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1
Baran, Yusuf. "Multiple Drug Resistance Mechanisms In Imatinib Resistat Human Chronic Myeloid Leukemia Cells." Phd thesis, METU, 2006. http://etd.lib.metu.edu.tr/upload/12607612/index.pdf.
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In this study, mechanisms of resistance to Imatinib-induced apoptosis in human K562 and Meg-1 chronic myeloid leukemia (CML) cells were examined. Continuous exposure of cells to step-wise increasing concentrations of Imatinib resulted in the selection of 0.2 and 1 μ
M imatinib resistant cells. Measurement of endogenous ceramide levels showed that treatment with Imatinib increased the generation of C18-ceramide significantly, which is mainly synthesized by the human longevity assurance gene 1 (hLASS1), in sensitive, but not in resistant cells. Mechanistically, analysis of mRNA and enzyme activity levels of hLASS1 in the absence or presence of Imatinib did not show any significant differences in the resistant cells when compared to its sensitive counterparts, suggesting that accumulation and/or metabolism, but not the synthesis of ceramide, might be altered in resistant cells. iv Indeed, further studies demonstrated that expression levels, and enzyme activity of sphingosine kinase-1 (SK-1), increased significantly in resistant K562 or Meg-1 cells. The expression levels of glucosyl ceramide synthase (GCS) also increased in resistant cells, comparing to the sensitive counterparts, which indicates conversion of pro-apoptotic ceramide to glucosyl ceramide. Expression analyses of BCR-ABL gene demonstrated that expression levels of BCR-ABL gene increased gradually as the cells acquired the resistance. However, Nucleotide sequence analyses of ABL kinase gene revealed that there was no mutation in Imatinib binding region of the gene in resistant cells. There was also an increase in expression levels of MDR1 gene in resistant cells, which transport the toxic substances outside of cells. In conclusion, these data show, for the first time, a role for endogenous ceramide synthesis via hLASS1 in Imatinib-induced apoptosis, and those alterations of the balance between the levels of ceramide and S1P. Mainly the overexpression of SK-1 seems to result in resistance to Imatinib in K562 cells. The cellular resistance may also result from conversion of ceramide to glucosyl ceramide, from overexpression of BCR-ABL and MDR1 genes but not due to mutations in Imatinib binding site of ABL kinase.
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Cheng, Man-ying, and 鄭文瑛. "Prescribing pattern of imatinib among chronic phase chronic myeloid leukaemia (CML) patients and its financial impact on Hong Kong." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/196548.
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Background: Chronic myeloid leukaemia (CML) is a haematological malignant disease involving haematopoietic stem cells. It is caused by a known reciprocal chromosomal t(9;22)(q34;q11) translocation, or known as Philadelphia chromosome. The translocation results in the formation of a chimeric BCR-ABL fusion gene. In the most recent guidelines published by NCCN and European LeukemiaNet in 2013, tyrosine kinase inhibitors (TKI) specifically inhibiting the Bcr-Abl tyrosine kinase, are the first-line therapy for patients with chronic phase CML. Imatinib is the oldest among the 3 TKI, and is the most commonly prescribed. Despite its proven therapeutic role in CML, imatinib is a drug of extreme high cost. Estimated annual drug cost is HKD$223,380for a standard 400mg adult daily dose. Therefore, this study aims to survey on the prescribing pattern of imatinib in CML patients, its funding status, response; and estimate its economic burden on the Hong Kong population.
Methodology: This is a retrospective patient chart review study. All patients who were diagnosed with CML from 2003 to 2012 and were managed in QMH or QEH were reviewed. Electronic records were retrieved to see whether imatinib was started as first-line treatment within 6 months of diagnosis. The reasons for not initiating imatinib were also investigated. Patients’ response to imatinib, and funding source for the drug, were documented. Annual drug cost of imatinib was estimated from all CML patients who attended all Hospital Authority institutions in 2012 who were prescribed with the drug.
Results: Total 153 patients from the 2 institutions were reviewed. One hundred twenty four (81%) of them started imatinib as first-line therapy within 6 months of diagnosis. Nine patients started second generation TKI as first-line. Among those who did not start TKI, the most common reasons are patient preference (3.9%) and financial difficulties (3.3%). Twelve paediatric patients are identified, and all but one of them started imatinib. Seventy one% patients on imatinib experienced side effects. Most frequently reported adverse reactions are thrombocytopenia, oedema and neutropenia. Twenty eight% switched to second generation TKI due to suboptimal response or intoleranceto imatinib. During their course of treatment, 46.3% patients on imatinib require social subsidy from Samaritan Fund. From the dispensing records, the average drug cost per patient per year is HK$113,902. The estimated annual cost burden on the whole Hong Kong population is HK$43,425,878.
Conclusion: The prescribing rate of imatinib in chronic phase CML patients in Hong Kong is comparable to overseas prescribing rate. The drug has become a significant financial burden to patients’ family and the society as a whole.published_or_final_version
Paediatrics and Adolescent Medicine
Master
Master of Medical Sciences
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Höijer, Jonas. "Prognostic Factors for 12 Month Major Molecular Response for Patients with Chronic Myeloid Leukemia." Thesis, Uppsala universitet, Statistiska institutionen, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-201419.
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Chronic Myeloid Leukemia is a kind of blood cancer with around 1 incidence per 100 000 persons/year. After the development of an effective treatment, imatinib, in the late 1990:s, the survival percentage has increased drastically. The high survival has turned the attention to different kinds of treatment responses, which in turn are good prognostic factors to future health status. In this thesis, the focus is on whether or not the patient has achieved a so called major molecular response after 12 month, or not. More precisely, the aim is to find prognostic factors to the 12 month response. In order to find prognostic factors for this binary response variable, a multivariate logistic regression analysis is conducted, with the goal of finding a parsimonious logistic model that describes the data. The analysis is done from a merged dataset from three earlier studies. The prognostic factors in the final model are treatment, 3 month response, and enlarged spleen. However, the residual analysis indicates that the model is incomplete, implying that further research needs to be done.
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Burgos, Espadinha Daniel António [Verfasser], and Andreas [Akademischer Betreuer] Trumpp. "Exploring combined treatment strategies to target quiescent chronic myeloid leukemia (CML) stem cells / Daniel António Burgos Espadinha ; Betreuer: Andreas Trumpp." Heidelberg : Universitätsbibliothek Heidelberg, 2016. http://d-nb.info/118073551X/34.
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Gunay, Neset Batuhan. "Studies Directed Towards The Synthesis Of Imatinib Mesylate ((gleevec), 4-(4-methyl-piperazin-1- Ylmethyl)-n-[4- Methyl-3-(4-pyridin-3-yl-pyrimidin-2- Ylamino)-phenyl]- Benzamide Methanesulfonate) Analogs." Master's thesis, METU, 2008. http://etd.lib.metu.edu.tr/upload/12610181/index.pdf.
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Imatinib mesylate is indicated for the treatment of chronic myeloid leukemia (CML) and unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). By the application of this anticancer drug, problems occurs in terms of stability and activity. Computer assisted design (CAD) works showed that the modification of the B and C part molecule can increase the effectivity of the drug. The new derivatives of the drug will be obtained to change some part of the B and C segments. The total
synthesis of a new imatinib mesylate will be done and the activity
tests are going to be determined in collaboration with other groups.
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Morales, Kimberly. "RAD52 DNA Binding Activity Can Be Targeted to Eliminate CML Stem Cells." Diss., Temple University Libraries, 2012. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/190030.
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BiologyPh.D.
BCR-ABL1 transforms hematopoietic stem cells into leukemia stem cells (LSCs) to induce chronic myeloid leukemia in chronic phase. Expression of BCR-ABL1 stimulates production of elevated levels of reactive oxygen species (ROS), which induce oxidative DNA damage. CML cells accumulate excessive amounts of ROS-induced DNA damage which can be converted to potentially lethal DNA double strand breaks (DSBs). BCR-ABL1 stimulates enhanced Rad51-mediated DSB repair by the homologous recombination repair (HRR) pathway. In these studies we show BCR-ABL1-transformed cells depend on Rad52-mediated HRR to promote repair of ROS-induced DSBs and that this activity is dependent on Rad52 binding to single-stranded DNA (ssDNA). Our results show in the absence of Rad52, BCR-ABL1-positive hematopoietic cells accumulated elevated numbers of DSBs as detected by enhanced γ--H2AX foci formation compared to cells with wild-type Rad52 which resulted in a decrease in proliferation and expansion of the Rad52-null LSC population. Expression of wild-type Rad52 in Rad52-null cells decreased the accumulation of DSBs and restored expansion of the LSC population. Inhibition of ROS with the antioxidants Vitamin E or N-acetyl cysteine exerted similar effects on the LSC population of Rad52-null cells as restoration of wild-type Rad52. Our studies also show Rad52's ssDNA-binding activity is required for the proliferation of CML cells as evidenced by the accumulation of DSBs and impairment of clonogenic potential in cells in which the Rad52-F79A ssDNA-binding deficient mutant was expressed. Inhibition of Rad52 DNA binding activity by a peptide aptamer targeting Rad52-F79 resulted in a synthetic lethal phenotype in BCR-ABL1-positive cells due to impairment of the Rad52-dependent HRR pathway, as demonstrated by immunofluorescence and HRR repair assays. Altogether we identify Rad52 as a novel target in the treatment of CML, and other BRCA1- and/or BRCA2-deficient cancers, by showing induction of synthetic lethality in proliferating BCR-ABL1-positive cells in which Rad52 ssDNA-binding activity is inhibited.
Temple University--Theses
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Küpper, Maja Kim [Verfasser], Wolfgang [Akademischer Betreuer] Wagner, and Gerhard [Akademischer Betreuer] Müller-Newen. "STAT3-mediated therapy resistance of malignant stem cells in chronic myeloid leukemia (CML) / Maja Kim Küpper ; Wolfgang Wagner, Gerhard Müller-Newen." Aachen : Universitätsbibliothek der RWTH Aachen, 2019. http://d-nb.info/1194067107/34.
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Giacopelli, Brian John. "Global DNA methylation analysis of chronic lymphocytic leukemia and acute myeloid leukemia reveals distinct clinically relevant biological subtypes." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1591114255694166.
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Pagliaro, Sarah Beatriz De Oliveira. "Transcriptional control induced by bcr-abl and its role in leukemic stem cell heterogeneity. Single-Cell Transcriptome in Chronic Myeloid Leukemia: Pseudotime Analysis Reveals Evidence of Embryonic and Transitional Stem Cell States Single Cell Transcriptome in Chronic Myeloid Leukemia (CML): Pseudotime Analysis Reveals a Rare Population with Embryonic Stem Cell Features and Druggable Intricated Transitional Stem Cell States A novel neuronal organoid model mimicking glioblastoma (GBM) features from induced pluripotent stem cells (iPSC) Experimental and integrative analyses identify an ETS1 network downstream of BCR-ABL in chronic myeloid leukemia (CML)." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASQ032.
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La leucémie myéloïde chronique est une hématopoïèse maligne clonale, caractérisée par l'acquisition de la translocation t (9;22) conduisant au chromosome Ph1 et à son homologue l'oncogène BCR-ABL, dans une cellule souche hématopoïétique très primitive. La LMC est un modèle de thérapies ciblées, car il a été démontré que la preuve de la faisabilité du ciblage de l'activité tyrosine kinase (TK) BCR-ABL à l'aide d'inhibiteurs de TK (TKI) entraîne des réponses et des rémissions majeures. Cependant, les problèmes actuels rencontrés dans ces thérapies sont la résistance des cellules souches leucémiques primitives et leur persistance qui serait liée à l'hétérogénéité des cellules souches au moment du diagnostic, ce qui conduit à la sélection clonale de cellules résistant aux thérapies TKI. J'ai appliqué la technologie de l'analyse du transcriptome des cellule uniques aux cellules de la LMC en utilisant un panel de gènes impliqués dans différentes voies, combinée à l'analyse d'inférence de trajectoire au modèle d'expression des gènes. Les résultats ont montré un état transitoire des cellules souches comprenant des gènes embryonnaires identifiés dans les cellules de la LMC au moment du diagnostic, ce qui pourrait contribuer à la résistance et à la persistance de la LSC. En outre, l'oncoprotéine Bcr-Abl est la tyrosine kinase constitutivement active produite par le gène chimérique BCR-ABL dans la leucémie myéloïde chronique (LMC). Les cibles transcriptionnelles de Bcr-Abl dans les cellules leucémiques n'ont pas été étudiées de manière approfondie. Une expérience de transcriptome utilisant la lignée cellulaire UT7 hématopoïétique exprimant BCR-ABL, a identifié la surexpression du facteur d'élongation eucaryote kinase 2 (eEF2K) qui joue un rôle majeur dans la survie des cellules en cas de privation de nutriments. Dans l'ensemble, les données suggèrent que la surexpression de eEF2K dans la LMC est associée à une sensibilité accrue à la privation de nutrimentsChronic myeloid leukemia is a clonal hematopoietic malignancy, characterized by the acquisition of the t (9;22) translocation leading to Ph1 chromosome and its counterpart BCR-ABL oncogene, in a very primitive hematopoietic stem cell. CML is a model of targeted therapies as the proof of concept of the feasibility of targeting the tyrosine kinase (TK) activity BCR-ABL using TK inhibitors (TKI) has been shown to lead to major responses and remissions. However, the current problems encountered in these therapies are primitive leukemic stem cells resistance and their persistence which is thought to be related to the heterogeneity of the stem cells at diagnosis leading to clonal selection of cells resisting to TKI therapies. I have applied the technology of single cell transcriptome analysis to CML cells using a panel of genes involved in different pathways combined with trajectory inference analysis to the gene expression pattern. The results showed a transitional stem cell states including embryonic genes identified in CML cells at diagnosis which could contribute to LSC resistance and persistence. Furthermore, the oncoprotein Bcr-Abl is the constitutively active tyrosine kinase produced by the chimeric BCR-ABL gene in chronic myeloid leukemia (CML). The transcriptional targets of Bcr-Abl in leukemic cells have not been extensively studied. A transcriptome experiment using the hematopoietic UT7 cell line expressing BCR-ABL, has identified the overexpression of eukaryotic elongation factor kinase 2 (eEF2K) which plays a major role in the survival of cells upon nutrient deprivation. Overall, the data suggest that overexpression of eEF2K in CML is associated with an increased sensitivity to nutrient-deprivation
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Rothe, Tino. "Anwendung mathematischer Modelle zur Vorhersage des Therapieverlaufs von CML-Patienten." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2018. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-231508.
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Hintergrund Die chronische myeloische Leukämie (CML) ist eine myeloproliferative Er- krankung, die aufgrund ihres Modellcharakters unter der Behandlung mit Tyrosin-Kinase- Inhibitoren (TKI) gut für eine Beschreibung mittels computerbasierter Modelle geeignet ist. Grundlage für die Entstehung einer CML ist die Bildung eines Philadelphia-Chromosoms durch eine Translokation der Chromosomen 9 und 22. Es resultiert das Onkogen BCR- ABL1, welches für eine konstitutiv aktive Tyrosinkinase codiert. Diese führt zu ungeregelter Proliferation der betroffen Zellen und zur Verdrängung der gesunden Blutbildung. Das überaktivierte Protein kann durch TKIs gezielt gehemmt werden. Damit ist es möglich, die Tumorlast erheblich zu senken und das Fortschreiten der Erkrankung aufzuhalten. Aktuell werden in der klinischen Anwendung außerhalb von Studien TKIs für die gesamte Lebensdauer der Patienten eingesetzt. Absetzstudien zeigten, dass circa 50% der Patienten nach einer über zwei Jahren nicht nachweisbaren BCR-ABL1-Last nach Behandlungsstopp kein erneutes Anwachsen der Tumorlast aufwiesen. Die Anwendung von computergestützten Modellsimulationen hilft, Zugriff auf die klinisch nur schwer zu messenden leukämischen Stammzellen zu bekommen und darüber Vorhersagen über den weiteren Therapieverlauf zu treffen. Aufgabenstellung Im Rahmen der vorliegenden Arbeit sollen Möglichkeiten der Übertragung von Patientendaten auf das etablierte Modell nach Roeder und Loeffler (2002) verbessert werden. Die vom Modell vorhergesagten Stammzellkinetiken sollen abschließend auf Praxistauglichkeit geprüft werden. Material und Methoden Aufgrund der Vergleichbarkeit zu früheren Untersuchungen erfolgte die Auswahl von 51 Patienten des deutsches Armes der IRIS-Studie. Deren Therapieverläufe wurden analysiert und können über eine biphasische exponentielle (biexponentielle) bzw. über eine stückweise lineare Funktion beschreiben werden. Als Erweiterung der Arbeiten von Horn et al. (2013) wurden alle Parameter der biexponentiellen Funktion in die Entwicklung neuer Methoden einbezogen. Zusätzlich wurde untersucht, ob die Einbeziehung von zensierten Messpunkte die Form der biexponentiellen Funktion verändert. Basierend auf den Therapiedaten der IRIS-Patienten erfolgte die Ermittlung eines Para meterraumes für Eingangsparameter der Modellsimulation (Modellparameter), welcher in 270.400 individuelle Paramterkombinationen unterteilt wurde. Es erfolgten anschließend die Simulation und Auswertung nach der biexponentiellen Beschreibung. Auf Basis dieser erheblich größeren Datengrundlage konnten zwei neue Verfahren der Modellparameteridentifikation für individuelle Patienten entwickelt werden. Einerseits wurde in Anlehnung an die Arbeit von Horn et al. (2013) ein Verfahren unter Nutzung der Regression vorgestellt. Andererseits konnte über den Vergleich der Abstände zwischen simulierten und realen Therapieverläufen eine Suche (lookup-table) etabliert werden. Die Berechnung des Abstandes zwischen Therapieverläufen ermöglicht gleichzeitig den Vergleich der verschiedenen Verfahren und damit eine Aussage über deren Anpassungsgüte. Zum Schluss wurde beispielhaft für einen Patienten das Verfahren der lookup-table angewendet und die resultierende Stammzellkinetik weiter analysiert. Ergebnisse Einführend erfolgte die Analyse der resultierenden biexponentiellen Funktion mit und ohne Einbeziehung von Messunsicherheiten. Es zeigte sich, dass der Verlauf dieser Funktion besonders in Bereichen, die von einbezogenen Messunsicherheiten betroffen sind, abweichend ist. Die Beschreibung des Langzeitverlaufs erfolgt jedoch annähernd gleich. Anschließend erfolgte die Validierung der Größe des vorsimulierten Datenpool anhand eines Vergleichs der statistischen Parameter von Patienten und Simulationen. Dieser zeigte sich dabei für die weiteren Untersuchungen geeignet. Die Nutzung der lookup-table zur Identifikation der am besten zu einem Patienten passenden Therapiesimulation ist überlegen sowohl gegenüber von der Horn et al. (2013) beschriebenen als auch in dieser Arbeit neu entwickelten Regressionsverfahren. Diese ergeben deutliche Abweichungen zwischen Patientendaten und Simulation. Eine Analyse des vorhergesagten Therapieverlaufes im Stammzellkompartiment ergibt jedoch, dass ähnliche Therapieverläufe im peripheren Blut durch stark unterschiedliche Stammzellkonfigurationen beschrieben werden können. Es resultiert eine starke Streuung der vorhergesagten Zeitpunkte eines möglichen Therapieendes. Schlussfolgerungen Die Nutzung der lookup-table zu Identifikation einer passenden Therapiesimulation ist hoch effektiv und anderen Verfahren, die auf Regression basieren, überlegen. Die etablierte Computersimulation nach Roeder und Loeffler (2002) bietet Zugriff auf die Therapie in der Ebene der Stammzellen. Die in weiteren Analysen gezeigten Streuungen der vorhergesagten Therapieverläufe im Stammzellkompartiment lassen den Schluss zu, dass Methoden zur Eingrenzung der Stammzellverläufe entwickelt werden müssen, um die Vorhersagen klinisch nutzbar zu machen. Weiterhin muss anhand von Messungen an Knochenmarkproben von realen Patienten geprüft werden, ob die von der Simulation postulierten Verläufe der Tumorlast im Stammzellkompartiment der realen Behandlung entsprechen. Ausblick Die in aktuellen Arbeiten beschriebene Rolle des Immunsystems im Therapieverlauf der CML (Saussele et al. 2016; Clapp et al. 2016) sollte in eine Verbesserung des Stammzellmodells nach Roeder und Loeffler (2002) einfließen. Weiterhin kann die Validierung der im Rahmen der Individualmedizin zu treffenden Absetzvorhersagen letztendlich nur über klinische Absetzuntersuchungen ermöglicht werdenBackground Chronic myeloic leukaemia (CML) is a myeloproliferative disease, which is well suited for modelling approaches. It is characterized by the oncogenic BCR-ABL1 fusion gene originating from an inverse translocation of the chromosomes 9 and 22 leading to the Philadelphia chromosome. The result is a constitutively activated tyrosine-kinase. This is followed by an extensive proliferation of leukaemic stem cells leading to a displacement of normal haematopoesis. The molecular specificity of CML forms the basis of a highly efficient, targeted therapy by tyrosine kinase inhibitors (TKIs). TKIs can decrease the tumour burden and slow down or eventually stop progressing of the disease. Currently, in clinical applications drugs are administered for the remaining life span. Interestingly, in recent treatment cessation trials patients were stopped after two years of non-detectable tumour burden and about 50% remained without relapse. The application of computer-based modelling helps to gain access to stem cell counts being difficult to measure clinically. This forms the basis for predictions of long-term therapy outcomes. Aim of this work This work aims on identifying a suitable algorithm to efficiently identify model simulations that optimally decribe individual patient kinetics. Furthermore, the clinical usability of the new methods was investigated. Material and methods The analysed group of patients was chosen out of the German cohort of the IRIS trial to ensure comparability to former investigations. It consists of 51 individuals. The course of leukaemic burden , i. e. leukaemic vs. non-leukaemic cells on a single patient level can be described as a biphasic exponential (bi-exponential) or a piecewise linear function. As an extension to former methods described by Horn et al. (2013) all parameters are included into further method development. Additionally, an investigation was conducted whether censored data points change the functional behaviour of a bi-exponential fit based on patients’ data. According to therapy data of all patients an input parameter space for the model simulation was delimited, such that all observed patient kinetics can be mimicked by the model. This parameter space was uniformly divided into 270.400 discrete parameter combinations. The therapy simulation of each combination was conducted and described by a bi-exponential function likewise to the patients’ fit. With the help of these huge variety of in silico therapies two new methods of model parameter identification for individual patients were developed. The first one is an advanced approach based on a regression model proposed by Horn et al. (2013). The second one by comparing distances between the patients’ and the models’ bi-exponential functions (lookup table). The comparison of the distances between different therapy courses (either simulated or patients’ data) was also used to compare the quality of different methods. As an example, for one patient the stem cell kinetics from the model were analysed in more detail and checked for robustness. Such a strategy, which might build the basis for clinical applications. Results A comparison between the different bi-exponential functions with and without censored data points revealed differences especially in the area in which censoring was performed. However, for the long-term tumour burden censored data had no influence. Secondly, an investigation was performed showing the sufficiency of the pre-simulated therapy courses for the new methods, i. e. lookup-table and regression models. The lookup- table turns out to be superior to identify a therapy simulation for a unique patient, since the complexity of linear regression models lead to increased deviations between patients’ therapy courses and the simulations. Unfortunately, distinct stem cell configurations lead to similar therapy descriptions in peripheral blood, assuming the correctness of the model. As a result, the prediction of a safe treatment cessation is often widely spread. Conclusions The new developed lookup-table to identify model simulations suitable for an individual patient is highly effective and superior to other methods using regression models. The simulation of the TKI treatment using the agent-based model of Roeder und Loeffler (2002) gives easy access to therapy courses on the level of leukaemic stem cells. Unfortunately, the finding of a well fitting simulation within the peripheral blood is not enough to provide a point of safe treatment cessation, since different stem cell configurations can lead to similar therapy courses. Additionally, it is necessary to check which of the assumed therapy courses on the stem cell level is appropriate. This could be done by gathering more information from bone-marrow punctures during the course of treatment. Outlook Investigations of new data showed the important role of the immune system in CML treatment (Saussele et al. 2016; Clapp et al. 2016). This should be taken into account by improving the model of Roeder und Loeffler (2002). Additionally, data from cessation trials can be used to validate the model assumptions
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Gunnarsson, Niklas. "Chronic myeloid leukemia and cancer." Doctoral thesis, Umeå universitet, Medicin, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-141144.
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Background Chronic myeloid leukemia (CML) is a relatively rare hematological malignancy with a constant incidence of approximately 90 new cases each year in Sweden (0.9 cases/100 000 inhabitants). The etiology is largely unknown but high doses of ionizing radiation are a known but rare risk factor. The treatment options were for a long time limited to chemotherapies i.e. hydroxyurea and busulfan, interferon’s and allogeneic hematopoietic stem cell transplantation and the median survival were only about four years. Since the beginning of the 21st century a new way of treating CML has been introduced, the tyrosine kinase inhibitors (TKI), leading to a rapid decrease in leukemic cells and symptoms. Due to the TKIs, the overall 5-year survival is nowadays approximately 85 % and CML patients have time to develop other diseases, including other malignancies. The aims of this thesis was to investigate the present and future prevalence of CML and the prevalence of other malignancies prior and subsequent to the diagnosis of CML, malignancies among first-degree relatives of persons with CML. In addition, the incidence of autoimmune and chronic inflammatory diseases among patients with CML was also investigated. Methods From the Swedish CML register, data over nearly all Swedish CML patients from 2002 and forward were obtained for paper II-IV. For paper I, the Swedish cancer register was used to identify all Swedish CML patients since 1970 and the Swedish cause of death register was used to identify an eventual date of death for these patients. With a constant incidence and the relative survival rates for CML patients between 2006 and 2012 as a model, the present and future prevalence was calculated. For paper II-IV, data from the Swedish cancer register was used to identify other malignancies than CML. For paper II, information about autoimmune and chronic inflammatory diseases was retrieved from the Swedish national patient register. For paper II and IV, five controls matched for year of birth, gender and county of residence were randomly selected from the Swedish register of the total population. To calculate odds ratio (OR), conditional logistic regression was used. To calculate the risk of a second malignancy for paper III, Standardized incidence ratio (SIR) was used. In paper IV, first-degree relatives (parents, siblings and offsprings) for both cases and controls were retrieved from the Swedish multi-Generation Register, where persons born later than 1932 and registered in Sweden at some time since 1961 are registered. Results Prevalence and survival As shown in paper I, the 5-year overall survival for CML patients increased remarkably from 0.18 to 0.82 between 1970 and 2012. The prevalence increased from 3.9 to 11.9 per 100 000 inhabitants in Sweden between 1985 and 2012. By assuming no further improvements in relative survival as compared to the survival rates between 2006 and 2012, the prevalence by 2060 is expected to increase to 22.0 per 100 000 inhabitants. This corresponds to 2 587 CML patients as compared to 1 137 CML patients in 2012. Malignancies, autoimmune and chronic inflammatory diseases prior to CML In study II, more than 45 000 person-years of follow-up were evaluated in 984 CML patients diagnosed between 2002 and 2012. With an OR of 1.47 (95 % CI 1.20–1.82) and 1.55 (95 % CI 1.21–1.98), respectively, the prevalence of prior malignancies and autoimmune diseases were significantly increased as compared to matched controls. On the other hand, no association between CML and chronic inflammatory diseases was shown. Second malignancies In 868 CML patients, diagnosed between 2002 and 2011, 52 malignancies were observed in the Swedish cancer register, as shown in paper III. When compared to expected rates in the background population, a significantly increased risk of second malignancies with a SIR of 1.52 (95 % CI 1.13–1.99) was shown. When looking at specific cancer types, gastrointestinal as well as nose and throat cancer were significantly increased. Familial aggregation of malignancies 984 CML patients were identified in paper IV. However, 184 had a birth date prior to 1932, subsequently only 800 patients were analyzed. Among them, 4 287 first-degree relatives were identified, compared to 20 930 first-degree relatives of the matched controls. 611 malignancies were retrieved; no significant increase of malignancies in first-degree relatives of CML patients was shown (OR 1.06; 95 % CI: 0.96–1.16). Conclusion Since CML patients nowadays have a high survival rate, the calculations in this thesis shows that the prevalence of CML will almost double by 2060. CML patients have an increased risk of developing malignancies prior and subsequent to the diagnosis of CML, suggesting a hereditary or acquired predisposition to develop cancer. Since there is no familial aggregation of malignancies in CML patients, a hereditary predisposition to develop cancer is unlikely to be part of the pathogenesis of CML, leaving an acquired predisposition more likely.
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Essafi, Abdelkader. "Role of Fox03a in Chronic Myeloid Leukaemia (CML) Pathogenesis." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487755.
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Chronic myeloid leukaemia (CML) is the neoplastic expansion of haematopoietic stem/progenitor cells caused by BCR-ABL, a constitutively active tyrosine kinase. CML progresses through three stages by the modulation of the proliferation, survival and differentiation of haematopoietic progenitor cells. This is reversed by the BCR-ABL specific inhibitor STI571 (Oleevec, Imatinib). BCR-ABL mediates its oncogenic activities through the activation of different pathways, most notably through the activation of the phosphoinositide 3-kinase (PI3K) / protein kinase B (PKB/AKT) pathway. The activation of this pathway recapitulated BCR-ABL transformation of haematopoietic progenitor cells, and its inhibition resulted in proliferation arrest. apoptosis and differentiation of CML cells. A major regulator of signals emanating from the PI3K1PKB pathway is the forkhead box 0 (FOXO) family of transcription factors. FOXOs and in particular, FOX03a, are important regulators of proliferation, survival, diiTerentiation and stress resistance. Therefore, FOX03a could be a potential mediator of BCR-ABL signalling in CML cells. Indeed, FOX03a was shown to be highly phosphorylated in BCR-ABL expressing cells. This inhibitory PKB-dependent phosphorylation was abolished after STI571 treatment, leading to FOX03a activation. I-Iere, FOX03a is shown to directly bind the BIM promoter in vitro and in vivo and activate its expression through a forkhead response element (FHRE). This resulted in the induction of apoptosis that was inhibited in FOX03a- or BIM-deficient BCR-ABL expressing cells. FOX03a also activated p27':ip l expression downstream of STI571 signalling, through direct binding and recruitment of p300 co-activator. CYCLIN D2, on the other hand, is downregulated in a FOX03a-dependent fashion. This repression is mediated by FOX03a direct activation of the BCL6 repressor, BCL6 then binds eYCLIN D2 promoter leading to its repression. The regulation of p27Kipi and CYCLIN D2 is important for the regulation of proliferation ofCML cells. STl571 treatment of K562 CML cells leads to their differentiation towards the erythroid lineage. This is shown to be mediated by FOX03a direct repression of IDl. FOX03a binds the FHRE site within the IDl promoter in vivo and in vitro, leading to its downregulation. The identification of IDl as R novel direct target of FOX03a dependent repression was further investigated to understand the molecular mechanisms involved in this regulation. FOX03a regulation of IDI was achieved through the direct binding of FOX03a to inhibitor of growth Ib (INO1b) protein, a p53 binding protein. The two proteins cooperate to recruit the mSIN3A/HDACl complex to IDl promoter, leading to histone tails' deacetylation. The deacetylation of histone tails result in a closed chromatin state favouring repression. FQX03a and INO1b bind IDI promoter at the FHRE and the adjacent AT rich region,· respectively. Furthermore, a genetic interaction between H JXO]a, ING1h and If) I is shown to regulate erythroid differentiati.on of STl571-treated ((562 cells.. ING 1b is also shown to attenuate FOX03a dependent activation by delaying the activation of proliferation but not the apoptotic genes. Together. these findings provide evidence for a role for FOX03a as a tumour suppressor. regulating survival. proliferation and differentiation of CML cells. They also provide insights into the transcriptional regulation by FOX03a, and the molecular mechanisms governing target gene expression. Interestingly, this work shows a mechanistic parallel between FOXO- and p53- dependent signalling, transcriptional regulation and proteinprotein interactions. This work is important for future targeted therapy in CML, and other malignancies and disease where the PI3K1AKT/FOXO signalling pathway is deregulated.
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Lu, W. "Characterisation of CCN3 signalling pathway in Chronic Myeloid Leukaemia (CML)." Thesis, Queen's University Belfast, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.517404.
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Patel, Hetal. "Investigation of multimolecular complexes and signalling in chronic myeloid leukaemia (CML)." Thesis, Imperial College London, 2008. http://hdl.handle.net/10044/1/7747.
Full textAbstract:
Chronic Myeloid Leukaemia (CML) arises as a consequence of the expression of a chimaeric fusion protein; p210BCR-ABL. Many publications report that p210BRR-ABL forms complexes with multiple cytoplasmic proteins which affect signalling pathways demonstrated in cell lines or transduced cells. This has been necessary because primary haemopoietic cell lysates contain a degradative activity which rapidly and permanently destroys p210BCR-ABL. We have identified that the degradative enzymes located in the cell lysosomes and have demonstrated substantial inhibition of the p210BCR-ABL-degradative activity by high pH lysis conditions. We show to the best of our knowledge, the first set of data demonstrating expression and immunoprecipitation of p210BCR-ABL and co-immunoprecipitation of adaptor proteins CBL, CRKL and GRB2. The degradative activity also affects ABL protein, preventing analysis of protein complexes of normal ABL but using the high pH lysis we have shown that normal ABL complexes with GRB2 potentially mediated via BCR or a direct association with ABL, this is different from some cell line data published which implies that proteins that complex with p210BCR-ABL do not complex with normal ABL. We also analysed complexes in two Ph-negative, acute lymphocytic leukaemia (ALL) cell lines, KG1a and HL60 cells and found ABL forms complexes with CBL, CRKL and GRB2 similar to CML. This data suggests that adaptor proteins which complex with p210BCR-ABL also form complexes with ABL in Ph- leukaemic cells and some of them form complexes in non-leukaemic cells. Thus, there may be CML-specific, leukaemia-associated and normal interactions with ABL proteins. Using confocal microscopy and a junction specific anti-BCR-ABL (b2a2) antibody we analysed the subcellular distribution of p210BCR-ABL and have shown that p210BCR-ABL is arranged in discrete foci in the cell cytoplasm in various CML cell lines and primary CML cells. Many studies have implicated CRKL as an important target of p210BCR-ABL that can be used as an indirect indicator of p210BCR-ABL protein tyrosine kinase activity. When we analysed co-localisation of p210BCR-ABL and CRKL, we found that CRKL also formed foci. However, the CRKL and p210BCR-ABL foci were completely or partially associated or separate in different regions of the same cell. Since CRKL in CML is phosphorylated by association with p210BCR-ABL, these data imply that binding of CRKL and p210BCR-ABL maybe in a state of dynamic equilibrium. Heterogeneity of protein complexes from patients in blast crisis (BC) was observed, where the p210BCR-ABL-CBL complex was absent in one CML BC patient. Effects of imatinib on protein complexes were analysed and we found that p210BCR-ABL-CRK1 and p210BCr-ABL- CBL complex dissociates over time of treatment however, the GRB2 remains in complex within the 24 hour treatment period which maybe a potential target in imatinib resistant CML cells.
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Heaney, Nicholas Benjamin. "Proteasome inhibition in chronic myeloid leukaemia." Thesis, Connect to e-thesis, 2009. http://theses.gla.ac.uk/832/.
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Thesis (MD.) - University of Glasgow, 2009.MD. thesis submitted to the Faculty of Medicine, Division of Cancer Sciences and Molecular Pathology, University of Glasgow, 2009. Includes bibliographical references. Print version also available.
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Hui, Chung-Yee Rosaline. "Role and regulation of FOXO transcription factors in chronic myeloid leukaemia (CML)." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444408.
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Roy, Swagata. "EVI1 isoform expression, knockdown and biological activity in chronic myeloid leukaemia (CML)." Thesis, Glasgow Caledonian University, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.547415.
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Ma, Leyuan. "Targeting Drug Resistance in Chronic Myeloid Leukemia: A Dissertation." eScholarship@UMMS, 2011. http://escholarship.umassmed.edu/gsbs_diss/870.
Full textAbstract:
Inhibiting BCR-ABL kinase activity with tyrosine kinase inhibitors (TKIs) has been the frontline therapy for CML. Resistance to TKIs frequently occurs, but the mechanisms remain elusive.
First, to uncover survival pathways involved in TKI resistance in CML, I conducted a genome-wide RNAi screen in human CML cells to identify genes governing cellular sensitivity to the first generation TKI called IM (Gleevec). I identified genes converging on and activating the MEK/ERK pathway through transcriptional up-regulation of PRKCH. Combining IM with a MEK inhibitor synergistically kills TKI-resistant CML cells and CML stem cells.
Next, I performed single cell RNA-seq to compare expression profiles of CML stem cells and hematopoietic stem cells isolated from the same patient. Among the genes that are preferentially expressed in CML stem cells is PIM2, which encodes a pro-survival serine-threonine kinase that phosphorylates and inhibits the pro-apoptotic protein BAD. Inhibiting PIM2 function sensitizes CML stem cells to IM-induced apoptosis and prevents disease relapse in a CML mouse model.
Last, I devised a CRISPR-Cas9 based strategy to perform insertional mutagenesis at a defined genomic location in murine hematopoietic Ba/F3 cells. As proof of principle, we showed its capability to perform unbiased, saturated point mutagenesis in a 9 amino acid region of BCR-ABL encompassing the socalled “gatekeeper” residue, an important determinant of TKI binding. We found that the ranking order of mutations from the screen correlated well with their prevalence in IM-resistant CML patients.
Overall, my findings reveal novel resistance mechanisms in CML and provide alternative therapeutic strategies.
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Rothe, Katharina. "Characterization of novel therapeutic targets in chronic myeloid leukemia." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/56175.
Full textAbstract:
The identification of BCR-ABL1 as the key molecular event in chronic myeloid leukemia (CML) has revolutionized treatment opportunities for early phase patients. Imatinib mesylate (IM) and other ABL1 tyrosine kinase inhibitors (TKIs) have been introduced into the clinic with remarkable effects. However, initial and acquired resistance, relapse and in particular, the persistence of CML stem cells upon TKI therapy represent critical challenges and warrant the identification of predictive biomarkers and novel, distinct targets for improved treatment strategies.
In this work, I investigated how CML stem and progenitor cells survive TKI therapy through intrinsic and bone marrow (BM) niche-associated mechanisms. I revealed that the core autophagy protease ATG4B, and the focal adhesion protein and serine/threonine kinase Integrin-linked kinase (ILK) play crucial roles in CML, and that they can be successfully targeted with small molecule inhibitors.
By comparing the expression of various core autophagy genes and proteins, ATG4B was identified as potential biomarker in CML to predict IM-responders versus IM-nonresponders prior to the initiation of therapy. Furthermore, my studies illustrated that deregulation of ATG4B is critical to autophagy, survival and growth of CML stem and progenitor cells. Inhibition or suppression of ATG4B decreased CML cell viability significantly and sensitized leukemic cells to TKI treatment highlighting ATG4B as a novel target in CML.
ILK was identified as a differentially expressed gene between CD34⁺ CML patient cells and healthy donors by RNA-sequencing (RNA-seq) analysis, and the importance of the ILK protein and its kinase functions in mediating TKI responses and resistance in CML stem and progenitor cells was demonstrated by ILK inhibitor (QLT0267) and ILK suppression studies. Moreover, various in vitro and in vivo assays showed that the simultaneous kinase inhibition of ILK and BCR-ABL1 is effective in targeting both leukemic stem and progenitor cells, including quiescent CML cells, and in the presence of stromal cells of the BM microenvironment that make TKI monotherapies ineffective.
Overall, these studies provide the first evidence of the importance of ATG4B and ILK in CML, and their potential as novel therapeutic targets for improved combination treatments with TKIs to specifically eliminate CML stem and progenitor cells.Medicine, Faculty of
Medical Genetics, Department of
Graduate
20
Ma, Leyuan. "Targeting Drug Resistance in Chronic Myeloid Leukemia: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/870.
Full textAbstract:
Inhibiting BCR-ABL kinase activity with tyrosine kinase inhibitors (TKIs) has been the frontline therapy for CML. Resistance to TKIs frequently occurs, but the mechanisms remain elusive.
First, to uncover survival pathways involved in TKI resistance in CML, I conducted a genome-wide RNAi screen in human CML cells to identify genes governing cellular sensitivity to the first generation TKI called IM (Gleevec). I identified genes converging on and activating the MEK/ERK pathway through transcriptional up-regulation of PRKCH. Combining IM with a MEK inhibitor synergistically kills TKI-resistant CML cells and CML stem cells.
Next, I performed single cell RNA-seq to compare expression profiles of CML stem cells and hematopoietic stem cells isolated from the same patient. Among the genes that are preferentially expressed in CML stem cells is PIM2, which encodes a pro-survival serine-threonine kinase that phosphorylates and inhibits the pro-apoptotic protein BAD. Inhibiting PIM2 function sensitizes CML stem cells to IM-induced apoptosis and prevents disease relapse in a CML mouse model.
Last, I devised a CRISPR-Cas9 based strategy to perform insertional mutagenesis at a defined genomic location in murine hematopoietic Ba/F3 cells. As proof of principle, we showed its capability to perform unbiased, saturated point mutagenesis in a 9 amino acid region of BCR-ABL encompassing the socalled “gatekeeper” residue, an important determinant of TKI binding. We found that the ranking order of mutations from the screen correlated well with their prevalence in IM-resistant CML patients.
Overall, my findings reveal novel resistance mechanisms in CML and provide alternative therapeutic strategies.
21
Alenzi, Faris Qaliyel Bady. "The role of apoptosis in normal haemopoiesis and in chronic myeloid leukaemia (CML)." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401213.
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關子祺 and Tsz-ki Kwan. "The detection of BCR-ABL kinase domain mutation in the management of chronic myeloid leukemia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B40738358.
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Kwan, Tsz-ki. "The detection of BCR-ABL kinase domain mutation in the management of chronic myeloid leukemia." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B40738358.
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Kiaii, Shahryar. "T cells in patients with B-cell chronic lymphocytic leukemia (B-CLL) and multiple myeloma (MM) : an immunological study /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-050-3/.
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Casetti, Luana. "New roles of STAT5 factors in chronic myeloid leukemia cell maintenance." Phd thesis, Université René Descartes - Paris V, 2013. http://tel.archives-ouvertes.fr/tel-00924475.
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The Chronic Myeloid Leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by the t(9:22) genetic translocation and expression of the oncogenic tyrosine kinase BCR-ABL . A first BCR-ABL Tyrosine Kinase Inhibitor (TKI), Imatinib (IM), was identified that inhibits proliferation of BCR-ABL expressing hematopoietic cells and leads to disease remission. However, BCR-ABL mRNA remains detectable in the most immature HSCs and discontinuation of IM results in clinical relapse. STAT5 factors play a crucial role in the CML pathogenesis of human primary CML cells. However, the contribution of the two related STAT5 genes, STAT5A and STAT5B, was unknown. We used an RNAinterference based strategy to analyze STAT5A or STAT5B roles in normal and CML cells. We showed that STAT5A/5B double knock-down (KD) triggers normal and CML cell apoptosis and suppressed long-term clonogenic potential of immature hematopoietic stem and progenitor cells known to be resistant to TKI treatment and responsible for residual disease. STAT5A loss alone was ineffective at impairing growth of both normal and CML cells under standard conditions. In contrast, STAT5A loss was sufficient to enhance Reactive Oxygen Species (ROS) which correlated with enhanced DNA damages in both normal and leukemic cells. We reported that STAT5A regulates oxidative stress through unconventional mechanisms, in a non-transcriptional-dependent manner. We further showed that, in contrast to primary cells at diagnosis, IM-resistant cells exhibited enhanced STAT5A dependence, by being sensitive to STAT5A single KD. To investigate the molecular basis of STAT5A activity in TKI-resistance and oxidative stress, we performed a transcriptomic analysis of STAT5 regulated genes. We identified Axl, which encodes a receptor tyrosine kinase, recently shown to be crucial in TKI-resistant CML cells. Specifically, Axl expression is enhanced by STAT5A. We investigated the role of Axl and we found that Axl KD did not affect survival of IM-sensitive CML cells. However, Axl KD decreased survival of IM-resistant cells, miming the activity of STAT5A. Moreover, Axl loss increased ROS levels in CML cells, promoting STAT5A anti-oxidant activity. We further sought to determine the expression of the Axl ligand, Gas6. Gas6 expression is dramatically reduced in CML primary cells at diagnosis compared to healthy cells. The strong and consistent down-regulation of Gas6 in CML cells suggested a possible role in the pathophysiology. Collectively, our findings highlight the pro-survival, stress protection and drug resistance roles of STAT5 factors, providing new understanding for medical treatment of CML patients. We suggest that STAT5A acts in synergy with Axl to face exogenous insults and propose a new mechanism by which CML cells increase their proliferation and reduce their motility by down-regulating Gas6 expression.
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Merchand, Reyes Giovanna. "Targeting myeloid cells as a potential Chronic Lymphocytic Leukemia therapeutic strategy." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1595259890785332.
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Lewis, Ian D. "Characterisation of normal and leukaemic stem cells in chronic myeloid leukaemia /." Title page, contents and abstract only, 1998. http://web4.library.adelaide.edu.au/theses/09PH/09phl6745.pdf.
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Willander, Kerstin. "Molecular genetic studies on Chronic Lymphocytic Leukemia and Acute Myeloid Leukemia - with focus on prognostic markers." Doctoral thesis, Linköpings universitet, Avdelningen för cellbiologi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-104951.
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The present thesis is focused on the prognostic value of genetic variations and alterations in the initiation and development of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) patients. Several prognostic markers based on genetic or chromosomal aberrations are today used in clinic in these heterogeneous diseases. Novel biomarkers have been identified through next generation sequencing techniques and some of them may be useful as prognostic markers in clinical diagnostic. In papers I-IV we have investigated some of this markers in CLL and AML tumor cells. In papers I and III we investigated the prognostic value of the MDM2 SNP309 in relation to the presence of TP53 mutations in tumor cells from CLL and AML patients. The SNP309 G-allele was associated with a shorter overall survival in TP53 wildtype CLL and non-normal karyotype AML patients. Mutations in the TP53 gene were found in 6.2% in CLL and 21.7% in AML and were always associated with adverse overall survival. This was most significant observed among the AML patients, where the three year survival was zero. In paper II we investigated mutations in NOTCH1 and NOTCH2 as prognostic biomarkers in CLL. Notch1 and Notch2 play critical roles in lineage differentiation of white blood cells. We found mutation only in NOTCH1 in a frequency of 6.7% and our analysis revealed a shorter overall survival for these. NOTCH1 mutations were almost mutually exclusive with TP53 mutations and represented together 12.9% in CLL patients, and they may both be strong prognostic biomarkers in CLL. In paper IV we studied mutations in the tricarboxylic acid cycle. Metabolic disturbances in cancer cells have been known for many years, but recently mechanistic explanations have been identified. Hot spot mutations in IDH1/2 genes, result in neomorphic enzyme activities that results in global hypermethylation of the cancer cell genome. We found mutations in 21% of the AML patients. Among the CN-AML patients there is a lack of prognostic markers and in this subgroup we found patients with IDH2 mutations to have a shorter overall survival (3 vs. 21 months (p=0.009) for mutated and wild-type patients, respectively). Additionally, we also studied a SNP in the IDH1 gene, and both the IDH2 mutations and the SNP showed to have a potential as a new prognostic markers in CN-AML. In summary, the results in papers I-IV have a potential to function as novel prognostic biomarkers in the clinic for therapeutic considerations and may also be targets for novel drugs for CLL and AML patients.
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Christiansson, Lisa. "Myeloid-Derived Suppressor Cells and Other Immune Escape Mechanisms in Chronic Leukemia." Doctoral thesis, Uppsala universitet, Klinisk immunologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-197604.
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Chronic myeloid leukemia (CML) is characterized by the Philadelphia chromosome, a minute chromosome that leads to the creation of the fusion gene BCR/ABL and the transcription of the fusion protein BCR/ABL in transformed cells. The constitutively active tyrosine kinase BCR/ABL confers enhanced proliferation and survival on leukemic cells. CML has in only a few decades gone from being a disease with very bad prognosis to being a disease that can be effectively treated with oral tyrosine kinase inhibitors (TKIs). TKIs are drugs inhibiting BCR/ABL as well as other tyrosine kinases. In this thesis, the focus has been on the immune system of CML patients, on immune escape mechanisms present in untreated patients and on how these are affected by TKI therapy. We have found that newly diagnosed, untreated CML patients exert different kinds of immune escape mechanisms. Patients belonging to the Sokal high-risk group had higher levels of myeloid-derived suppressor cells (MDSCs) as well as high levels of the programmed death receptor 1 (PD-1)-expressing cytotoxic T cells compared to control subjects. Moreover, CML patients had higher levels of myeloid cells expressing the ligand for PD-1, PD-L1. CML patients as well as patients with B cell malignacies had high levels of soluble CD25 in blood plasma. In B cell malignacies, sCD25 was found to be released from T regulatory cells (Tregs). Treatment with the TKIs imatinib or dasatinib decreased the levels of MDSCs in peripheral blood. Tregs on the other hand increased during TKI therapy. The immunostimulatory molecule CD40 as well as NK cells increased during therapy, indicating an immunostimulatory effect of TKIs. When evaluating immune responses, multiplex techniques for quantification of proteins such as cytokines and chemokines are becoming increasingly popular. With these techniques a lot of information can be gained from a small sample volume and complex networks can be more easily studied than when using for example the singleplex ELISA. When comparing different multiplex platforms we found that the absolute protein concentration measured by one platform rarely correlated with the absolute concentration measured by another platform. However, relative quantification was better correlated.
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Beaver, Melissa A. "A Secondary Analysis of Imatinib Adherence Among Patients with Chronic Myeloid Leukemia." Thesis, The University of Arizona, 2010. http://hdl.handle.net/10150/156890.
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Background: Two recent studies have identified a strong association between treatment adherence and treatment response in patients with chronic myeloid leukemia (CML) treated with imatinib; and suggested a possible 7-10% tolerance margin for nonadherence before impaired treatment response is likely to occur. Objective: To determine at what percentage of dosing adherence of imatinib impaired treatment response (suboptimal response of incomplete cytogenetic response is likely to occur; and, conversely, at what percent of dosing adherence positive treatment response is likely to ensue CML patients.
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Xu, Yan. "Sipa1 deficiency unleashes a host-immune mechanism eradicating chronic myelogenous leukemia-initiating cells." Kyoto University, 2018. http://hdl.handle.net/2433/232472.
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Chen, Yaoyu. "Critical Molecular Pathways in Cancer Stem Cells of Chronic Myeloid Leukemia: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/536.
Full textAbstract:
Chronic myeloid leukemia (CML) is a disease characterized by the expansion of granulocytic cells. The BCR-ABL tyrosine kinase inhibitor imatinib, the frontline treatment for Ph+ leukemias, can induce complete hematologic and cytogenetic response in most chronic phase CML patients. Despite the remarkable initial clinic effects, it is now recognized that imatinib will unlikely cure patients because a small cell population containing leukemic stem cells (LSCs) with self-renewal capacity is insensitive to tyrosine kinase inhibitors.
In Chapter I, I briefly review the BCR-ABL kinase and its related signaling pathways. BCR-ABL kinase activates several signaling pathways including MAPK, STAT, and JNK/SAPK. BCR-ABL also mediates kinase-independent pathways through SRC family kinases. I will also discuss pathways involving β-catenin, hedgehog, FoxO and Alox5 are critical to the regulation of self-renewal and differentiation in LSC of CML.
As detailed in Chapter II, I describe our work evaluating the effects of omacetaxine, a novel CML drug inducing cell apoptosis by inhibition of protein synthesis, on self-renewal and differentiation of LSCs and BCR-ABL-induced CML and acute lymphoblastic leukemia (B-ALL) in mice. We found that treatment with omacetaxine decreased the number of LSCs and prolonged the survival of mice with CML or B-ALL.
In chapter III, I describe that Alox5 is an essential gene in the function of LSCs and CML development. We show evidence that Alox5 affects differentiation, cell division, and survival of long-term LSCs. Treatment of CML mice with a 5-LO inhibitor also impaired the function of LSCs similarly and prolonged survival.
In chapter IV, I present evidence of our work showing a further dissection the Alox5 pathway by comparing the gene expression profiles of wild type and Alox5-/- LSCs. We show that Msr1 deletion causes acceleration of CML development. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and β-catenin.
Taken together, these results demonstrate that some pathways including Alox5 and Msr1 play an important role in regulating the self-renewal and differentiation of LSC. More efforts should be put into developing the novel strategies that may effectively target LSCs and thus cure CML.
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Lin, Hanyang. "Identification and characterization of novel therapeutic targets and biomarkers in chronic myeloid leukemia." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/58470.
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Chronic myeloid leukemia (CML) has long served as a paradigm for new insights into the cellular origin, pathogenesis and treatment of human cancers. ABL tyrosine kinase inhibitor (TKI) therapies have had remarkable effects on treatment of early phase CML. However, TKI monotherapies are not curative, and initial and acquired TKI resistance remain clinically challenging. Particularly, CML stem/progenitor cells are insensitive to TKIs. Therefore, novel treatments and predictive biomarkers are clearly needed. In this work, I studied the biological effects of dual BCR-ABL and JAK2 suppressions on TKI-nonresponder stem/progenitor cells, and identified and characterized novel microRNA (miRNA) biomarkers in these cells.
I examined the biological effects of a new JAK2 inhibitor, BMS-911543, in combination with TKIs on CD34⁺ CML cells from IM-nonresponders. I demonstrated that combination therapy significantly reduces JAK2/STAT5 and CRKL activities, induces apoptosis, inhibits colony growth, and eliminates leukemic stem cells in vitro, while sparing healthy counterparts. I further showed that oral BMS-911543 combined with dasatinib is more effective in eliminating leukemic cells in an aggressive mouse model of BCR-ABL⁺ human leukemia.
Next, I identified differentially expressed miRNAs in CD34⁺ CML cells using RNA-seq analysis, and validated the results in additional samples using high-throughput qPCR. Potential miRNA target genes were also identified by integrating miRNA expression profiles with gene expression profiles using strand-specific RNA-seq. These studies revealed that expression of miR-185 is significantly reduced in CD34⁺ CML cells from TKI-nonresponders compared to TKI-responders. Restoration of miR-185 expression by lentiviral transduction in CD34⁺ TKI-nonresponder cells significantly impairs survival of these cells and sensitizes them to TKI treatment in vitro and in vivo. Additionally, I validated the target genes of miR-185 to rationalize its roles in CML. Lastly, I demonstrated that the expression levels of several miRNAs, including miR185, were restored in patients treated with nilotinib, suggesting their potential as biomarkers to predict clinical response to TKI therapies.
These studies have uncovered the biological significance of JAK2 and miR-185 in regulation of the properties of drug-insensitive CML stem/progenitor cells, and their potential as therapeutic targets for improved treatments with TKIs especially in patients at risk of developing TKI resistance.Medicine, Faculty of
Experimental Medicine, Division of
Medicine, Department of
Graduate
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Verter, Erol. "TEL/ABL pathogenesis chronic myelogenous leukemia and small bowel syndrome /." Waltham, Mass. : Brandeis University, 2009. http://dcoll.brandeis.edu/handle/10192/23230.
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Marsico, Paolo. "The effects of targeted therapy on cell viability and apoptosis on CML and AML cell lines." Thesis, University of Chester, 2019. http://hdl.handle.net/10034/621798.
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Tyrosine kinase inhibitors (TKIs) are currently the first therapy option for chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) patients. However, many patients affected by CML and AML may develop resistance to TKIs or may not recover under this treatment regime. New potential and more effective treatments are recently emerging. Heat shock protein inhibitors (HSPIs) and the proteasome inhibitor Bortezomib are drugs which have been yet to be successfully tested on leukemic patients, despite being successful on other malignancies such as multiple myeloma (MM). The combination between HSPIs and Bortezomib could potentially be successful in killing leukemic cells, by enhancing their respective molecular mechanisms. Indeed, HSPIs would bind to HSP72 avoiding the protein to exert its ligase function to the proteasome, whilst Bortezomib could stop the ubiquitinated proteins to enter the proteasome and ultimately inducing apoptosis. To test the effects of such combination, cell viability was measured via MTS assay, apoptosis levels were tested through Annexin V\PI assays. Involvement of HSP72 and pro-survival protein Bcl-2 were measured via flow-cytometry. The cells were administered with HSPIs and Bortezomib first as single agents for 24 hours, to establish working minimal concentration. Also, the drugs were tested for a shorter time, to understand when the drugs start to be effective. It emerged that one hour is sufficient for the drugs to give an initial effect in terms of cell viability and apoptosis. Following, combination experiments of HSPIs and Bortezomib were performed; the first drug was administered for one hour, the second following one hour and the cells were incubated for 24 hours. This was repeated alternatively for both type of drugs on the different cell lines. MTS and Annexin V\PI showed that there is not a synergistic effect between drugs, but instead there is antagonism. No necrosis was found at any level of the study. The cells were then probed for HSP72 and Bcl-2, to investigate their involvement in apoptosis mechanisms. Following 6 hours of combined and single agent treatment, both type of drugs inhibit HSP72 but failed to reduce the expression of Bcl-2, particularly on AML cells. It is thus proposed that CML and AML cells may die by apoptosis following a short time of treatment with HSPIs and Bortezomib by an extrinsic pathway of apoptosis, independent from Bcl-2 involvement and from mitochondrial pathway of apoptosis. This study may be the first to indicate a potential use of HSPIs and Bortezomib on CML and AML patients for a short time of treatment, although not in combination. Future studies are needed to further investigate the mechanisms of action of these drugs, aiming to potentially give CML and AML patients another successful therapy option to overcome resistance to canonic chemotherapy.
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Kauffman, Melissa R. "Effect of GSK-3β Knock Down on Chronic Myelogenous Leukemia Cell Response toIFN-γ Stimulation." Ohio University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1586885920548761.
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Korfi, Koorosh. "Epigenetic programming defines stem cell identity and entry into the proliferative compartment in chronic myeloid leukaemia (CML)." Thesis, University of Glasgow, 2012. http://theses.gla.ac.uk/3929/.
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Chronic myeloid leukaemia (CML) is a haematological malignancy that is identified by the presence of a fusion oncogene, BCR-ABL1, which is a constitutive tyrosine kinase. The discovery of tyrosine kinase inhibitors (TKIs) over that past decade has resulted in significantly improved survival rates and disease management in CML patients. However, a subpopulation of BCR-ABL1+ cells in the niche are found which exhibit stem cell-like features, such as self-renewal and quiescence. These CML stem cells (LSCs) are shown to be insensitive to TKI treatment and are capable of deriving the disease during the relapse. Consequently, the elimination of LSCs is a primary goal of current research. Therefore, the aim of this thesis was to obtain a global view of the cellular processes that maintain stem cell identity in CD34+ CD38- LSCs as well as identify those processes which initiate the transition to proliferative CD34+ CD38+ CML progenitor cells (LPCs). A combined approach was exploited to investigate genome-wide gene expression profiles and histone modification signatures of normal HSCs and committed progenitors (HPCs), and their LSC and LPC counterparts. Despite having increased activity in pathways involved in cell division and proliferation, expression levels of the pathways involved in stem cell identity were not significantly different in LSCs to those found in HSCs. These pathways included Wnt, TGF-β signalling, and several novel neurotransmitter signalling pathways. By examining genome-wide histone modification patterns using ChIP-sequencing it was shown that the stem cell identities of HSCs and LSCs are programmed at the epigenetic level. All of the pathways which confer stem cell identity to both HSCs and LSCs are significantly enriched for bivalent gene promoters having both the H3K4me3 and H3K27me3 marks. These similarities were most evident in neurotransmitter signalling and it was demonstrated that these pathways are capable of promoting LSC maintenance in vitro. Intriguingly, although the stem cell entry into the proliferative state occurs through the repression of many of the same stem cell identity pathways in both HSCs and LSCs, it was shown that epigenetic reprogramming in CML mediates this repression via a different mechanism than in normal HSCs. Furthermore, abnormalities in levels of several chromatin enzymes were identified that are likely to be responsible for the epigenetic reprogramming of CML cells. The work presented in this thesis defines the chromatin landscape of a cancer stem cell for the first time and provides new therapeutic targets for the eradication of TKI resistant CML stem cells.
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Yazdanparast, Haniyeh [Verfasser], and Viktor [Akademischer Betreuer] Umansky. "Myeloid cells and therapy resistance in Chronic Lymphocytic Leukemia / Haniyeh Yazdanparast ; Betreuer: Viktor Umansky." Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177385988/34.
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Filho, Pedro Aurio Maia. "Genotoxicity and mutagenicity in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors." Universidade Federal do CearÃ, 2017. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=19044.
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Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgicoChronic myelogenous leukemia (CML) is a myeloproliferative disease of hematopoietic stem cells, characterized by the presence of the Philadelphia (Ph) chromosome, originating from a reciprocal translocation between the long arms of chromosomes 9 and 22, forming the gene BCR-ABL, which encodes a BCR-ABL oncoprotein with constitutive tyrosine kinase activity. The clinical course of CML is often divided into three phases: chronic, accelerated, and blast. The treatment of choice for the chronic phase is the first-generation tyrosine kinase inhibitor (TKI), imatinib mesylate, and for refractory patients, second-generation TKIs (dasatinib or nilotinib) are used. Studies have shown that residual leukemia may persist even in the best responders to TKI, since therapy is not curative. In this context, the present study aimed to evaluate the genotoxicity and mutagenicity of TKI in patients with CML followed at the hematology clinic of the Walter CantÃdio University Hospital (HUWC). It is a cross-sectional study with 44 patients with clinical and molecular diagnosis of CML. Patients were stratified into three groups: diagnosis (CML D) (n = 5), use of first generation TKI (CML) (n = 31) and use of second generation TKI (CML) (n = 8). The control group (CG) consisted of apparently healthy individuals. Genotoxicity and mutagenicity were analyzed by the comet assay and micronucleus test. Statistical analysis of the data was performed using the GraphPad Prism 6.0 program using the Kruskal-Wallis or ANOVA, Mann Whitney or T-student tests, depending on the normality of the data and the level of significance was 5% (p < 0.05). Patients with CML had a statistically higher ADN damage index (DI) compared to CG (p < 0.0001). When the patients were stratified, a progressive increase of the DNA ID was verified in the groups: CML D, CML G1 and CML G2, respectively, relative to GC (p < 0.05). Patients with CML had a statistically higher micronucleus index (NMI), nucleoplasmic bridge index (NPI) and nuclear bud index (NBI) compared to the CG (p < 0.05). By stratifying patients with CML, it was found that patients in the G1 and G2 CML groups had statistically higher NMI and NPI compared to CG (p <0.001). NMI was also elevated in the CML G2 group in relation to the patients in the CML D group (p <0.01). The nuclear bud index (NBI) did not present statistical difference in the analyzes performed after the stratification of the groups. The TKI revolutionized CML therapy, improving patient survival. However, these results point to the relevance of studies that evaluate the possible genotoxic and mutagenic effects of this therapy in the long term. The mechanisms involved should be elucidated for the purpose of improving treatment as well as assessing the clinical impact this harm may cause.
A leucemia mielÃide crÃnica (LMC) à uma doenÃa mieloproliferativa das cÃlulas-tronco hematopoÃticas, caracterizada pela presenÃa do cromossomo Philadelphia (Ph), originado a partir de uma translocaÃÃo recÃproca entre os braÃos longos dos cromossomos 9 e 22, formando o gene BCR-ABL, que codifica uma oncoproteÃna BCR-ABL com atividade tirosino-quinase constitutiva. O curso clÃnico da LMC à frequentemente dividido em trÃs fases: crÃnica, acelerada e blÃstica. O tratamento de escolha para a fase crÃnica à o inibidor de tirosino-quinase (ITK) de primeira geraÃÃo, mesilato de imatinibe, e para os pacientes refratÃrios, utiliza-se os ITK de segunda geraÃÃo (dasatinibe ou nilotinibe). Estudos tÃm demonstrado que a leucemia residual pode persistir mesmo nos melhores respondedores aos ITK, uma vez que a terapia nÃo à curativa. Nesse contexto, o presente estudo objetivou avaliar a genotoxicidade e mutagenicidade dos ITK em pacientes com LMC acompanhados no ambulatÃrio de hematologia do Hospital UniversitÃrio Walter CantÃdio (HUWC). Trata-se de um estudo transversal com 44 pacientes com diagnÃstico clÃnico e molecular de LMC. Os pacientes foram estratificados em trÃs grupos: ao diagnÃstico (LMC D) (n=5), em uso de ITK de primeira geraÃÃo (LMC G1) (n=31) e em uso de ITK de segunda geraÃÃo (LMC G2) (n=8). O grupo controle (GC) foi composto por indivÃduos aparentemente saudÃveis. A genotoxicidade e mutagenicidade foram analisadas atravÃs do ensaio cometa e teste de micronÃcleos. A anÃlise estatÃstica dos dados foi realizada atravÃs do programa GraphPad Prism 6.0 utilizando-se os testes de KruskalâWallis ou ANOVA, Mann Whitney ou T-student, dependendo da normalidade dos dados e o nÃvel de significÃncia foi de 5% (p < 0,05). Pacientes com LMC apresentaram Ãndice de dano (ID) no DNA estatisticamente mais elevado em comparaÃÃo ao GC (p < 0,0001). Quando os pacientes foram estratificados, foi verificado um aumento progressivo do ID no DNA nos grupos: LMC D, LMC G1 e LMC G2, respectivamente, em relaÃÃo ao GC (p < 0,05). Pacientes com LMC apresentaram Ãndice de micronÃcleos (IMN), Ãndice de pontes nucleoplasmÃticas (IPN) e Ãndice de buds nucleares (IBN) estatisticamente mais elevados em comparaÃÃo com o GC (p < 0,05). Ao se estratificar os pacientes com LMC, foi verificado que pacientes dos grupos LMC G1 e G2 apresentaram IMN e IPN estatisticamente mais elevados em comparaÃÃo ao GC (p < 0,001). O IMN tambÃm foi elevado no grupo LMC G2 em relaÃÃo aos pacientes do grupo LMC D (p < 0,01). O Ãndice de bud nuclear (IBN) nÃo apresentou diferenÃa estatÃstica nas anÃlises realizadas apÃs a estratificaÃÃo dos grupos. Os ITK revolucionaram a terapia da LMC, melhorando a sobrevida dos pacientes. No entanto esses resultados alertam para a relevÃncia de estudos que avaliem os possÃveis efeitos genotÃxicos e mutagÃnicos dessa terapia a longo prazo. Os mecanismos envolvidos devem ser elucidados com a finalidade de aprimorar o tratamento, bem como avaliar o impacto clÃnico que esse dano pode causar.
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Bolton, Elisabeth Spring. "Genomic Instability Originates From Leukemia Stem Cells In a Mouse Model of CML-CP." Diss., Temple University Libraries, 2013. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/234916.
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Microbiology and ImmunologyPh.D.
In chronic myelogenous leukemia (CML), activation of BCR-ABL, the product of the bcr-abl chimeric gene, leads to constitutive activation of pathways that increase genomic instability through endogenous production of reactive oxygen species (ROS) that cause oxidative DNA damage and inactivate the function of repair proteins leading to unfaithful DNA repair. If misrepaired, oxidative DNA damage, such as 8-oxoguanine (8-oxoG), may result in point mutations and/or DNA double-strand breaks (DSBs) leading to drug resistance to the BCR-ABL kinase inhibitor imatinib mesylate (IM) and accumulation of chromosomal aberrations associated with malignant CML progression from a benign chronic phase (CP) to a fatal blast phase (BP). To determine which population of CML-CP cells, leukemia stem cells (LSCs) and/or leukemia progenitor cells (LPCs), displays elevated levels of ROS and oxidative DNA damage, and whether these elevated levels of ROS and oxidative DNA damage in CML-CP subpopulations result in the accumulation of genomic instability, we employed the tetracycline-inducible SCLtTA/BCR-ABL transgenic mouse model. We showed that LSCs, including the quiescent subpopulation, but not LPCs, displayed elevated levels of ROS and oxidative DNA damage, perhaps due to deregulated expression of genes involved in ROS metabolism, resulting in genomic instability manifested by both point mutations and genetic alterations. We also examined the effect of IM on ROS, oxidative DNA damage and genomic instability displayed by CML-CP subpopulations, and determined that elevated ROS and oxidative DNA damage were not inhibited by IM in quiescent LSCs, nor was genomic instability and deregulated gene expression prevented. To explore underlying mechanisms, i.e. BCR-ABL expression levels, by which CML-CP cells accumulate genomic instability, we examined the effect of low and high BCR-ABL expression on ROS and oxidative DNA damage in BCR-ABL-transduced human CD34+ cells. We detected elevated ROS and oxidative DNA damage in high BCR-ABL-expressing CD34+ cells compared to low BCR-ABL-expressing cells. Furthermore, BCR-ABL exerted a kinase-dependent effect on ROS-dependent DNA damage. These data support the hypothesis that genomic instability may originate from LSCs, but do not exclude the potential role of LPCs, and may have important clinical implications for CML treatment since additional genetic aberrations that encode primary resistance may protect LSCs, including the quiescent subpopulation, from eradication by tyrosine kinase inhibitors (TKIs), and the continuous accumulation of genetic errors may trigger disease relapse and progression.
Temple University--Theses
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Gugliotta, Gabriele <1981>. "Clinical outcome and biological characteristics of Chronic Myeloid Leukemia patients treated with nilotinib front-line." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amsdottorato.unibo.it/6760/.
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The present work reports the outcome of the GIMEMA CML WP study CML0811, an independent trial investigating nilotinib as front-line treatment in chronic phase chronic myeloid leukemia (CML). Moreover, the results of the proteomic analysis of the CD34+ cells collected at CML diagnosis, compared to the counterpart from healthy donors, are reported.
Our study confirmed that nilotinib is highly effective in the prevention of the progression to accelerated/blast phase, a condition that today is still associated with high mortality rates. Despite the relatively short follow-up, cardiovascular issues, particularly atherosclerotic adverse events (AE), have emerged, and the frequency of these AEs may counterbalance the anti-leukemic efficacy. The deep molecular response rates in our study compare favorably to those obtained with imatinib, in historic cohorts, and confirm the findings of the Company-sponsored ENESTnd study. Considering the increasing rates of deep MR over time we observed, a significant proportion of patients will be candidate to treatment discontinuation in the next years, with higher probability of remaining disease-free in the long term. The presence of the additional and complex changes we found at the proteomic level in CML CD34+ cells should be taken into account for the investigation on novel targeted therapies, aimed at the eradication of
the disease.
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Crockett, Harriet. "American ginseng and its interactions with Imatinib mesylate (Gleevec) on K562 chronic myeloid leukemia cells /." Available to subscribers only, 2007. http://proquest.umi.com/pqdweb?did=1453231751&sid=4&Fmt=2&clientId=1509&RQT=309&VName=PQD.
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Zhang, Haojian. "The Molecular Mechanisms for Maintenance of Cancer Stem Cells in Chronic Myeloid Leukemia: A Dissertation." eScholarship@UMMS, 2012. https://escholarship.umassmed.edu/gsbs_diss/614.
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Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder associated with the Philadelphia chromosome (Ph) that arises from a reciprocal translocation between chromosomes 9 and 22, thereby resulting in the formation of the chimeric BCR-ABL oncogene encoding a constitutively activated tyrosine kinase. BCR-ABL tyrosine kinase inhibitors (TKIs) induce a complete hematologic and cytogenetic response in the majority of chronic phrase CML patients. However, TKIs cannot efficiently eradicate leukemia stem cells (LSCs) because of the insensitivity of LSCs to TKIs. Therefore, developing new strategies to target LSCs is necessary and critical for curing CML, and success of this approach depends on further understanding the molecular mechanisms by which LSCs survive and are maintained.
In Chapter I, I briefly introduce CML disease, BCR-ABL oncoprotein, and TKIs. I also describe the identification and features of LSCs. Several key pathways in LSCs including Wnt/ß-catenin, hedgehog, FoxO, Bcl6 and HIF1, are discussed. I also propose our strategy to identify unique molecular pathways that are important for LSCs but not their normal stem cell counterparts.
In Chapter II, I describe our finding about the function of the positive regulator, HIF1α, in CML development and LSC survival. I show that loss of HIF1α impairs the maintenance of CML through impairing cell cycle progression and inducing apoptosis of LSCs, and I also report that p16Ink4a and p19Arf mediate the effect of HIF1α on LSCs, as knockdown of p16Ink4a and p19Arf rescues the defective colony-forming ability of HIF1α-/- LSCs.
As detailed in Chapter III and IV, through comparing the global gene expression profiles of LSCs and HSCs, I find two novel regulators, Blk and Scd1, which act as tumor suppressors in CML development. In Chapter III, I show that Blk is markedly down-regulated by BCR-ABL in LSCs, and that c-Myc and Pax5 mediate this down-regulation. Deletion of Blk accelerates CML development; conversely, Blk overexpression significantly delays the development of CML and impairs the function of LSCs. I also demonstrate that p27, as a downstream effector, is involved in the function of Blk in LSCs. Blk also functions as a tumor suppressor in human CML stem cells, and inhibits the colony-forming ability of human CML cells. In Chapter IV, I investigate the function of another negative regulator, Scd1, in CML LSCs, and find that expression of Scd1 is down-regulated in mouse LSCs and human CML cells. We report that Scd1 acts as a tumor suppressor in CML, as loss of Scd1 causes acceleration of CML development and overexpression of Scd1 delays CML development. Using a colony-forming assay, I demonstrate that Scd1 impairs the maintenance of LSCs due to the change of expression of Pten, p53 and Bcl2. Importantly, I find that both Blk and Scd1 do not affect normal hematopoietic stem cells (HSCs) or hematopoiesis.
Taken together, our findings demonstrate that HIF1α is required for the maintenance of CML LSCs, and conversely that Blk and Scd1 suppress the function of LSCs, suggesting that combining TKI treatment with specific targeting of LSCs will be necessary for curing CML.
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Warnqvist, Anna. "Feeling the zeros : Modeling individual responses, measured against time, to treatment of chronic myeloid leukemia." Thesis, Uppsala universitet, Statistiska institutionen, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-323855.
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In this paper response curves of patients with chronic myeloid leukemia are modeled using one and two-level censored models. Two-level models (also called mixed models) allow random effects and censored models are used to account for the large amount of values too small to be detected. The curves are observed from start of medication to a maximum of 36 months (9 measurement points). The data set is divided into two: "excellent responders" and "other". The "excellent responders" are modeled with a simple cubic censored model, and only one of the background variables measured at time zero ("blasts"), is found to be significant in explaining variation in the change curves, and even this with certain reservations. "Other" are modeled with a cubic two-level censored model and hemoglobin and eosinophile levels, as well as amount of blasts, are significant in explaining variation in this group.
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Roos, Cecilia. "Studies of leukotriene C4 synthase expression and regulation in chronic myeloid leukaemia /." Karlstad : Faculty of Technology and Science, Biomedical Science, Karlstads universitet, 2008. http://www.diva-portal.org/kau/abstract.xsql?dbid=1598.
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Grockowiak, Élodie. "Role of the Bone Morphogenetic Proteins pathway in tyrosine kinase inhibitors resistance in Chronic Myeloid Leukemia." Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1253.
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La leucémie Myéloïde Chronique est un néoplasme myéloprolifératif causé par l'expression de la kinase oncogène BCR-ABL. Les Inhibiteurs de Tyrosine Kinase (ITK) spécifiques de BCR-ABL ont révolutionné la prise en charge de la maladie. Les ITK ne sont cependant pas curatifs ; en effet, certaines cellules souches leucémiques (CSL) sont résistantes aux ITK, et persistent dans la moelle osseuse des patients même en rémission prolongée. Ces CSL sont probablement responsables de la rechute chez 60% de ces patients après arrêt des ITK. 30% des patients développent une résistance aux ITK via des mécanismes inconnus. Dans un contexte sain, les Bone Morphogenetic Proteins (BMP) régulent différentes propriétés des cellules souches hématopoïétiques. Nous avons mis en évidence que les patients atteints de LMC présentent une altération de la voie BMP avant leurs mises sous traitement, avec une hausse de l'expression du récepteur dans les cellules leucémiques immatures, amplifiée par de forts taux de BMP2/4 produits par le microenvironnement des CSL, la niche. Ici, nous démontrons que ces altérations sont maintenues chez les patients sous traitement, et sont activement impliquées dans la résistance aux ITK. Les patients résistants présentent une surexpression de BMPR1b dans les CSL et un maintien de forts taux de BMP produits à la fois par les cellules leucémiques mais aussi par les cellules stromales. Les BMP permettent la survie des CSL via l'expression du récepteur BMPR1b et induisent l'expression de TWIST-1, un facteur de transcription précédemment identifié par l'équipe comme induisant la résistanceChronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm caused by the expression of the oncogenic protein kinase, BCR-ABL. The Tyrosine Kinase Inhibitors (TKI) specifics of BCR-ABL kinase dramatically changed the outcome of CML, turning a life-threatening disease into a chronic illness. However, TKI are not yet curative since most CML patients still retain progenitors and leukemic stem cells (LSC) in bone marrow permanently. Thus, approximately 60% of patients that achieve Complete Molecular Remission =2 years relapse following TKI withdraw. Moreover, some patients develop true resistance to TKI, with ~30% due to unknown mechanisms. In chronic phase CML (CP-CML), LSC survive, sustain interactions with their niche where resistance mechanisms can occur, responsible for disease persistence and relapse following treatment cessation. In normal bone marrow, Bone Morphogenetic Proteins (BMP) pathway regulate the fate and proliferation of normal hematopoietic stem cells, as well as interactions with their niche. The deregulations of this pathway drive early steps of CML development. In newly diagnosed CP-CML patients, high concentration of BMP2/4 in the leukemic niche allows LSC maintenance and sustains a permanent pool of leukemic progenitors expressing elevated levels of BMPR1b receptor. Here, we report that alterations of the BMP pathway persist in TKI-CML resistant patients. As compared to patients in Complete Cytogenetic Remission (CCyR), cells isolated from TKI-resistant patients display a high level of BMPR1b expression in immature cells and high levels of BMP2/4 in bone marrow, provided by the niche and by the leukemic immature cells themselves. BMP allow leukemic stem cells resistance to treatments through binding to BMPR1b. Interestingly, BMP2/4-treated cells overexpressed TWIST-1, a transcription factor that we previously identified as a predictive factor of CML resistance
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Maifrede, Silvia. "EGR-1 TUMOR SUPPRESSOR IN BCR-ABL DRIVEN LEUKEMIA." Diss., Temple University Libraries, 2015. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/321048.
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Molecular Biology and GeneticsPh.D.
Chronic Myelogenous Leukemia (CML) is a hematological disease originated with a chromosomal translocation t(9;22)(q34;q11) in a pluripotent hematopoietic stem cell. CML typically evolves in 3 different clinical phases: chronic and accelerated phases, and blast crisis. Disease progression is associated with the acquisition of secondary mutations that can be of very diverse origins, including inactivation of tumor suppressor genes, as well as inhibition of differentiation, DNA repair and telomere maintenance. While current therapies are very often successful, the remaining issues of resistance and the fact that therapy will not cure CML make it important that new therapy capable of effectively curing it be developed. The early growth response-1 (Egr-1) gene is a zinc-finger transcription factor localized to the human chromosome 5. Egr-1 belongs to a family of early response genes whose expression is rapidly stimulated by growth factors, hormones and neurotransmitters. In addition, Egr-1 is a myeloid differentiation primary response (MYD) gene, and is a positive regulator of terminal myeloid differentiation that potentiates macrophage differentiation. It also has been shown that Egr-1 plays a role in the development, growth control and survival of several cell types, such as T cells, B cells, and neuronal cells in addition to myeloid cells. There is a large amount of evidence consistent with Egr-1 behaving as a tumor suppressor in hematopoietic cells, both in vivo & in vitro, in both humans & mice, making it a prime candidate for a role in CML. In this study we asked if Egr-1 would behave as a tumor suppressor in CML. To answer that we investigated the function of Egr-1 in BCR-ABL driven leukemia using a mouse m bone marrow transplantation (BMT) model. We observe that loss of Egr-1 accelerates the onset of BCR-ABL driven CML. Furthermore, through Facs analysis we showed that most animals developed myeloid leukemia, determined by the observation that the majority of GFP+ cells in the BM were positive for Gr-1 and negative for B220. Interestingly a small cohort of mice developed B-cell acute lymphoid leukemia (B-ALL); this included both WT BCR-ABL and Egr-1 KO BCR-ABL BM-transplanted groups. In addition, we demonstrated that the loss of Egr-1 caused a more aggressive leukemia, which resulted not only in more rapid onset of disease but also greater enlargement of spleen and liver, as well as a tendency to more aggressive lung infiltration of leukemic cells. We also showed that decreased apoptosis, increased proliferation rates and resulting increased viability are consistent with, and probably contribute to, the increased leukemic potential of Egr-1 KO BCR-ABL BM. In addition, we demonstrated that Egr-1 expression was downregulated in BCR-ABL expressing BM cells in vitro, and in spleens of transplanted leukemic mice. Moreover, a very interesting observation, consistent with the rapid onset and aggression of disease, was that the bone marrow of leukemic mice caused by Egr-1 KO BCR-ABL BM transplantation, were enriched with lineage negative BCR-ABL-expressing cells, significantly more so than what was observed in WT BCR-ABL-transplanted mice. That this is also an enrichment of leukemia initiating cells was demonstrated using bone marrow from primary transplantation in a secondary bone marrow transplantation assay. Furthermore, using serial replating assays of colony forming units (CFUs), it was demonstrated that Egr-1 KO BCR-ABL-expressing BM had higher self-renewal ability than WT BCR-ABL-expressing BM, exhibiting an enrichment of primitive stem cells and fewer differentiated cells relative to WT counterparts. Finally, we also analyzed expression of Egr-1 in samples of CML human patients; the results are intriguing but due to small sample size inconclusive. Further inquiry on Egr-1 in CML, including expanding the study of human CML, signaling analysis, interaction of Egr gene family members in leukemia, and gain of function experiments should identify novel players that can impact on the aggressiveness of the disease, predict outcome for currently established therapies, as well identify targets for treatment regimens or adjunct therapy. In addition, these studies can provide a paradigm for understanding how Egr-1 functions as a tumor suppressor for other cancers and types of leukemia, and also delineate pathways that can be activated/inhibited by drugs, including reactivating Egr-1 expression.
Temple University--Theses
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Kumari, Ashu [Verfasser], and Andreas [Akademischer Betreuer] Burchert. "Elucidation of mechanism of disease resistance and persistence in chronic myeloid leukemia / Ashu Kumari. Betreuer: Andreas Burchert." Marburg : Philipps-Universität Marburg, 2011. http://d-nb.info/1014851823/34.
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Mascarenhas, Cintia do Couto 1982. "Avaliação de mutações pontuais no gene ABL por metodo de cromatografia liquida desnaturante de alta performance (D-HPLC) em pacientes com leucemia mieloide cronica tratados com inibidores de tirosina quinase." [s.n.], 2009. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308623.
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Orientadores: Carmino Antonio de Souza, Katia Borgia Barbosa PagnanoDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: O desenvolvimento da Leucemia Mielóide Crônica (LMC) tem como característica a formação do cromossomo Philadelphia que envolve a quebra do gene BCR gerando um rearranjo molecular denominado BCR-ABL, cujo produto final é uma proteína de fusão citoplasmática que determina a patogenia da doença. Esta proteína é uma tirosina quinase (TK) que possui capacidade de auto-ativação e para a inativação desta proteína, foram desenvolvidos os inibidores da tirosina quinase (ITK), que tem a capacidade de se ligar no mesmo sítio de ligação da molécula de ATP. Esta ligação impede a transferência dos grupos fosfatos aos substratos subseqüentes, bloqueando a cascata de transdução de sinais e prevenindo a ativação das vias mitogênica dependente da quinase Bcr-Abl e anti-apoptóticas levando à morte do fenótipo BCR-ABL.Um dos principais mecanismos de resistência ao tratamento com ITK são as mutações pontuais, sendo a T315I foco de estudos mais detalhados por tornar a proteína mutante altamente insensível a todas as drogas inibidoras da proteína TK disponíveis atualmente Foi utilizado neste trabalho a técnica de D-HPLC para fazer screening de mutações nos pacientes com LMC com resposta sub ótima ou falha de tratamento de acordo com os critérios da Leukemia Net. Para o screening do éxon 6 foram selecionados 93 pacientes com LMC: 5 eram intolerantes, 67 resistentes e 21 com resposta subótima. Como controle negativo foi usado o sangue periférico doadores de sangue do Hemocentro da UNICAMP. Para o screening de mutações de todo o gene BCR-ABL foram estudados 37 pacientes com LMC e como controle negativo, usamos a linhagem celular HL60 que não possui a translocação BCR-ABL. No screening do éxon 6, 23 amostras (25%) mostraram um perfil de eluição no D-HPLC anormal em relação ao controle, o que sugeriu a presença de mutação. A sobrevida global (OS) para todo grupo foi de 80% em uma mediana de tempo de observação de 30 meses. OS para pacientes sem mutações foi de 87% e para os pacientes com mutações foi de 56% em uma mediana de tempo de observação 37 e 10 meses, respectivamente (p <0,0001, RR = 68). No screening de todo o gene BCR-ABL 17 (46%) tiveram perfil cromatográfico diferente do controle Como estávamos estabelecendo a padronização do método, procedemos com o seqüenciamento de todas as amostras e os resultados obtidos foram comparados com a seqüência depositada no banco de dados GenBank (U07563). Das 17 amostras com alteração do perfil cromatográfico, observamos a presença de mutação em 13 amostras. Acreditamos que isso se deva a sensibilidade do método de D-HPLC que é capaz de identificar tanto polimorfismos quanto mutações com maior eficiência que o seqüenciamento. Em resumo, o D-HPLC demonstrou ser um método sensível e prático para o acompanhamento do aparecimento de mutações no domínio da quinase na rotina clínica. Mutações nessa região estudada são clinicamente relevantes e podem conferir um pior prognóstico. A detecção precoce pode ser uma ferramenta importante para otimizar a terapêutica na LMC.
Abstract: The development of chronic myeloid leukemia (CML) is the formation of the characteristic Philadelphia chromosome involving breach of the BCR gene generating a molecular rearrangement called BCR-ABL, whose final product is a cytoplasmic fusion protein that determines the pathogenesis of the disease. This is a protein tyrosine kinase (TK) that has self-ativaçãoe to inactivate this protein have developed the inhibitors of tyrosine kinase (ITK), which has ability to connect on the same site of binding of molecule of ATP. This connection prevents the transfer of phosphate groups to substrates subsequent, blocking the cascade of signal transduction and preventing the activation of mitogenic pathways dependent kinase BCR-ABL and anti leading to apoptotic death phenotype of BCR-ABL.One major mechanisms of resistance to treatment with ITK are mutations off, and the T315I focus of more detailed studies by making mutant protein highly insensitive to all drugs Inhibit TK protein currently available was used in this work to D-HPLC technique to screening for mutations in patients with CML with sub-optimal response or failure of treatment according to the criteria Leukemia Net For the screening of exon 6 were selected 93 CML patients: 5 were intolerant, 67 resistant and 21 with answer sub-optimal. The negative control we used the peripheral blood donors Blood from the blood of UNICAMP. For the screening of mutations throughout the BCR-ABL gene were studied 37 patients with CML and control negative, we used the HL60 cell line that does not have the translocation BCR-ABL. In the screening of exon 6, 23 samples (25%) showed a profile of the D-HPLC elution abnormal in the control, which suggested the presence of mutation. The overall survival (OS) for whole group was 80% in a median time of observation of 30 months. OS for patients with mutations was 87% and for patients with mutations was 56% in the median observation time of 37 and 10 months respectively (p <0.0001, RR = 68). In screening the entire gene BCR-ABL 17 (46%) had chromatographic profile different from the control we were setting the standardization of methods, procedures with the sequencing of all samples and the results were compared with the sequence deposited in the GenBank database (U07563). Of the 17 samples with change the chromatographic profile, we observed the presence of mutation in 13 samples. We believe that this is due to sensitivity of the method of D-HPLC is able to identify the mutations both polymorphisms with greater efficiency to the sequencing. In summary, the D-HPLC has proved a sensitive and practical method for monitoring the appearance of mutations in the kinase domain in the clinical routine. Mutations studied in this region are clinically relevant and may confer worse prognosis. Early detection can be a tool important to optimize therapy in CML.
Mestrado
Ciencias Basicas
Mestre em Clinica Medica
50
Toofan, Parto. "Using induced pluripotent stem cells (IPSCS) as a replacement for in vivo models to screen novel therapies in chronic myeloid leukaemia (CML)." Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7729/.
Full textAbstract:
Tyrpsine kinase inhibitors (TKIs) effectively target progenitors and mature leukaemic cells but prove less effective at eliminating leukaemic stem cells (LSCs) in patients with chronic myeloid leukaemia (CML). Several reports indicate that the TGFβ superfamily pathway is important for LSC survival and quiescence. We conducted extensive microarray analyses to compare expression patterns in normal haemopoietic stem cells (HSC) and progenitors with CML LSC and progenitor populations in chronic phase (CP), accelerated phase (AP) and blast crisis (BC) CML. The BMP/SMAD pathway and downstream signalling molecules were identified as significantly deregulated in all three phases of CML. The changes observed could potentiate altered autocrine signalling, as BMP2, BMP4 (p<0.05), and ACTIVIN A (p<0.001) were all down regulated, whereas BMP7, BMP10 and TGFβ (p<0.05) were up regulated in CP. This was accompanied by up regulation of BMPRI (p<0.05) and downstream SMADs (p<0.005). Interestingly, as CML progressed, the profile altered, with BC patients showing significant over-expression of ACTIVIN A and its receptor ACVR1C. To further characterise the BMP pathway and identify potential candidate biomarkers within a larger cohort, expression analysis of 42 genes in 60 newly diagnosed CP CML patient samples, enrolled on a phase III clinical trial (www.spirit-cml.org) with greater than 12 months follow-up data on their response to TKI was performed. Analysis revealed that the pathway was highly deregulated, with no clear distinction when patients were stratified into good, intermediate and poor response to treatment. One of the major issues in developing new treatments to target LSCs is the ability to test small molecule inhibitors effectively as it is difficult to obtain sufficient LSCs from primary patient material. Using reprogramming technologies, we generated induced pluripotent stem cells (iPSCs) from CP CML patients and normal donors. CML- and normal-derived iPSCs were differentiated along the mesodermal axis to generate haemopoietic and endothelial precursors (haemangioblasts). IPSC-derived haemangioblasts exhibited sensitivity to TKI treatment with increased apoptosis and reduction in the phosphorylation of downstream target proteins. 4 Dual inhibition studies were performed using BMP pathway inhibitors in combination with TKI on CML cell lines, primary cells and patient derived iPSCs. Results indicate that they act synergistically to target CML cells both in the presence and absence of BMP4 ligand. Inhibition resulted in decreased proliferation, irreversible cell cycle arrest, increased apoptosis, reduced haemopoietic colony formation, altered gene expression pattern, reduction in self-renewal and a significant reduction in the phosphorylation of downstream target proteins. These changes offer a therapeutic window in CML, with intervention using BMP inhibitors in combination with TKI having the potential to prevent LSC self-renewal and improve outcome for patients. By successfully developing and validating iPSCs for CML drug screening we hope to substantially reduce the reliance on animal models for early preclinical drug screening in leukaemia.