SHIP1 in acute lymphoblastic leukemia." Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p1465620.
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Thesis (M.S.)--University of California, San Diego, 2009.Title from first page of PDF file (viewed July 22, 2009). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 63-69).
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Kay, Gillian. "Characterisation of the lymphoblast β-adrenergic receptor in bipolar depression." Thesis, Imperial College London, 1991. http://hdl.handle.net/10044/1/46859.
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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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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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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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Kanerva, Jukka. "Prognostic factors in childhood acute lymphoblastic leukemia (ALL)." Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/kanerva/.
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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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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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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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Thörn, Ingrid. "Minimal Residual Disease Assessment in Childhood Acute Lymphoblastic Leukemia." Doctoral thesis, Uppsala universitet, Institutionen för genetik och patologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-101028.
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Traditionally, response to treatment in hematological malignancies is evaluated by light microscopy of bone marrow (BM) smears, but due to more effective therapies more sensitive methods are needed. Today, detection of minimal residual disease (MRD) using immunological and molecular techniques can be 100 times more sensitive than morphology. The main aim of this thesis was to compare and evaluate three currently available MRD methods in childhood acute lymphoblastic leukemia (ALL): (i) real-time quantitative PCR (RQ-PCR) of rearranged antigen receptor genes, (ii) multicolor flow cytometry (FCM) of leukemia-associated immunophenotypes and (iii) real-time quantitative PCR of fusion gene transcripts (RT-PCR). In paper I, we assessed the applicability of RQ-PCR in a population-based cohort of childhood ALL diagnosed in Sweden between 2002-2006. Clonal IG/TCR rearrangements were identified in the 96% of the 279 ALL cases. Using RQ-PCR, the quantitative range of 10-3 was reached in 93% of B-cell precursor (BCP) ALL and 86% of T-cell ALL (T-ALL) by at least one target gene. In paper II, we compared MRD detection using both RQ-PCR and FCM in the context of NOPHO ALL-2000 protocol. By applying the stratification threshold of ≥0.1% MRD late during induction therapy (day 29), we could demonstrate that both methods can predict the risk of BM relapse but not extramedullary relapse. However, the threshold of ≥0.2% MRD appears to be more optimal using RQ-PCR in BCP ALL, whilst in T-ALL, the results indicate that RQ-PCR is preferable for MRD assessment. The stability of RNA in vitro is a critical factor when using sensitive molecular techniques such as MRD detection. In paper III, we evaluated the influence on MRD detection when blood is collected in tubes with RNA stabilization reagents (PAX gene Vacutatiner®) compared to collection in EDTA-tubes (non-stabilized). We analyzed 68 matched samples from chronic myeloid leukemia patients and the results indicated that non-stabilized blood processed within 30 hours is preferable for MRD detection. In paper IV, follow-up samples from eight children with Philadelphia positive (Ph+) ALL were evaluated with the three available MRD methods. MRD measured by the fusion gene transcripts (BCR-ABL1) appeared to be the most sensitive method, however, precise quantification can be difficult and the other methods are thus complementary. In conclusion, all three applied MRD methods are useful and correlate to each other, although not necessary exchangeable in individual patients. We also conclude that MRD assessment by RQ-PCR, based on rearranged IG/TCR genes and multicolor FCM are predictive for identification of high risk childhood ALL patients.
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Nordlund, Jessica. "Gene Expression and DNA Methylation in Acute Lymphoblastic Leukemia." Doctoral thesis, Uppsala universitet, Molekylär medicin, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-179680.
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Pediatric acute lymphoblastic leukemia (ALL) is the most common malignancy in children, which results from the malignant transformation of progenitor cells in the bone marrow into leukemic cells. The precise mechanisms for this transformation are not well defined, however recent studies suggest that aberrant regulation of gene expression or DNA methylation may play an important role. Hence, the aim of this thesis was to use novel methods to investigate genome-wide gene expression and DNA methylation patterns in a large collection of primary ALL cells from pediatric patients. With these studies, we aimed to increase the understanding of factors that regulate gene expression and DNA methylation in ALL. In the first study of the thesis we found that data obtained from genome-wide digital gene expression analysis enabled excellent cytogenetic subtype-specific classification of ALL cells and revealed new features of gene expression within the disease, such as prevalent antisense transcription and alternative polyadenylation. In the second study we used technology developed for large-scale single nucleotide polymorphism (SNP) genotyping for quantitative analysis of allele-specific gene expression (ASE), revealing widespread ASE in ALL cells. Analysis of DNA methylation in promoter regions of the genes displaying ASE using DNA-microarrays revealed frequent regulation of gene expression by DNA methylation. In the third study, using the same DNA methylation array, we identified differences in the DNA methylation patterns in ALL cells at diagnosis compared to healthy mononuclear cells from the bone marrow of the same children at remission. In the fourth study we measured the DNA methylation of >450,000 CpG sites across the genome in a large collection of ALL samples and non-leukemic control cells. We found that ALL cells displayed highly divergent DNA methylation patterns depending on their cytogenetic subtype and widespread regions of differential methylation were enriched for repressive histone marks. DNA methylation levels at distinct regions in the genome were substantially increased at relapse compared to matched cells from diagnosis. Collectively, the results presented in this thesis provide new insights into the patterns of gene expression and epigenetic changes in ALL and further increase our understanding of the development and progression of the disease, which will hopefully lead to better treatment options in the future.
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Akers, Stephen Matthew. "Modeling central nervous system involvement in acute lymphoblastic leukemia." Morgantown, W. Va. : [West Virginia University Libraries], 2010. http://hdl.handle.net/10450/11227.
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Thesis (Ph. D.)--West Virginia University, 2010.Title from document title page. Document formatted into pages; contains x, 102 p. : ill. (some col.). Includes abstract. Includes bibliographical references.
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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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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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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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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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Thörn, Ingrid. "Minimal Residual Disease Assessment in Childhood Acute Lymphoblastic Leukemia." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-101028.
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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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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/.
Full textAbstract:
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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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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Robinson, Hazel M. "Acquired abnormalities of chromosome 21 in acute lymphoblastic leukaemia." Thesis, University of Southampton, 2008. https://eprints.soton.ac.uk/161483/.
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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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Shaw, Collin M. "Increased Glutathione Metabolic Defense Capabilities in Cultured Alzheimer's Diseased Lymphoblast Cell Lines." PDXScholar, 1998. https://pdxscholar.library.pdx.edu/open_access_etds/1703.
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The hypothesis to be tested states that the pathology of Alzheimer's disease (AD) involves elevated levels of oxidative stress, resulting in elevated levels of cellular oxidative defense mechanisms. If the premise is true, than AD pathologically afflicted cells should have a higher demand for glutathione (GSH) as an innate oxidative defense mechanism hence; greater GSH concentrations, increased GSH resynthesis capabilities, and increased levels of cystathionine gamma-lyase (CNase). Alzheimer diseased and age matched control lymphoblast cells, obtained from OHSU's Oregon Brain Aging Study, were cultured, and GSH biochemistry was subsequently evaluated. GSH was depleted by exposing cells to the GSH depleting agent diethylmaleate (DEM) and the resulting GSH concentrations were measured. GSH resynthesis was measured after depleting GSH with DEM, to a level of approximately half base GSH concentration, then removing the depleting agent, resuspending the cells in fresh medium (DEM-free), and subsequently measuring GSH levels. GSH concentrations were measured by HPLC, and all data was normalized to cellular protein concentration. Cellular CNase specific activity levels were measured by adding cytasthionine, the CNase substrate, and then measuring the amount of cysteine produced by means of the DTNB assay. The AD cell lines showed no increase in base levels of GSH as compared to control cell lines. The AD cell lines showed a statistically significant increase in GSH resynthesis capabilities and cystathionine gamma-lyase specific activity levels. These findings add further weight to the AD oxidative stress hypothesis, which is based on the premise that the causative agent of AD pathogenesis is an increase in the level of cellular free radicals produced.
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Heidari, Mansour. "Investigation of the molecular function of the nuclear oncoprotein HOX11 in human t-cell leukaemia." Murdoch University, 2003. http://wwwlib.murdoch.edu.au/adt/browse/view/adt-MU20060815.123509.
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HOXll, the prototypical member of the HOXll family (HOX11, HOXllLl and HOXllL2) was originally discovered as a transcriptional regulator aberrantly expressed in tumours with an immature T-cell phenotype (T-ALL) as a result of
specific chromosomal translocations involving T-cell receptor loci. Subsequently, it was revealed that HOXll is required for normal spleen development since newborn
Hoxll-/- mice exhibit asplenia. In both its normal and abnormal roles, HOXll has been postulated to function by binding regulatory elements within specific target genes
to control gene transcription. However, very few genomic targets of HOX11 have been identified and little is known about its mode of action. In this study, we sought to
further understand the role of HOX11 in controlling differentiation and cell growth by 1) determining the identity of genomic sequences that are directly bound by HOXll and 2) determining the identity of proteins which exist within HOXll-containing nuclear complexes.
To identify direct HOXll target sequences, a whole genome PCR-based screening method was employed using immobilised recombinant HOXll that had first been expressed as a biologically active GST fusion protein. Using this approach, restriction enzyme-cleaved human genomic DNA was selected for high-affinity HOXll binding sites. Unexpectedly, almost all clones isolated contained sequences derived from satellite 2 DNA that, together with related satellite 3 DNA, is found on most chromosomes at transcriptionally inactive pericentromeric heterochromatin. The specific binding of HOXl1 to satellite 2 DNA was verified by bandshift assays using
both recombinant HOXll protein and nuclear extract derived from the T-ALL cell line, ALL-SIL. DNA-protein complexes containing HOX11 were identified by their ablation upon addition of HOXl1 antibody.
To confirm that HOXll associates with pericentromeric heterochromatin in vivo, HOXll was characterised in terms of its nuclear localisation during interphase in
unsynchronised leukaemic T-cells (ALL-SIL) harbouring a translocation involving the HOXll locus. Using indirect immunofluorescence and confocal microscopy, HOXll
antibody produced a punctate pattern of staining in the nucleus with discrete areas of dense staining superimposed on a diffuse distribution of HOXll protein. By dual staining, the bright HOXll foci correlated with centromeres since they overlapped with signals detected by an antibody specific for the centromeric protein CENP-B. Further evidence for a direct interaction of HOXll with satellite 2 DNA was provided by chromatin immunoprecipitation assay. In the presence of HOXll antibody, DNA fragments containing satellite 2 sequences were irnmunoprecipitated from sheared, cross-linked ALL-SIL chromatin but not from chromatin isolated from the HOXll-negative T-cell line PER-1 17. Finally, using a combination of immunoprecipitation with HOXll antibody, gel electrophoresis and mass peptide fingerprinting, a set of nuclear proteins were identified as potential HOXll interactors which are known to either localise to centromeric regions or act as regulators of gene expression. Together, these results implicate HOXl 1 in a functional interaction with centromeric heterochromatin,
which may be a key feature of this oncoprotein in terms of both its T-cell transformation and transcriptional regulatory functions.
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Liaw, Tracy Yun En Children's Cancer Institute Australia for Medical Research Faculty of Medicine UNSW. "Characterisation of novel anticancer agents in childhood acute lymphoblastic leukaemia." Publisher:University of New South Wales. Children's Cancer Institute Australia for Medical Research, 2009. http://handle.unsw.edu.au/1959.4/43558.
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Tubulin-binding agents (TBAs) are employed widely in cancer treatment, including childhood acute lymphoblastic leukaemia (ALL). Despite their success, resistance to TBAs can be a major clinical problem. Mechanisms mediating resistance to TBAs that target the colchicine-binding site on β-tubulin, along with novel therapeutic strategies were investigated. 2-Methoxyestradiol (2ME2) is a multi-targeted TBA active in various cancer types, yet its efficacy and mechanisms(s) of action in haematological malignancies are not well evaluated. To improve understanding of mechanisms(s) of action and drug resistance, leukaemia cells, CCRF-CEM, were selected for resistance to 2ME2. These resistant cells displayed reduced drug-induced mitotic arrest and increased tubulin polymer levels. Moreover, the resistant cells also acquired β-tubulin mutations that affected microtubule stability and induced conformational change(s) to the 2ME2-binding site on β-tubulin. Two of the mutations resided in the colchicine-binding site, yet did not affect colchicine sensitivity, suggesting that 2ME2 and colchicine differ in their binding to β-tubulin. These 2ME2-resistant leukaemia cells have provided novel insights into microtubule stability and drug-target interactions to the tubulin molecule. Differential proteomics analysis identified alterations in the expression of cytoskeletal proteins in the 2ME2-resistant leukaemia cells, including a significant increase in class II β-tubulin. Furthermore, γ-enolase and galectin-1 were up-regulated and class IVb β-tubulin was down-regulated in 2ME2-resistant cells. Gene specific knockdown of class II β-tubulin expression in neuroblastoma cells using small interfering RNA increased sensitivity to 2ME2 and other colchicine-binding agents, suggesting that class II β-tubulin plays a functional role in drug resistance and sensitivity. In a clinically relevant NOD/SCID ALL mouse xenograft model, orally active 2ME2 and its analogue, ENMD-1198, increased survival rates in human ALL xenografts compared to control mice. ENMD-1198 showed better activity than 2ME2 against the ALL xenografts. Combining two microtubule-destabilising agents, ENMD-1198 and vincristine, demonstrated synergistic effect by causing microtubule disruption, angiogenesis and cell proliferation inhibition, and apoptosis induction in leukaemia cells. Importantly, ENMD-1198 and vincristine combination was more potent than single agent treatment in a vincristine-resistant ALL xenograft. In conclusion, this thesis identified novel mechanisms of resistance to 2ME2 and developed a new therapeutic strategy that could improve the treatment of drug refractory childhood ALL.
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Gottardo, Nicholas G. "Oncogenes and prognosis in childhood T-cell acute lymphoblastic leukaemia." University of Western Australia. School of Paediatrics and Child Health, 2008. http://theses.library.uwa.edu.au/adt-WU2009.0039.
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[Truncated abstract] The treatment of childhood acute lymphoblastic leukaemia (ALL) is one of the great success stories of paediatric oncology, transforming a universally fatal disease into one where 75 to 90% of children are now cured. Although in the past survival for children with T-cell ALL (T-ALL) lagged behind that of children with pre-B ALL, the use of contemporary intensified treatment strategies has significantly diminished this difference, with many investigators reporting similar cure rates for both groups of patients. Despite these marked improvements, numerous challenges still face physicians treating children with T-ALL. Firstly, there have been no additional major improvements in outcome over the last decade, despite additional treatment intensification. Secondly, effective regimens remain elusive for treating children with relapsed T-ALL or patients with resistant disease. Finally, there is a need to identify patients currently potentially overtreated and thus unnecessarily subjected to acute and long term toxicities without benefit. A major challenge therefore, is the identification of novel reliable prognostic markers, in order to identify patients at high risk of relapse and conversely those least likely to relapse, to guide therapy appropriately. Children predicted with a high risk of relapse would be candidates for intensification of therapy and/or novel experimental agents. Conversely, patients predicted to be at low risk of relapse could be offered clinical trials using reduced intensity therapy, thereby minimising toxicity. '...' Crucially, the 3-gene predictor was validated in a completely independent cohort of T-ALL patients, also treated on CCG style therapy. Our 3-gene predictor appears to identify a high risk group of patients which require alternative therapeutic strategies in order to attain a cure. This study has also identified a potential novel agent for the treatment of T-ALL, which may be used as an anthracycline potentiator or anthracycline-sparing agent. We hypothesised that genes associated with a relapse signature provide promising targets for novel therapies. We tested the hypothesis that CFLAR, an inhibitor of the extrinsic apoptotic pathway and a member of the 3-gene predictor may be involved in the development of resistance to chemotherapy. To test our hypothesis we used a novel agent, 2-cyano-3, 12-dioxooleana-1,9 (11)-dien-28-oic acid (CDDO), previously shown to inhibit CFLAR protein, in two cell lines established in our laboratory from paediatric patients diagnosed with T-ALL. We found that CDDO displayed single agent activity at sub-micromolar concentrations in both cell lines tested. Importantly, minimally lethal doses of CDDO resulted in significant enhancement of doxorubicin mediated cytotoxicity in one of the cell lines assessed. The findings presented as part of this thesis have revealed the value of gene expression analysis of childhood T-ALL for identifying novel prognostic markers. This study has shown that expression profiles may provide better prognostic information than currently available clinical variables. Additionally, genes that constitute a relapse signature may provide rational targets for novel therapies, as demonstrated in this study, which assessed a potential novel agent for the treatment of T-ALL.
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Larery, Angela R. D. McGill Jerry C. "Hierarchical neuropsychological functioning among pediatric survivors of acute lymphoblastic leukemia." [Denton, Tex.] : University of North Texas, 2007. http://digital.library.unt.edu/permalink/meta-dc-3949.
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Van, Vlierberghe Pieter. "Moleciular-genetic insights in pediatric T-cell acute lymphoblastic leukemia." [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2008. http://hdl.handle.net/1765/12225.
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Withycombe, Janice Squires. "Early Weight Gain and Obesity in Childhood Acute Lymphoblastic Leukemia." Diss., The University of Arizona, 2012. http://hdl.handle.net/10150/223340.
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Obesity is a recognized problem for children treated for acute lymphoblastic leukemia (ALL) and is present in roughly one fourth of children by the end of therapy. Obesity may lead to immediate health threats, such as an increased risk for cancer relapse, or may cause future heath issues such as diabetes, metabolic syndrome, hypertension, additional cancers, depression or cardiovascular disease. The purpose of this study was to determine if weight gain during two individual cycles of therapy (Induction or Delayed Intensification Cycle 1) were predictive of obesity (defined as body mass index ≥ 95th percentile for age and gender) at the end of treatment. This study retrospectively examined height and weight data from 1,017 childhood leukemia patients treated on Children's Oncology Group (COG) protocol number 1961. This study included patients that had fully completed therapy on protocol 1961 and who were between the ages of 2-20 years. Percentiles and z-scores for age and gender specific body mass index (BMI) were calculated using the height and weight measurements obtained at the beginning of each cycle of chemotherapy. Univariate and multivariate logistic regression analyses were performed. BMI z-score at the beginning of therapy and difference in BMI z-score during Induction were significant predictors (p<0.0001) of BMI ≥ 95th percentile at the end of maintenance in both males and females. A one unit increase in the difference of BMI z-score during Induction resulted in a 3.03 odds ratio (OR) for obesity at the end of therapy for males (95% CI, 1.90 to 4.84) and a 4.15 OR for females (95% CI, 2.32 to 7.43). The change in BMI z-score during Delayed Intensification I was not found to be significant in relationship to obesity at the end of therapy. Weight gain during Induction consisted of ≥ 20% increase in weight for 3.9% of the study participants. Weight gain during Induction therapy of childhood ALL treatment may be useful in predicting patients at increased risk for obesity development during therapy. Early identification of these at risk patients can assist with interventions aimed at normalizing weight gain during therapy.
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Breen, Marie Elizabeth. "The erythropoietin receptor in TEL-AML1 positive acute lymphoblastic leukaemia." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.579773.
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The TEL-AMLl fusion is the result of t(12;21) (p13;q22), the most frequent chromosomal translocation in childhood B-cell ALL. Recent studies have found a positive correlation with TEL-AMLl and EpoR expression. Three possible mechanisms of up-regulation were investigated in this study: Gene expression analysis, DNA methylation and microRNAs. Microarray analysis compared TEL-AMLl positive and negative gene expression profiles to identify differentially expressed genes. Genes with well known roles in haematopoiesis were also examined. GATA-2 showed a similar expression profile to EpoR, with a higher expression found in TEL-AMLl positive cells. Over-expression of GATA-2 increased EpoR expression further in TEL-AMLl positive cells providing evidence of a link between GATA-2 and EpoR expression in the presence of the fusion protein. DNA methylation analysis of EpoR and GATA-2 promoter regions showed a much higher level of methylation in TEL-AMLl negative cells. After treatment with a demethylating agent EpoR levels did not increase indicating EpoR expression was not epigenetically controlled. However, demethylation of GATA-2 increased expression in both TEL-AMLl positive and negative samples indicating a direct role for DNA methylation with GATA-2 expression. MicroRNAs are short non-coding RNA molecules with the ability to post-transcriptionally regulate genes by binding to the 3•UTR. Taqman microRNA arrays allowed simultaneous analysis of 667 commonly found microRNAs in both TEL-AMLl positive and negative cells. Arrays were analysed and compared with target prediction results to identify microRNAs that could target EpoR and GATA-2. Over-expression of miR-362 showed down-regulation of EpoR protein levels. Over-expression of miR-650 showed down-regulation of both GATA-2 and EpoR. Together these results support a theory of an "EpoR friendly" environment in TEL-AMLl positive cells to aid and promote EpoR expression. This includes an increase in GATA-2 and a decrease in DNA methylation and microRNA expression. These factors are reversed in TEL-AMLl negative cells to hinder EpoR expression.
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Thornton, Nadia. "L-alanosine : selective treatment in relapsed childhood acute lymphoblastic leukaemia." Thesis, University of Newcastle Upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440588.
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Inman, Louise. "The c-Kit signalling pathway and acute non-lymphoblastic leukaemogenesis." Thesis, University of the West of England, Bristol, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365066.
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Reid, George. "Mammalian asparaginases of possible therapeutic significance in acute lymphoblastic leukaemia." Thesis, University of Strathclyde, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.303368.
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Steele, Jeremey Peter Charles. "The severe combined immune deficient model of acute lymphoblastic leukaemia." Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.298191.
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Chou, J.-L. "In vitro induction of differentiation of human lymphoblastic leukaemic cells." Thesis, University of Cambridge, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.377217.
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Srisukkham, Worawut. "An intelligent decision support system for acute lymphoblastic leukaemia detection." Thesis, Northumbria University, 2017. http://nrl.northumbria.ac.uk/36140/.
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The morphological analysis of blood smear slides by haematologists or haematopathologists is one of the diagnostic procedures available to evaluate the presence of acute leukaemia. This operation is a complex and costly process, and often lacks standardized accuracy owing to a variety of factors, including insufficient expertise and operator fatigue. This research proposes an intelligent decision support system for automatic detection of acute lymphoblastic leukaemia (ALL) using microscopic blood smear images to overcome the above barrier. The work has four main key stages. (1) Firstly, a modified marker-controlled watershed algorithm integrated with the morphological operations is proposed for the segmentation of the membrane of the lymphocyte and lymphoblast cell images. The aim of this stage is to isolate a lymphocyte/lymphoblast cell membrane from touching and overlapping of red blood cells, platelets and artefacts of the microscopic peripheral blood smear sub-images. (2) Secondly, a novel clustering algorithm with stimulating discriminant measure (SDM) of both within- and between-cluster scatter variances is proposed to produce robust segmentation of the nucleus and cytoplasm of lymphocytic cell membranes. The SDM measures are used in conjunction with Genetic Algorithm for the clustering of nucleus, cytoplasm, and background regions. (3) Thirdly, a total of eighty features consisting of shape, texture, and colour information from the nucleus and cytoplasm of the identified lymphocyte/lymphoblast images are extracted. (4) Finally, the proposed feature optimisation algorithm, namely a variant of Bare-Bones Particle Swarm Optimisation (BBPSO), is presented to identify the most significant discriminative characteristics of the nucleus and cytoplasm segmented by the SDM-based clustering algorithm. The proposed BBPSO variant algorithm incorporates Cuckoo Search, Dragonfly Algorithm, BBPSO, and local and global random walk operations of uniform combination, and Lévy flights to diversify the search and mitigate the premature convergence problem of the conventional BBPSO. In addition, it also employs subswarm concepts, self-adaptive parameters, and convergence degree monitoring mechanisms to enable fast convergence. The optimal feature subsets identified by the proposed algorithm are subsequently used for ALL detection and classification. The proposed system achieves the highest classification accuracy of 96.04% and significantly outperforms related meta-heuristic search methods and related research for ALL detection.
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Borssén, Magnus. "DNA methylation as a prognostic marker i acute lymphoblastic leukemia." Doctoral thesis, Umeå universitet, Patologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-127225.
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Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Most ALL cases originate from immature B-cells (BCP-ALL) and are characterized by reoccurring structural genetic aberrations. These aberrations hold information of the pathogenesis of ALL and are used for risk stratification in treatment. Despite increased knowledge of genetic aberrations in pediatric T-cell ALL (T-ALL), no reliable molecular genetic markers exist for identifying patients with higher risk of relapse. The lack of molecular prognostic markers is also evident in patients with relapsed ALL. During the last decades, aberrant epigenetic mechanisms including DNA methylation have emerged as important components in cancer development. Telomere maintenance is another important factor in malignant transformation and is crucial for long-term cell survival. Like DNA methylation, telomere length maintenance has also been implicated to reflect outcomes for patients with leukemia. In this thesis, the prognostic relevance of DNA methylation and telomere length was investigated in pediatric ALL at diagnosis and relapse. The telomere length (TL) was significantly shorter in diagnostic ALL samples compared to normal bone marrow samples collected at cessation of therapy, reflecting the proliferation associated telomere length shortening. Prognostic relevance of TL was shown in low-risk BCP-ALL patients where longer telomeres at diagnosis were associated with higher risk of relapse. Genome-wide methylation characterization by arrays in diagnostic T-ALL samples identified two distinct methylation subgroups denoted CIMP+ (CpG Island Methylator Phenotype high) and CIMP- (low). CIMP- T-ALL patients had significantly worse outcome compared to CIMP+ cases. These results were confirmed in a Nordic cohort treated according to the current NOPHO-ALL2008 protocol. By combining minimal residual disease (MRD) status at treatment day 29 and CIMP status at diagnosis we could further separate T-ALL patients into risk groups. Likewise, the CIMP profile could separate relapsed BCP-ALL patients into risk groups, where the CIMP- cases had a significantly worse outcome compared to CIMP+ cases. From these data we conclude that DNA methylation subgrouping is a promising prognostic marker in T-ALL, as well as in relapsed BCP-ALL two groups where reliable prognostic markers are currently missing. By elucidating the biology behind the different CIMP profiles, the pathogenesis of ALL will be further understood and may contribute to new treatment strategies.
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Lund, Bendik. "Host Genome Variation and Toxicity in Childhood Acute Lymphoblastic Leukaemia." Doctoral thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for laboratoriemedisin, barne- og kvinnesykdommer, 2014. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-24171.
Full textAbstract:
Kreft er den vanligste medisinske dødsårsaken hos barn mellom 1 og 15 år. Akutt lymfatisk leukemi (ALL) er den vanligste kreftformen hos barn og i Norge får ca. 30-40 barn ALL hvert år. Behandlingen strekker seg over 2,5 år og består av 6-12 ulike cellegifter i forskjellige kombinasjoner i tillegg til støttebehandling og overvåkning. Behandlingen medfører mange bivirkninger, bl.a. nedsatt immunforsvar som gir økt risiko for infeksjoner. Den totale overlevelsen for barn med ALL er i dag på ca. 80-85%. Av de som dør etter å ha fått diagnosen skyldes dette for ca. 75% kreftsykdommen i seg selv hvorav de fleste skjer etter tilbakefall av sykdommen (residiv-relaterte dødsfall). De resterende 25% av dødsfallene skyldes bivirkninger av behandlingen, noe som kalles behandlingsrelatert død (TRD, treatment-related death). I denne studien har vi undersøkt forekomst, risikofaktorer og dødsårsaker hos 88 TRD-tilfeller blant 2700 pasienter med ALL i de fem nordiske landene Sverige, Danmark, Finland, Island og Norge. Forekomsten av TRD var 3,2% og denne holdt seg uendret fra den første ALL protokollen (NOPHO ALL 1992) til den neste (NOPHO ALL 2000). Risikofaktorer var kjønn (pike), behandlings-risikogruppe (høy-risk), T-celle sykdom, Down syndrom og gjennomgått beinmargstransplantasjon. Av dødsårsaker skyldtes 75% infeksjoner, 10% blødninger, 10% spesifikk organsvikt og 5% direkte kreftcelle-påvirkning (tumor byrde). Vi har ingen god forklaring på hvorfor noen blir mer syke av behandlingen enn andre. Det er derfor grunn til å tro at genetiske faktorer spiller inn. I de siste 10 årene har man forstått vesentlig mer om den naturlige genetiske variasjon hos menneske. Vi ville undersøke om ulike mønstre av en vanlig forekommende variasjon i det menneskelige genom, nemlig enkeltnukleotidpolymorfisme (eng.: single nuclotide polymorphism, SNP) kunne spille en rolle for risiko for alvorlige infeksjoner under leukemibehandlingen. Vi undersøkte 34000 SNP’er relatert til ALL sykdommen hos barn og fant 24 SNP’er som var assosiert til risiko for infeksjon under behandlingen. Ved hjelp av CART-analyse (classification and regression tree) identifiserte vi 4 SNP’er som inngikk i en SNP-profil som var i stand til å forutsi risiko for infeksjoner de første 50 dagene av behandlingen med stor nøyaktighet. SNP’ene tilhører genene OR51F1, CBR1, POLDIP3 og CCL11 som bl.a. regulerer cellegiftomsetning, cellevekst og betennelsesreaksjoner. Hvis disse funnene blir bekreftet i tilsvarende studier vil denne kunnskapen kunne brukes til bedre å «skreddersy» behandlingen til enkeltpasienter og dermed redusere forekomsten av alvorlige bivirkninger. I moderne genanalyser inngår ofte mange genvarianter samtidig. Det benyttes som regel DNA fra blodprøver, noe som kan være vanskelig å få tak i fra pasienter som ikke lenger er i live. Vi ønsket derfor å undersøke om det var mulig å analysere biologiske markører på arkivmateriale fra leukemipasienter, dvs. beinmargsutstryk og -biopsier. DNA ble ekstrahert fra beinmargsprøvene og deretter kvantitert. Pga. små mengder DNA fra hver pasientprøve ble det gjort hel-genom amplifisering (whole genome amplification, WGA) som et forsøk på å øke DNA mengden i prøvene. Deretter ble prøvene analysert for to typer genmarkører, 10 såkalte korte tandem repetisjoner (eng.: short tandem repeats, STRs) og 34000 SNP’er. Resultatene ble sammenliknet med tilsvarende markørundersøkelser på blod og vi fant at 90% av STR-markørene lot seg gjenskape fra arkivmaterialet. For SNP-markørene fikk vi tilfredsstillende resultat for bare 7 av 34 prøver, men to av prøvene ga svært godt resultat. WGA fungerte ganske bra for noen av prøvene, men dårligere sammenliknet med prøver uten WGA. Konklusjonen ble at bruk av gamle beinmargsprøver til multiple genanalyser er mulig, men analysemetoden må forbedres.Cancer remains the leading cause of disease-related mortality among children aged 1-14 years in developed countries. Acute lymphoblastic leukaemia (ALL) is the most common malignancy in childhood and accounts for about 25% of all childhood cancers. In Norway about 30-40 children are diagnosed with ALL each year. Treatment comprises of a combination of 6-12 different chemotherapy drugs administered over a period of 2.5 years with additional supportive care. Side effects remain a great challenge for both patients and physicians. One of the most common side effects is immunosuppression which increases the risk of infection. Today, the overall survival rate in childhood ALL is 80-85%. About 75% of deaths related to ALL are caused by the disease itself, most after relapse, but about 25% of deaths are caused by treatment and are classified as treatment-related deaths (TRDs). In this study, the incidence, risk factors and causes of death were investigated for 88 TRDs among 2,700 patients in the Nordic countries Sweden, Denmark, Finland, Iceland and Norway. The incidence of TRD was 3.2%, which was stable in the two protocols, the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL 1992 and ALL 2000 protocols. The risk factors identified were female gender, treatment risk-group, T-cell disease, Down syndrome and stem cell transplantation. Seventy-five percent of the deaths were related to infection, 10% to bleeding or thrombosis, 10% to organ failure and 5% to the tumour burden. We have no good explanation as to why some patients experience more severe infections than others, even when receiving the same drugs, drug dosage and supportive care. It is reasonable to believe that genetic factors play a role. In accordance with the increasing understanding of host genetic variation the past 10 years, we investigated 34,000 single nucleotide polymorphisms (SNPs) relevant in childhood ALL in a Danish ALL cohort including 69 children and detected 24 SNPs which associated with infections during induction treatment. Through CART-analysis (classification and regression tree) a four-SNP risk profile were identified as highly predictive of risk of infections during the 50 days induction treatment. The four SNPs belong to the genes R51F1, CBR1, POLDIP3 and CCL11 which regulate drug metabolism, cell-growth and inflammation. If these findings are replicated in larger studies, such knowledge may be useful for developing personalized medicine with more tailored therapy and supportive care, which will hopefully reduce the severity of side effects and increase overall survival. Studies involving multiple biological markers, such as SNPs and short tandem repeats (STRs), often use high-quality DNA extracted from blood samples. However, blood samples are not always easy to obtain from study participants, especially if the patient has died. Archival bone marrow samples from patients with leukaemia are available and represent a potential DNA source. We were interested in exploring whether such archival material is usable for the analysis and identification of multiple markers. DNA from 21 bone marrow smears and 13 bone marrow biopsies were extracted and quantified. Because of small amounts of DNA from each sample whole genome amplification (WGA) was applied. Ten different STR-markers and 34,000 SNPs were analysed and compared with corresponding blood samples. For the STR markers 90% detection rates were obtained. Shorter markers (107bp-242bp) from samples stored 0-3 years gave better results compared with longer markers (219bp-317bp) stored 4-10 years. Multiple SNP analysis was more complicated and only seven of 34 archival samples gave acceptable results (SNP call-rates above 50%). However, in two samples, nearly 100% of SNP-markers were detected. Although increasing the total amount of DNA, WGA reduced the analysis quality. In conclusion, DNA from archival bone-marrow samples might be used in multiple marker analysis, but adjustments of the laboratory set-up are essential to optimize this method.
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Dormon, Katherine Louise. "Investigating the evolution of dexamethasone resistance in acute lymphoblastic leukaemia." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3737.
Full textAbstract:
The evolution of ALL from presentation to relapse is often accompanied by the emergence of resistance to commonly used chemotherapeutics, including dexamethasone (Dex), a synthetic glucocorticoid that has been the backbone of ALL treatment since the 1950s. In order to investigate the evolution of drug resistance we focused on the L707 cells, a matched Dex-sensitive presentation and Dex-resistant relapse pair from a patient with t(17;19) B ALL. A major genetic difference between presentation and relapse is a 5q deletion spanning 6 genes, including NR3C1, the glucocorticoid receptor and the site of action for Dex. It was found previously that the L707 presentation engrafts and proliferates faster than the relapse cells in the NSG mouse model. The loss of NR3C1 was hypothesised as the cause for reduced fitness of the relapse. This thesis investigated this, and the mechanisms behind the Dex resistance in the L707 relapse. Using shRNA approaches to look at the function of the genes in the relapse 5q deletion identified NR3C1 as the major driver of resistance but did not provide evidence that loss resulted in reduced fitness. Further in depth analysis of the L707 cells using microarrays has shown that the differences between presentation and relapse extend past the genetic differences, including alterations in transcriptional programmes. To identify further novel drivers of resistance, a whole genome in vivo CRISPR screen was carried out, implicating several genes in leukaemic fitness and Dex resistance as well as being a proof of concept for the use of these screens in primary material. Finally, an incidental finding that 697 pre B leukaemic cell line was Dex resistant in vivo, but not in vitro, and examination of these cells using RNA sequencing resulted in the finding that alterations in transcription induced by the murine microenvironment may be responsible for this change.
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Rocchetti, Francesca. "Study of calcineurin pro-oncogenic role in acute lymphoblastic leukemia." Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCC166.
Full textAbstract:
Malgré les avancés thérapeutiques, le pronostic des leucémies aiguës lymphoblastiques (LAL) reste mauvais. Notre laboratoire a montré que la calcineurine (Cn) est requise pour le maintien à long terme des LAL-T. Sa délétion est associée à la dérégulation de l'expression de plusieurs gènes, dont TRNP1 et NFIB, qui sont nouveaux dans le contexte des LAL-T. Nous avons montré que la suppression de leur expression a un effet délétère sur les cellules leucémiques de LAL-T in vitro et in vivo. Cn est aussi activée dans les LAL-B BCR-ABL+. Des travaux publiés ont proposé que son inhibition par la cyclosporine A (CsA) sensibilise les cellules leucémiques aux inhibiteurs de BCR-ABL. Nous montrons ici que cette sensibilisation est indépendante de l'inhibition de Cn. En effet, son inactivation génique n'affecte ni le maintien, ni la propagation de ces LAL-B in vivo. In vitro, la CsA sensibilise ces cellules leucémiques aux inhibiteurs de BCR-ABL en présence ou non de Cn. Le pronostic des patients atteints de LAL-B est mauvais lorsqu'ils présentent la délétion du gène codant pour le facteur de transcription Ikaros (IKZF1). Dans un modèle murin de LAL-B combinant BCR-ABL avec la perte d'un allèle de IKZF1 dans le lignage B, now montrons une accélération de l'émergence de la maladie et une dérégulation de gènes préférentiellement exprimés dans les cellules souches/progéniteurs hématopoïétiques précoces. Ceci suggère que la perte d'un allèle de IKZF1 permet la reprogrammation des progéniteurs B, cellules d'origine de ces leucémies, vers un stade plus primitif et indifférencié, augmentant ainsi l'agressivité de la maladieAlthough acute Iymphoblastic leukemia (ALL) cure rates improved in the last decades, outcome for primary resistant and relapsed patients remains poor. Our laboratory showed that calcineurin (Cn) is essential to T-ALL Leukemia Initiating Cells activity. Its deletion is associated with strong anti-leukemic effects and to the deregulation of several genes, including TRNP1 and NFIB, which have never been reported in T-ALL. Here, we demonstrate that silencing of these genes is deleterious to T-ALL cells both in vitro and in vivo, unravelling new actors involved in leukemogenesis. Cn is activated in BCR-ABL+ B-ALL (Ph+ B-ALL) as well and its inhibition by cyclosporin A (CsA) was reported to sensitize leukemic cells to BCR-ABL inhibitors in a mouse model of the disease. We demonstrate here that this sensitization is due to off-target effects of CsA, since Cn genetic deletion did not affect BCR-ABL-induced B-ALL maintenance and propagation in two mouse models of the disease. Moreover, CsA similarly sensitized Cn+ and Cn- leukemic cells to BCR-ABL inhibitors in vitro. The outcome of B-ALL is particularly poor when patients present deletions of IKZF1, the gene encoding the transcription factor Ikaros, which are observed in >800/0 of Ph+ B-ALL cases. Using a mouse model of BCR-ABL-induced B-ALL in which one copy of Ikaros can be specifically deleted in pro-B cells, we observed acceleration of leukemia onset and a stem-cell/early progenitor-like transcriptomic signature. Thus, the loss of one copy of Ikaros allows the reprogramming of the pro/pre-B cell of origin towards a more primitive, undifferentiated state, likely explaining the increased aggressiveness of the disease
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Larery, Angela R. D. "Hierarchical neuropsychological functioning in pediatric survivors of acute lymphoblastic leukemia." Thesis, University of North Texas, 2007. https://digital.library.unt.edu/ark:/67531/metadc3949/.
Full textAbstract:
Acute lymphocytic leukemia (ALL) is one of the most common types of pediatric cancers. Improvements in treatment within the last 20 years have resulted in reduced mortality and a greater focus upon quality of life. Several researchers have documented neuropsychological impairments in children following treatment for ALL; however, there have not been any comparative studies documenting differences in neuropsychological functioning based upon treatment modality despite the documented effects of radiation therapy and combined radiation/chemotherapy upon the developing brain. In addition, past studies have focused on unitary measures, ignoring the hierarchical relationship between basic cognitive functions and more abstract skills. This study examined the neuropsychological functioning of 81 children who were treated for ALL at a metropolitan children's hospital. All children were tested a minimum of two years after the final treatment session and were administered the NEPSY. Results do not support any interactions or main effects with the exception of the age of the child at diagnosis. Children diagnosed prior to the age of 5 showed greater impairments on tasks measuring attention, memory, and visuospatial reasoning in comparison to peers diagnosed after age 6.
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Berks, Richard. "In vitro models of TEL/AML1-positive acute lymphoblastic leukaemia." Thesis, University of York, 2012. http://etheses.whiterose.ac.uk/3160/.
Full textAbstract:
Acute lymphoblastic leukaemia (ALL) is the most common cancer in children, and is characterised by the proliferation of immature lymphoid cells in the bone marrow. The fusion gene TEL/AML1, generated by the chromosome translocation t(12;21), is the most common single genetic aberration in B-lineage ALL, and is formed from the transcription factors TEL and AML1 (coded for by the genes ETV6 and RUNX1, respectively). However, it is still not clear how the presence of TEL/AML1 causes the development of leukaemia. In addition, the importance of a common secondary mutation in TEL/AML1+ leukaemia, the loss of the untranslocated ETV6 allele, is still subject to debate. The role of TEL/AML1 in malignant haematopoiesis has been previously studied in a variety of models, include in vivo mouse models, in vitro TEL/AML1+ cell lines, and ex vivo patient samples. Each of these models has contributed great amounts to our knowledge about TEL/AML1+ leukaemia; however, each type of model has its disadvantages. Here, a new model is presented which aims to complement these other models, based upon human embryonic stem cells (hESCs) expressing a TEL/AML1 transgene. These transgenic hESCs were shown to be capable of multipotent haematopoietic development, including towards B lymphocytes. The consequence of the loss of TEL in TEL/AML1+ leukaemia is not fully known. Here I provide two insights into this frequent secondary mutation. Firstly, a gene expression microarray revealed the transcriptional role of TEL and illuminated how its loss might contribute to progression of TEL/AML1+ leukaemia. Secondly, the functional role of TEL in proliferation and apoptosis was further investigated, which provided further insight about the clonal evolution of TEL/AML1+ leukaemia. In addition, new discoveries were made of potential partners for heterodimeric transcription factor complexes and targets for TEL repression, which provide new avenues for future studies. Taken together, the data presented in this thesis provides the basis for renewed study into TEL/AML1+ leukaemia which could address remaining questions about the disease.