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1
Lo, Carfield. « Identified of novel splicing variants of livin in acute myeloid leukemia ». Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B41897031.
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Vo, Thanh-Trang. « Mitochondrial Priming Determines Chemotherapeutic Response in Acute Myeloid Leukemia ». Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10384.
Texte intégralRésumé :
Gain- and loss-of-function studies of the BCL-2 family of proteins have shown that they can impact chemotherapeutic sensitivity. However, cells contain myriad anti-apoptotic and pro-apoptotic BCL-2 family members making it difficult to predict cell fate decisions based on the initial conditions of these proteins. BH3 profiling is a tool that measures mitochondrial priming, the readiness of a cell to die through the intrinsic (or mitochondrial) apoptotic pathway. Priming is due to the cumulative effect of the BCL-2 family of proteins that act as the gate keepers of the mitochondrial apoptotic pathway. Priming is measured by determining the sensitivity of mitochondria to perturbation by peptides derived from the BH3 domains of pro-apoptotic proteins. Using BH3 profiling, we now have a functional readout that can quantify priming and assess its contribution to drug sensitivity. Here we show that priming affects the sensitivity of acute myeloid leukemia (AML) cell lines to various standard chemotherapeutics, especially topoisomerase II inhibitors. Priming predicts clinical response to conventional induction chemotherapy as well as the long term maintenance of remission in AML patients. Interestingly, the priming of normal hematopoietic stem cells (HSCs) sits at the boundary line between the priming of cured and refractory patient AML. This HSC priming likely defines the therapeutic index since AML that are lower primed than HSCs are often refractory and cannot be cured without transplantation. Additionally, our BH3 profiles revealed that AML cells are more sensitive to BCL-2 antagonism than normal HSCs, which are primarily dependent on MCL-1. Indeed, we were able to kill primary refractory AML cells in vitro with the BCL-2 antagonist ABT-737 at doses that left HSCs unharmed. Cumulatively, these findings show that priming is a major mechanistic determinant of AML response in vitro and in the clinic to standard induction chemotherapy. With the ability to predict outcome, BH3 profiling may offer physicians and patients a promising tool for treatment decision-making.
3
Lo, Carfield, et 盧德心. « Identified of novel splicing variants of livin in acute myeloid leukemia ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B41897031.
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4
Nakatani, Kana. « Inhibition of CDK4/6 and autophagy synergistically induces apoptosis in t(8;21) acute myeloid leukemia cells ». Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263584.
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Lainey, Elodie. « Evaluation préclinique de l’azacytidine et de l’erlotinib seuls ou en association dans le traitement des syndromes myélodysplasiques ». Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T066.
Texte intégralRésumé :
Les syndromes myélodysplasiques (SMD) sont un ensemble d’hémopathies clonales de la cellule souche. Ils touchent les sujets âgés et se caractérisent par une hématopoïèse inefficace, une différenciation anormale et une transformation fréquente en leucémie aiguë myéloblastique (LAM). La prise en charge thérapeutique a considérablement évolué ces dix dernières années, principalement avec l’arrivée de la 5-azacytidine (Aza) dans les SMD de haut risque. Malheureusement, il existe fréquemment un échec ou une perte de réponse rapide au traitement responsable d’une survie médiane globale de seulement quelques mois. La compréhension des mécanismes d’action des agents hypométhylants, la mise en évidence des facteurs biologiques impliqués dans la résistance à l’Aza ou encore l’identification de nouvelles associations de molécules constitue donc un enjeu majeur. Plusieurs équipes, dont la nôtre, ont démontré que l’erlotinib (Erlo) (inhibiteur de l’activité kinase de l’EGFR (Epidermal Growth Factor Receptor)) possède des effets antinéoplasiques dans les SMD/LAM. Compte tenu de sa toxicité modérée, cet inhibiteur de tyrosine kinase est actuellement en essai clinique en France et aux États-Unis dans les SMD en échec d’Aza. Dans ce travail, nous avons tenté de comprendre les mécanismes d’action impliqués dans l’activité de l’Aza et de l’Erlo seuls ou en association. Nous avons observé que l’Aza et la décitabine (un autre agent hypométhylant) induisent la déphosphorylation et la translocation dans le noyau du facteur de transcription FOXO3A où il réactive l’expression de gènes cibles tels que les facteurs pro apoptotiques PUMA et BIM. Cet effet observé rapidement, suggère un effet « off target » non lié à une reprogrammation épigénétique. La phosphorylation constitutive de FOXO3A étant considérée comme un facteur de mauvais pronostic dans les LAM, cette observation soulève l’intérêt potentiel des agents hypométhylants dans cette pathologie. Nous avons également identifié deux nouvelles cibles de l’Erlo : les SRC-kinases et la voie mTOR/p70S6K dont l’inhibition par des inhibiteurs biochimiques induit un arrêt du cycle cellulaire en G0/G1 sans apoptose ni différenciation confirmant l’hypothèse d’une action « multikinase » de l’Erlo. Par ailleurs, nous avons mis en évidence une activité synergique sur l’apoptose de l’association Aza et Erlo sur des lignées cellulaires de SMD/LAM et sur des cellules de patients. Cet effet n’a pas été retrouvé avec la décitabine ni les autres inhibiteurs de tyrosine kinase testés. La potentialisation de l’apoptose semble liée à plusieurs mécanismes associant l’augmentation de la concentration intracellulaire d’Aza via l’inhibition des transporteurs ABC, un arrêt de la prolifération, une activation des voies apoptotiques caspases-dépendantes et indépendantes et une activation des dommages à l’ADN. En conclusion, ce travail a permis l’identification de nouvelles cibles de l’Erlo et de l’AZA et a révélé un effet synergique entre ces deux molécules. Ces résultats précliniques encourageants suggèrent que cette association pourrait apporter un potentiel bénéfice chez les patients atteints de SMD/LAM, notamment ceux devenus réfractaires à l’AzaMyelodysplasic syndromes (MDS) constitute a diverse group of malignant clonal disorders that typically occur in elderly people. MDS are characterized by ineffective hematopoiesis, refractory cytopenias, morphologic dysplasia and increased potential to transform into acute myeloid leukemia (AML). Treatment of MDS has progressed considerably in recent years with the emergence of new approval agents such as azacytidine (aza)(a hypomethylating agent (HMA)) in higher-risk MDS. However, there are still a significant proportion of patients who do not respond to therapy with aza. Therefore, understanding the mechanisms of action of HMAs, identifying predictive factors for aza resistance and combining HMAs with other active compounds in MDS represent a challenging area to improve MDS/AML treatment. Previous works showed that erlotinib (an inhibitor of the epidermal growth factor receptor (EGFR)) exhibits antineoplastic effects in MDS/AML. Due to its limited toxicity profile, this tyrosine kinase inhibitor is currently being evaluated after failure of aza in two clinical trials. In this project, we aimed at understanding the molecular mechanisms involved in the activity of aza and erlo alone or in combination. We observed that aza and decitabine (another HMA related to aza) induces dephosphorylation and translocation to nucleus of the transcriptional regulator FOXO3A promoting the upregulation of the pro-apoptotic factors PUMA and BIM. This effect could be an “off target” effect and could contribute the bebenfical role of HMA in AML as constitutive phosphorylation of FOXO3A has been shown to be an adverse prognostic factor. We discovered new target for erlo, Src-kinase kinases and mTOR that are implicated in the cell-cycle arrest but not in the induction of apoptosis or differentiation confirming the “multikinase” activity of erlo. We found that the combination of aza and erlo demonstrated synergistic induction of apoptosis in MDS/AML cell lines and in some patient cells. This effect was not observed with decitabine or other tyrosine kinase inhibitors frequently used in onco-hematology. We demonstrated that potentiation of cell death is associated with different mechanisms such as intracellular accumulation of aza (via inhibition of ABC transporters), cell cycle arrest with inhibition of leukemic cells growth, caspase-dependent and -independent induction of apoptosis and DNA damage level. In conclusion, this work identified new targets of aza and erlo and revealed a synergistic induction of apoptosis upon co-treatment suggesting that this drug combination might be promising for SMD/AML treatment SMD/AML, especially the resistant patients
6
Tailler, Maximilien. « Les dérégulations de l’apoptose dans les syndromes myélodysplasiques et les leucémies aigues myéloïdes ». Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T059.
Texte intégralRésumé :
Les syndromes myélodysplasiques (SMD) peuvent être conçus comme des conditions pré-leucémiques dans lesquelles l’apoptose avorte les produits de différenciation de cellules souches mutées, potentiellement malignes. Néanmoins, peut-être à cause d’une inhibition progressive de l’apoptose, les SMD se transforment fréquemment en leucémies aiguës myéloïdes (LAM). Nos données indiquent que les SMD à faible risque se caractérisent par l’absence d’activation de NF-κB au sein des cellules portant des altérations cytogénétiques typiques. Par contre, dans les SMD à haut risque de transformation en LAM (ainsi que dans les LAM post-SMD), les cellules souches hématopoïétiques et leurs produits de différenciation montrent une translocation activatrice des sous-unités p50/p65 de NF-κB. L’utilisation d’antagonistes de IKK provoque une inhibition de NF-κB conduisant à une apoptose accélérée, ainsi l’activation de NF-κB serait responsable de la suppression progressive de l’apoptose et donc de la transformation maligne. Ce projet de thèse a consisté à comprendre les mécanismes impliqués dans la dérégulation de l’apoptose dans les SMD/LAM ; ainsi qu’à utiliser des technologies de criblage pour permettre une meilleure compréhension des voies de signalisation impliquées, et à adapter de nouveaux outils d’analyse. Au cours d’une première étude, nous avons montré que les inhibiteurs de méthyltransférase de l’ADN et les inhibiteurs d’histones déacétylases induisent efficacement l’apoptose dans la lignée cellulaire SMD/LAM P39, parallèlement à une inhibition de la translocation de NF-κB du cytoplasme au noyau. Dans une seconde étude, nous avons montré que l’inhibition pharmacologique du récepteur Flt3 induit une inhibition de la voie NF-κB, et pourrait être une cible thérapeutique pertinente. Dans une troisième étude, nous avons montré que l’auto-activation d’ATM chez les patients atteints de SMD/LAM joue un rôle dans l’activation constitutive de NF-κB suggérant qu’ATM serait également une bonne cible thérapeutique dont l’inhibition pourrait réduire le défaut d’apoptose des cellules SMD et LAM. Et enfin, grâce à l’optimisation d’une technique d’analyse d’images à haut débit, nous avons identifié deux composés capables d’induire la mort cellulaire des lignées cellulaires LAM in vitro : le zinc pyrithione et la ouabain. Leurs effets d’inhibition du signal de survie NF-κB, conduisant à une réduction de l’expression de protéines anti-apoptotiques, suggèrent que ces composés pharmaceutiques pourraient être utilisés comme des agents anti-leucémiques. Ce projet de thèse nous a permis de mettre en évidence le potentiel anti-leucémique de différents agents impliqués dans les principales voies de signalisation de l’apoptose dérégulées dans les SMD/LAM, qui pourraient prochainement servir de cibles pour de nouveaux essais thérapeutiquesMyelodysplastic syndrome (MDS) is a group of hematopoietic stem cell disorders that is characterized by an ineffective hematopoiesis (finaly leading to blood cytopenias) and by a high risk of progression to acute myeloid leukemia (AML). It can therefore be viewed as a preleukemic condition in which apoptosis aborts the differentiation products of potentially malignant mutated (stem) cells. The progression of MDS into AML is associated with progressive inhibition of apoptotsis (by e.g. the expression of antiapoptotic proteins) and a negative prognostic value, suggesting that loss of the apoptotic program could favor the MDS-to-AML transition. Therefore the present project aimed at understanding the mechanisms involved in the deregulation of apoptosis in MDS and AML and the characterization of their underlying signaling pathways by means of standard biochemical and high throughput screening approaches. Our previous work showed that inhibitors of DNA methyltransferases and histone deacetylases effectively induced apoptosis in AML cells in vivo which was associated with an inhibition of NF-κB-dependent transactivation of survival signals. We further found that the pharmacological inhibition of the Flt3 receptor in AML cells decreased NF-κB activation and might therefore constitute a relevant therapeutic target for the treatment of AML. In line with these findings we demonstrated that the constitutive activation of ATM in high-risk MDS and AML patients accounts for the activation of NF-κB suggesting ATM as yet another drugable target for antileukemic therapy. Finally we generated a high throughput image based screening platform, which enabled us to perform large scale drug screening approaches and to identify two compounds with antileukemic properties. Both agent, pyrithione zinc (PZ) and Ouabain (OUA) efficiently induced cell death in AML cells in vitro associated with the inhibition of NF-κB. PZ and OUA exerted significant anticancer effects in vivo, on human AML cells xenografts as well as ex vivo, on CD34+ (but not CD34-) malignant myeloblasts from AML patients. Summarizing this project allowed us to shed some light on the importance of NF-κB during MDS to AML progression and at the same time it helped to identify drugable targets and agents with potential anticancer properties for the treatment of leukemia
7
Shah, Viral Virendra [Verfasser]. « Enhancing PARP inhibition mediated DNA Damage and leveraging inherent anti-apoptotic dependencies in acute myeloid leukemia / Viral Virendra Shah ». Mainz : Universitätsbibliothek der Johannes Gutenberg-Universität Mainz, 2020. http://d-nb.info/1223205320/34.
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Yaseen, Mumtaz. « Proteomics of Acute Myeloid Leukemia : ». Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-69882.
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Palle, Josefine. « Optimizing Chemotherapy in Childhood Acute Myeloid Leukemia ». Doctoral thesis, Uppsala University, Department of Women's and Children's Health, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9189.
Texte intégralRésumé :
Despite major advances in our understanding of the biology of childhood acute myeloid leukemia (AML) and the development of new cytotoxic drugs, the prognosis of long-term survival is still only 60-65 %.
In the present research, we studied the pharmacokinetics of drugs used in the induction therapy of childhood AML and performed in vitro drug sensitivity testing of leukemic cells from children with AML.
The aims of the studies were to correlate the results of the analysis to biological and clinical parameters and to identify subgroups of AML with specific drug sensitivity profiles in order to better understand why treatment fails in some patients and how therapy may be improved.
Blood samples were analysed to study the pharmacokinetics of doxorubicin (n=41), etoposide (n=45) and 6-thioguanine (n=50). Doxorubicin plasma concentration and total body clearance were correlated to the effect of induction therapy, and doxorubicin plasma concentration was an independent factor for complete remission, both in univariate and multivariate analysis including sex, age, and white blood cell count at diagnosis. For etoposide and 6-thioguanine no correlation was found between pharmacokinetics and clinical effect. Children with Down syndrome (DS) tended to reach higher blood concentrations of etoposide and thioguanine nucleotides, indicating that dose reduction may be reasonable to reach the same drug exposure as in children without DS.
Leukemic cells from 201 children with newly diagnosed AML, 15 of whom had DS, were successfully analysed for in vitro drug sensitivity by the fluorometric microculture cytotoxicity assay (FMCA). We found that samples from children with DS were highly sensitive to most drugs used in AML treatment. In non-DS children, the t(9;11) samples were significantly more sensitive to cytarabine (p=0.03) and doxorubicin (p=0.035) than other samples. The findings might explain the very favorable outcome reported in children with DS and t(9;11)-positive AML. A specific drug resistance profile was found for several other genetic subgroups as well. A detailed study of MLL-rearranged leukemia showed that cellular drug sensitivity is correlated both to partner genes and cell lineage, findings that support the strategy of contemporary protocols to include high-dose cytarabine in the treatment of patients with MLL-rearrangement, both in AML and acute lymphoblastic leukemia (ALL).
Our results indicate that drug resistance and pharmacokinetic studies may yield important information regarding drug response in different sub-groups of childhood AML, helping us to optimize future chemotherapy in childhood AML.
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Watson, Alexander Scarth. « Autophagy in hematopoiesis and acute myeloid leukemia ». Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:2e66c5c3-4774-44d1-8345-d0dc827da16d.
Texte intégralRésumé :
Acute myeloid leukemia (AML) develops following oncogenic alterations to hematopoietic stem (HSC) and progenitor cells (HSPCs) in the bone marrow, resulting in dysregulated proliferation of immature myeloid progenitors that interferes with normal hematopoiesis. Understanding the mechanisms of HSPC protection against damage and excessive division, and how these pathways are altered during leukemic progression, is vital for establishing effective therapies. Here, we show that autophagy, a lysosomal degradation pathway, is increased in HSPCs using a novel imaging flow cytometry autophagy assay. Loss of hematopoietic autophagy following deletion of key gene Atg5 resulted in increased HSC proliferation, leading to HSC exhaustion and bone marrow failure. Although erythrocyte and lymphocyte populations were negatively impacted by autophagy loss, myeloid cells showing immature characteristics were expanded. Deletion of Atg5 in an AML model resulted in increased proliferation under metabolic stress, dependent on the glycolytic pathway, and aberrant upstream mTOR signaling. Moreover, modulation of Atg5 altered leukemic response to culture with stromal cells. Finally, primary AML cells displayed multiple markers of decreased autophagy. These data suggest a role for autophagy in preserving HSC function, partially through suppression of HSPC proliferation, and indicate that decreased autophagy may benefit AML cells. We postulate that modulation of autophagy could help maintain stem cell function, for example during transplantation, and aid AML therapy in a setting-specific manner.
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Zhang, Lu [Verfasser]. « Immunogenicity of leukemia stem cells in acute myeloid leukemia / Lu Zhang ». Ulm : Universität Ulm. Medizinische Fakultät, 2012. http://d-nb.info/1020022574/34.
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Demajo, Meseguer Santiago 1985. « ZRF1-mediated transcriptional regulation in acute myeloid leukemia ». Doctoral thesis, Universitat Pompeu Fabra, 2014. http://hdl.handle.net/10803/283478.
Texte intégralRésumé :
Acute myeloid leukemia (AML) is frequently linked to epigenetic abnormalities and
deregulation of gene transcription, which lead to aberrant cell proliferation and accumulation of
undifferentiated precursors. ZRF1, a recently characterized epigenetic factor involved in
transcriptional regulation, is highly overexpressed in human AML, but it is not known whether
it plays a role in leukemia progression. In this thesis, we have investigated the function of
ZRF1-mediated transcriptional regulation in AML. We demonstrate that ZRF1 depletion
decreases cell proliferation, increases apoptosis and induces cell differentiation in human AML
cells. Treatment with retinoic acid (RA), a differentiating agent currently used to treat certain
AMLs, leads to a functional switch of ZRF1 from a negative regulator to an activator of
differentiation. At the molecular level, ZRF1 controls the RA-regulated gene network through
its interaction with the RA receptor α (RARα) and its binding to RA target genes. Our genomewide
expression study reveals that ZRF1 regulates the transcription of nearly half of RA target
genes. Consistent with our in vitro observations that ZRF1 regulates proliferation, apoptosis,
and differentiation, ZRF1 depletion strongly inhibits leukemia progression in xenograft mouse
models. Finally, ZRF1 knockdown cooperate with RA treatment in leukemia suppression in
vivo. Taken together, our results show that ZRF1 is a key transcriptional regulator in leukemia
progression and suggest that ZRF1 inhibition could be a novel strategy to be explored for AML
treatment.La leucèmia mieloide aguda (LMA) està relacionada freqüentment amb anomalies epigenètiques i desregulació de la transcripció gènica, que provoquen una proliferació cel·lular aberrant i l'acumulació de precursors indiferenciats. ZRF1, un factor epigenètic caracteritzat recentment i implicat en la regulació transcripcional, es troba altament sobreexpressat en la LMA humana, però es desconeix si juga cap paper en la progressió de la malaltia. En aquesta tesi, s'ha investigat la funció de ZRF1 en la regulació transcripcional en la LMA. Es demostra que el silenciament de ZRF1 provoca una disminució de la proliferació, un increment de l'apoptosi i una inducció de la diferenciació en cèl·lules de LMA humana. El tractament amb àcid retinoic (AR), un inductor de la diferenciació que es fa servir actualment per a tractar determinades LMAs, produeix un canvi funcional en ZRF1, que passa de repressor a activador de la diferenciació. A nivell molecular, ZRF1 controla la xarxa de gens regulada per l’AR a través de la seva interacció amb el receptor de l'AR α (RARα) i la seva unió als gens diana de l'AR. El nostre estudi d'expressió a nivell de tot el genoma revela que ZRF1 regula la transcripció de gairebé la meitat dels gens diana de l'AR. En concordança amb les nostres observacions in vitro que mostren que ZRF1 regula la proliferació, l'apoptosi i la diferenciació, el silenciament de ZRF1 provoca una forta inhibició en la progressió de la leucèmia en models de xenotrasplantament en ratolí. Finalment, el silenciament de ZRF1 coopera amb el tractament amb AR en la supressió de la leucèmia in vivo. Conjuntament, aquests resultats mostren que ZRF1 és un regulador transcripcional clau en la progressió de la leucèmia i suggereixen que la inhibició de ZRF1 podria ser una nova estratègia a explorar en al tractament de la LMA.
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Belt, Alex J. « Zebrafish Model of MLL-Rearranged Acute Myeloid Leukemia ». VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5600.
Texte intégralRésumé :
Acute myeloid leukemia (AML) is the second most common type of leukemia and accounts for 80% of adult acute leukemia cases and is characterized by the accumulation of poorly or undifferentiated myeloid blast cells. Standard treatment includes chemotherapy, which if unsuccessful, is followed by more rigorous chemotherapy as well as stem cell transplantation. Considering most patients are over the age of 45, these more rigorous therapies are not always possible, and as such, new therapies must be developed. Furthermore, AML patients harboring a chromosomal rearrangement involving Multiple Lineage Leukemia (MLL) that results in the expression of an MLL fusion protein exhibit far worse prognoses than patients without. In recent years, Danio rerio (zebrafish) has emerged as a powerful model organism for investigating human blood malignancies due to the conservation of hematopoiesis between humans and zebrafish. The first objective of this study was to develop a transient transgenic AML model in zebrafish, and the second objective was to determine if co-treatment with two medications currently in human trials for AML, Venetoclax and Flavopiridol, would be more effective than using either drug individually. In order to develop a transient transgenic AML model, we first developed a DNA construct encoding a known mixed lineage leukemia (MLL) fusion protein associated with human AML, MLL-ENL, driven by the zebrafish lysozyme C (lyz) promoter, which drives myeloid specific expression in zebrafish. We then microinjected single-cell zebrafish embryos with DNA encoding lyz driven MLL-ENL along with transposase mRNA to facilitate the genomic integration of MLL-ENL. Injected embryos were first tested for MLL-ENL expression, and subsequently tested for AML phenotypic characteristics, via whole mount in-situ hybridization (WISH) at 72 hours post fertilization (hpf). First, WISH analysis utilizing a human MLL riboprobe verified MLL-ENL expression in injected embryos, and WISH analysis utilizing the same MLL riboprobe revealed an expansion and clustering of MLL positive cells in injected embryos, characteristic of an AML phenotype. Embryos injected with MLL-ENL DNA were then treated with either DMSO (vehicle), 200 nanomolar (nM) Venetoclax, 200 nM Flavopiridol, or 200 nM Venetoclax and 200 nM Flavopiridol from 24 hpf to 72 hpf. MLL WISH analysis of injected and treated embryos revealed a reduction in MLL positive cells in both Venetoclax treated embryos and Flavopiridol treated embryos, and an even greater reduction in MLL positive cells in embryos treated with both Venetoclax and Flavopiridol, compared to controls. Although further analysis is required to be confident, these data suggest that we successfully developed an AML transient transgenic model in zebrafish. Furthermore, these data suggest that Venetoclax and Flavopiridol co-treatment could yield better outcomes for AML patients than treatment with either drug individually.
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Doepfner, Kathrin T. « Targeting receptor tyrosine kinase signaling in acute myeloid leukemia / ». Zürich, 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000253043.
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Holt, Bronno van der. « Translational studies in elderly patients with acute myeloid leukemia ». [S.l.] : Rotterdam : [The Author] ; Erasmus University [Host], 2007. http://hdl.handle.net/1765/10514.
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Teleanu, Maria-Veronica [Verfasser]. « RUNX1 mutations in acute myeloid leukemia / Maria-Veronica Teleanu ». Ulm : Universität Ulm, 2017. http://d-nb.info/1135665141/34.
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Cheung, Man-sze, et 張敏思. « Characterization of Leukemic stem cells in acute myeloid Leukemia ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B40687582.
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Cheung, Man-sze. « Characterization of Leukemic stem cells in acute myeloid Leukemia ». Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B40687582.
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Varchol, Karen. « Parental occupational exposures and acute myeloid leukemia in offspring / ». The Ohio State University, 2000. http://rave.ohiolink.edu/etdc/view?acc_num=osu1488203857250743.
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Valia, Dhvani. « EMERGING NATURAL KILLER CELL IMMUNOTHERAPY FOR ACUTE MYELOID LEUKEMIA ». Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1561938259242716.
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Prenkert, Malin. « On mechanisms of drug resistance in acute myeloid leukemia ». Doctoral thesis, Örebro universitet, Hälsoakademin, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-10603.
Texte intégralRésumé :
In this thesis focus has been to increase the knowledge and understanding of some of the mechanisms responsible for drug resistance in acute myeloid leukemia, as well as identify possibilities to predict drug resistance at diagnosis. We have studied the intracellular behavior of cytostatic drugs and their main metabolites (paper I) and the cellular response to cytostatic drugs (paper III). A new flow cytometry in vitro chemosensitivity assay was developed, to enable identification of viable myeloid cells and determination of drug sensitivity (paper II). Finally, possible new markers involved in drug resistance were investigated (paper IV). In conclusion we found that idarubicin and daunorubicin are equally toxic at the same intracellular concentrations. The contribution of the main metabolites to the cytotoxic effects of idarubicin and daunorubicin, in both drug sensitive and drug resistant human myeloid leukemia cells, is low. It is most likely the pharmacokinetic properties of idarubicin and daunorubicin that confer their main cytotoxic effect. With the new flow cytometry chemosensitivity assay we selectively identified viable CD13/CD33 expressing myeloid cells and found that the cytotoxicity results correlated to clinical parameters, such as secondary AML and resistant disease. Short-term exposure of leukemia cell lines with different levels of drug resistance to ara-C revealed that Pgp mRNA and protein ex-pression levels, as well as GSTπ mRNA levels, were rapidly up-regulated. Clinically, this up-regulation may be of importance for the sequential scheduling of daunorubicin and ara-C during the induction treatment of AML. CRIM1 has never been studied in the context of drug resistance before. We show for the first time that baseline expression of CRIM1 mRNA is much higher in drug resistant leukemia cells compared to drug sensitive cells. We also found a co-variance between CRIM1 and Pgp mRNA expression levels in leukemia cell lines with different levels of drug resistance, suggesting that CRIM1 may be useful as a marker of drug resistance.
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Mhadgut, Hemendra M. D., Chandana M. D. Kamireddy, Alok M. D. Sinha, Sakshi M. D. Singal et Devapiran M. D. Jaishankar. « Innumerable bone lesions : An atypical presentation of Acute Myeloid Leukemia ». Digital Commons @ East Tennessee State University, 2021. https://dc.etsu.edu/asrf/2021/presentations/19.
Texte intégralRésumé :
Acute myeloid leukemia(AML) is the most common acute leukemia among adults in the United states with approximately 19,940 people being diagnosed of this disease in 2020 and 11,180 deaths. It is a heterogenous group of malignancy characterized by clonal expansion of blast with myeloid lineage in the bone marrow, peripheral blood and/or other tissues.
Our patient is a 79-year-old male who presented to the hospital with reports of sharp, throbbing low back pain for one month, moderately controlled with pain medications. He reported 5 lb. weight loss with decreased appetite over one month but denied other constitutional symptoms. MRI Lumbar spine revealed multiple foci of marrow signal abnormality compatible with extensive metastatic disease. CT chest, abdomen and pelvis did not show any lesions concerning for primary or metastatic malignancy. CBC revealed normal WBC count, platelet count and hemoglobin level (with macrocytosis, MCV 104.7). Initial work up including Vitamin B12 and folic acid level, TSH, SPEP/IFE, serum light chain ratio and quantitative immunoglobulins were within normal limits. Pathology from a CT guided bone biopsy of the L spine lesion was concerning for high grade myeloid neoplasm. Patient had a bone marrow biopsy done at another hospital which was read as most consistent with acute myeloid leukemia (AML) with monocytic differentiation, with findings of hypocellular marrow, extensive fibrosis with focal areas of large clusters of immature cells, positive for MPO, CD33, CD43 and CD 56, Ki-67 of 60-80%. Cytogenetics showed an abnormal male karyotype with trisomy 8. FISH was negative for other AML or MDS related abnormalities. Given the above findings of AML and advanced age, patient was started on treatment with hypomethylating agent Decitabine along with BCL-2 inhibitor, Venetoclax. A repeat bone marrow biopsy after two cycles of the above regimen revealed progressive disease with extensive fibrosis and 80-90% blast on a core biopsy sample. Due to poor response to above regimen, lack of effective treatment options in older patients with AML and declining functional status, decision was made to pursue best supportive care.
AML usually presents with symptoms of fevers, fatigue, dyspnea or bleeding. Skeletal lesions are usually associated with a diagnosis of multiple myeloma, or other solid organ malignancies and rare in AML. Extra medullary involvement of AML is known to happen in 2.5%-9% of patients and is termed as Myeloid Sarcoma. Due to the low incidence, prospective study data is limited. This entity is treated similarly to AML, depending on risk stratification by cytogenetics, age and targetable mutations which also govern its prognosis. This case highlights the importance of increased awareness and high index of suspicion among medical providers regarding this atypical presentation of AML since if missed or misdiagnosed could delay treatment and lead to poor outcomes.
23
Namasu, Carolina Yaeko [Verfasser]. « The role of ABR in myeloid differentiation and acute myeloid leukemia / Carolina Yaeko Namasu ». Halle, 2017. http://d-nb.info/116614061X/34.
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24
Putwain, Sarah Lucy. « The role of Sox4 in acute myeloid leukaemia ». Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648624.
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25
Nagura, Eiichi, Saburo Minami, Koichiro Nagata, Yoshihisa Morishita, Hideo Takeyama, Hiroshi Sao, Hisamitsu/ Suzuki et al. « Acute myeloid leukemia in the elderly : 159 Nagoya case studies ». Nagoya University School of Medicine, 1999. http://hdl.handle.net/2237/5348.
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26
Eriksson, Anna. « Studies of New Signal Transduction Modulators in Acute Myeloid Leukemia ». Doctoral thesis, Uppsala universitet, Cancerfarmakologi och beräkningsmedicin, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-182440.
Texte intégralRésumé :
Acute myeloid leukemia (AML) is a life-threatening malignant disorder with dismal prognosis. AML is characterized by frequent genetic changes involving tyrosine kinases, normally acting as important mediators in many basic cellular processes. Due to the overexpression and frequent mutations of the FMS-like receptor tyrosine kinase 3 (FLT3) in AML, this tyrosine kinase receptor has become one of the most sought after targets in AML drug development. In this thesis, we have used a combination of high-throughput screens, direct target interaction assays and sequential cellular screens, including primary patient samples, as an approach to discover new targeted therapies. Gefitinib, a previously known inhibitor of epidermal growth factor receptor and the two novel tyrosine kinase inhibitors AKN-032 and AKN-028, have been identified as compounds with cytotoxic activity in AML. AKN-028 is a potent inhibitor of FLT3 with an IC50 value of 6 nM in an enzyme assay, but also displaying in vitro activity in a variety of primary AML samples, irrespective of FLT3 mutation status or quantitative FLT3 expression. AKN-028 shows a sequence dependent in vitro synergy when combined with standard cytotoxic agents cytarabine or daunorubicin, with better efficacy when cells are exposed to standard chemotherapy simultaneously or for 24 hours prior to adding AKN-028. Antagonism is observed when cells are pre-treated with AKN-028, possibly explained by the cell cycle arrest induced by the compound. In vivo cytotoxic activity and good oral bioavailability have made AKN-028 a candidate drug for clinical studies and the compound is presently investigated in an international two-part multicenter phase I/II study. Results from microarray studies performed to further elucidate the mechanism of action of AKN-028, revealed significantly altered gene expression induced by AKN-028 in both AML cell lines and in primary AML cells, with an enrichment of the Myc pathway among the downregulated genes. Furthermore, tyrosine kinase activity profiling shows a dose-dependent kinase inhibition by AKN-028 in all AML samples tested. Interestingly, cells with a high overall kinase activity were more sensitive to AKN-028. Provided conformation in a larger set of samples, kinase activity profiling may give useful information in individualizing treatment of patients with AML.
27
Ho, Siu-ki, et 何肇騏. « DNA methylation patterns in t(8;21) acute myeloid leukemia patients ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47151389.
Texte intégralRésumé :
Acute myeloid leukemia (AML) is a heterogeneous disease both clinically and
biologically. Approximately 55% of AML harbour karyotypic changes, and one of the most common chromosomal aberrations is the t(8;21)(q22;q22), which leads to the AML1-ETO fusion protein. Previous studies have found that this fusion protein recruits the N-CoR/mSin3A/HDAC complex, thereby acts as a transcriptional repressor. Recently, DNA methylation array studies have shown that DNA methylation patterns can stratify AML cases into different subgroups, and some of these correspond to certain chromosomal abnormalities, such as the t(8;21). These findings suggest a possible link between the fusion transcript AML1-ETO and epigenetic modifications. Additionally, c-kit mutations have emerged as an important disease modifier in the t(8;21) AML and are correlated with poor overall survival and event free survival in patients with t(8;21) AML. We therefore sought to investigate whether there are different DNA methylation patterns in t(8;21) AML with or without c-kit mutations. In our series, 52.2% of the t(8;21) AMLs harbored c-kit mutations, which were correlated with poor event free survival. We next performed pyrosequencing on a selected panel of genes and pinpointed the THBS4 and PAWR genes as hypermethylated in their promoter CpG islands in 86.4% and 59.1% of the t(8;21) AML patients, respectively. These data suggest that THBS4 and PAWR may be important in the pathogenesis of t(8;21) AML.published_or_final_version
Pathology
Master
Master of Philosophy
28
Han, Ho-chun, et 韓浩俊. « JAK-STAT pathway as potential target of acute myeloid leukemia ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B50534208.
Texte intégralRésumé :
Acute myeloid leukemia (AML) is a group of heterogeneous diseases characterized by an abnormal increase in myeloblasts. Despite intensive chemotherapy and allogeneic bone marrow transplantation, the treatment outcome of AML remains unsatisfactory, with a cure rate of only about 30%. Therefore, novel therapeutic strategies targeting the pathogenetic pathways of leukemia initiation and progression are needed. Using intracellular phospho-flow analysis with normal bone marrow as reference, we detected an increase in phosphorylated-STAT5 (pSTAT5) in three leukemic cell lines (K562, KG-1 and ML-2) and 15 primary AML samples. Treatment with specific JAK2 inhibitor TG101209 and JAK2/3 inhibitor AG490 significantly reduced pSTAT5 level and leukemia cell growth associated with an increase in apoptosis and decrease in cellular proliferation. The clonogenic activities of these leukemia cell lines were also significantly reduced. Furthermore, treatment with these inhibitors in K562 and KG-1 also significantly reduced the WNT signaling activity, as enumerated by the TOP/FLASH luciferase assay. In addition, genes associated with oncogenic potential and anti-apoptosis were significantly reduced, consistent with the pathogenetic role of JAK-STAT pathway.
In summary, the present study highlighted the importance of the JAK2-STAT5 signaling pathway in sustaining AML. The results may open up a new avenue whereby new therapeutic strategies targeting AML can be designed.published_or_final_version
Medicine
Master
Master of Philosophy
29
Man, Cheuk-him, et 文卓謙. « Mechanism of sorafenib resistance in FLT3-ITD⁺ acute myeloid leukemia ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193461.
Texte intégralRésumé :
Acute myeloid leukemia (AML) is a group of heterogeneous diseases characterized by an abnormal increase in myeloblasts in circulation and/or bone marrow. Internal tandem duplication (ITD) of the fms-like tyrosine kinase 3 (FLT3) gene occurs in about 30% of AML and is associated with an inferior prognosis. Tyrosine kinase domain (TKD) mutations occur in about 5% with uncertain prognostic significance. Intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT) are the mainstays of treatment. However these approaches have reached a deadlock with a cure rate of 30-40%. Targeting FLT3 in AML with multi-tyrosine-kinase inhibitors has been evaluated in Phase II/III clinical trials. Despite an initial clearance of myeloblasts, the leukemia invariably progresses despite continuous treatment. The mechanisms of drug resistance and leukemia progression, hence the effective therapeutic strategies are currently unknown, limiting its clinical application.
These issues were addressed in the present study. In the first part, 13 patients with chemo-refractory or relapsed FLT3-ITD+ AML received sorafenib 200-400 mg twice daily of whom 12 patients achieved clearance or near clearance of bone marrow blasts after a median of 27 days (range 21-84 days). There was evidence of myeloid differentiation of the leukemia blasts at remission. Leukemia progression occurred in 9 patients after a median of 72 days (range 54-287 days) and in 4 out of 6 patients it was dominated by clones carrying double FLT3-ITD and -TKD mutations. Microarray studies comparing myeloblasts before sorafenib treatment (sorafenib naïve) and at subsequent progression (sorafenib resistant) demonstrated up-regulation of 64 genes including ALDH1A1, JAK3 and TESC whose functions were unknown in AML. Transplantation of sorafenib naïve and resistant myeloblasts into NOD/SCID mice recapitulated their clinical behavior when the animals were treated with sorafenib. Both ITD and TKD mutations at D835 were identified in leukemia initiating cells (LICs) from sorafenib naïve samples. These results suggested that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations.
In the second part, the gene encoding tescalcin (TESC), that was up-regulated at sorafenib resistance and was known to activate a sodium/hydrogen exchange (NHE1), was evaluated to examine its link with TKI resistance. TESC was highly expressed in FLT3-ITD+ AML cell lines MOLM-13 and MV4-11 and its knock-down by siRNA lowered intracellular pH and induced apoptosis. The results were recapitulated by treatment with a NHE1 inhibitor, 5-(N,N-Hexamethylene)amiloride (HMA). Induction of sorafenib resistance in MOLM-13 cell line (MOLM-13-RE) significantly increased its sensitivity to HMA. HMA treatment of MOLM-13 and MV4-11 as well as primary FLT3-ITD+ AML cells significantly reduced leukemia initiation in NOD/SCID mouse xenotransplantation. Normal CD34+ cells engraftment was not affected. HMA treatment significantly enhanced suppression of FLT3 signaling by sorafenib even in sorafenib resistant cell lines. These observations provided novel information about the pathogenetic role of TESC-NHE1-pHi in sorafenib resistance in AML.
In conclusion, the information derived from the present study has provided mechanistic insights to the emergence of drug resistance during sorafenib treatment and important guide for future therapeutic strategies targeting FLT3-ITD+ AML.published_or_final_version
Medicine
Doctoral
Doctor of Philosophy
30
Xue, Liting. « Oncogene Function in Pre-Leukemia Stage of INV(16) Acute Myeloid Leukemia : A Dissertation ». eScholarship@UMMS, 2010. http://escholarship.umassmed.edu/gsbs_diss/740.
Texte intégralRésumé :
The CBFbeta-SMMHC fusion protein is expressed in acute myeloid leukemia (AML) samples with the chromosome inversion inv(16)(p13;q22). This fusion protein binds the transcription factor RUNX with higher affinity than its physiological partner CBFbeta and disrupts the core binding factor (CBF) activity in hematopoietic stem and progenitor cells. Studies in the Castilla laboratory have shown that CBFbeta-SMMHC expression blocks differentiation of hematopoietic progenitors, creating a pre-leukemic progenitor that progresses to AML in cooperation with other mutations. However, the combined function of cumulative cooperating mutations in the pre-leukemic progenitor cells that enhance their expansion to induce leukemia is not known. The standard treatment for inv(16) AML is based on the use of non-selective cytotoxic chemotherapy, resulting in a good initial response, but with limited long-term survival. Therefore, there is a need for developing targeted therapies with improved efficacy in leukemic cells and minimal toxicity for normal cells.
Here, we used conditional Nras+/LSL-G12D; Cbfb+/56M; Mx1Cre knock-in mice to show that allelic expression of oncogenic N-RasG12D expanded the multi-potential progenitor (MPP) compartment by 8 fold. Allelic expression of Cbfbeta-SMMHC increased the MPPs and short-term hematopoietic stem cells (ST-HSCs) by 2 to 4 fold both alone and in combination with N-RasG12D expression. In addition, allelic expression of oncogenic N-RasG12D and Cbfbeta-SMMHC increases survival of pre-leukemic stem and progenitor cells. Differential analysis of bone marrow cells determined that Cbfb+/MYH11 and Nras+/G12D; vii Cbfb+/MYH11 cells included increased number of blasts, myeloblasts and promyelocytes and a reduction in immature granulocytes, suggesting that expression of N-RasG12D cannot bypass Cbfbeta-SMMHC driven differentiation block.
N-RasG12D and Cbfbeta-SMMHC synergized in leukemia, in which Nras+/G12D; Cbfb+/MYH11 mice have a shorter median latency than Cbfb+/MYH11 mice. In addition, the synergy in leukemogenesis was cell autonomous. Notably, leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC showed higher (over 100 fold) leukemia-initiating cell activity in vivo than leukemic cells expressing Cbfbeta-SMMHC (L-IC activity of 1/4,000 and 1/528,334, respectively).
Short term culture and biochemical assays revealed that pre-leukemic and leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC have reduced levels of pro-apoptotic protein Bim compared to control. The Nras+/G12D; CbfbMYH11 pre-leukemic and leukemic cells were sensitive to pharmacologic inhibition of MEK/ERK signaling pathway with increasing apoptosis and Bim protein levels but not sensitive to PI3K inhibitors. In addition, knock-down of Bcl2l11 (Bim) expression in Cbfbeta-SMMHC pre-leukemic progenitors decreased their apoptosis levels.
In collaboration with Dr. John Bushweller’s and other research laboratories, we recently developed a CBFbeta-SMMHC inhibitor named AI-10-49, which specifically binds to CBFbeta-SMMHC, prevents its binding to RUNX proteins and restores CBF function. Biochemical analysis in human leukemic cells showed that AI-10-49 has significant specificity in reducing the viability of leukemic cells expressing CBFbeta-SMMHC (IC50= 0.83μM), and negligible toxicity in normal cells. Likewise, mouse Nras+/G12D; viii Cbfb+/MYH11 leukemic cells were sensitive to AI-10-49 (IC50= 0.93μM). By using the NrasLSL-G12D; Cbfb56M mouse model, we also show that AI-10-49 significantly prolongs the survival of mice bearing the leukemic cells. Preliminary mechanistic analysis of AI-10-49 activity has shown that AI-10-49 increased BCL2L11 transcript levels in a dose and time dependent manner in murine and human leukemic cells, suggesting that the viability through BIM-mediated apoptosis may be targeted by both oncogenic signals.
My thesis study demonstrates that Cbfbeta-SMMHC and N-RasG12D promote the survival of pre-leukemic myeloid progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define NrasLSL-G12D; Cbfb56M mice as a valuable genetic model for the study of inv(16) AML targeted therapies. For instance, the novel CBFbeta-SMMHC inhibitor AI-10-49 shows a significant efficacy in this mouse model. This small molecule will serve as a promising first generation drug for targeted therapy of inv(16) leukemia and also a very useful tool to understand mechanisms of leukemogenesis driving by CBFbeta-SMMHC.
31
Xue, Liting. « Oncogene Function in Pre-Leukemia Stage of INV(16) Acute Myeloid Leukemia : A Dissertation ». eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsbs_diss/740.
Texte intégralRésumé :
The CBFbeta-SMMHC fusion protein is expressed in acute myeloid leukemia (AML) samples with the chromosome inversion inv(16)(p13;q22). This fusion protein binds the transcription factor RUNX with higher affinity than its physiological partner CBFbeta and disrupts the core binding factor (CBF) activity in hematopoietic stem and progenitor cells. Studies in the Castilla laboratory have shown that CBFbeta-SMMHC expression blocks differentiation of hematopoietic progenitors, creating a pre-leukemic progenitor that progresses to AML in cooperation with other mutations. However, the combined function of cumulative cooperating mutations in the pre-leukemic progenitor cells that enhance their expansion to induce leukemia is not known. The standard treatment for inv(16) AML is based on the use of non-selective cytotoxic chemotherapy, resulting in a good initial response, but with limited long-term survival. Therefore, there is a need for developing targeted therapies with improved efficacy in leukemic cells and minimal toxicity for normal cells.
Here, we used conditional Nras+/LSL-G12D; Cbfb+/56M; Mx1Cre knock-in mice to show that allelic expression of oncogenic N-RasG12D expanded the multi-potential progenitor (MPP) compartment by 8 fold. Allelic expression of Cbfbeta-SMMHC increased the MPPs and short-term hematopoietic stem cells (ST-HSCs) by 2 to 4 fold both alone and in combination with N-RasG12D expression. In addition, allelic expression of oncogenic N-RasG12D and Cbfbeta-SMMHC increases survival of pre-leukemic stem and progenitor cells. Differential analysis of bone marrow cells determined that Cbfb+/MYH11 and Nras+/G12D; vii Cbfb+/MYH11 cells included increased number of blasts, myeloblasts and promyelocytes and a reduction in immature granulocytes, suggesting that expression of N-RasG12D cannot bypass Cbfbeta-SMMHC driven differentiation block.
N-RasG12D and Cbfbeta-SMMHC synergized in leukemia, in which Nras+/G12D; Cbfb+/MYH11 mice have a shorter median latency than Cbfb+/MYH11 mice. In addition, the synergy in leukemogenesis was cell autonomous. Notably, leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC showed higher (over 100 fold) leukemia-initiating cell activity in vivo than leukemic cells expressing Cbfbeta-SMMHC (L-IC activity of 1/4,000 and 1/528,334, respectively).
Short term culture and biochemical assays revealed that pre-leukemic and leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC have reduced levels of pro-apoptotic protein Bim compared to control. The Nras+/G12D; CbfbMYH11 pre-leukemic and leukemic cells were sensitive to pharmacologic inhibition of MEK/ERK signaling pathway with increasing apoptosis and Bim protein levels but not sensitive to PI3K inhibitors. In addition, knock-down of Bcl2l11 (Bim) expression in Cbfbeta-SMMHC pre-leukemic progenitors decreased their apoptosis levels.
In collaboration with Dr. John Bushweller’s and other research laboratories, we recently developed a CBFbeta-SMMHC inhibitor named AI-10-49, which specifically binds to CBFbeta-SMMHC, prevents its binding to RUNX proteins and restores CBF function. Biochemical analysis in human leukemic cells showed that AI-10-49 has significant specificity in reducing the viability of leukemic cells expressing CBFbeta-SMMHC (IC50= 0.83μM), and negligible toxicity in normal cells. Likewise, mouse Nras+/G12D; viii Cbfb+/MYH11 leukemic cells were sensitive to AI-10-49 (IC50= 0.93μM). By using the NrasLSL-G12D; Cbfb56M mouse model, we also show that AI-10-49 significantly prolongs the survival of mice bearing the leukemic cells. Preliminary mechanistic analysis of AI-10-49 activity has shown that AI-10-49 increased BCL2L11 transcript levels in a dose and time dependent manner in murine and human leukemic cells, suggesting that the viability through BIM-mediated apoptosis may be targeted by both oncogenic signals.
My thesis study demonstrates that Cbfbeta-SMMHC and N-RasG12D promote the survival of pre-leukemic myeloid progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define NrasLSL-G12D; Cbfb56M mice as a valuable genetic model for the study of inv(16) AML targeted therapies. For instance, the novel CBFbeta-SMMHC inhibitor AI-10-49 shows a significant efficacy in this mouse model. This small molecule will serve as a promising first generation drug for targeted therapy of inv(16) leukemia and also a very useful tool to understand mechanisms of leukemogenesis driving by CBFbeta-SMMHC.
32
Slape, Christopher Ian. « Molecular characterisation of translocations involving chromosome band 1p36 in acute myeloid leukaemia ». Title page, table of contents and abstract only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09phs6313.pdf.
Texte intégralRésumé :
"October 2002" Bibliography: leaves 159-198. This thesis describes the mapping of the breakpoints of three different chromosome rearrangements, all involving 1p36, in acute myeloid leukaemia (AML) patients, and an investigation into the molecular outcomes of these rearrangements.
33
Chandran, Priya. « Bone Marrow Microenvironment in Acute Myleoid Leukemia ». Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/24301.
Texte intégralRésumé :
Acute myeloid leukemia (AML) often remains refractory to current chemotherapy and transplantation approaches despite many advances in our understanding of mechanisms in leukemogenesis. The bone marrow “niche” or microenvironment, however, may be permissive to leukemia development and studying interactions between the microenvironment and leukemia cells may provide new insight for therapeutic advances. Mesenchymal stem cells (MSCs) are central to the development and maintenance of the bone marrow niche and have been shown to have important functional alterations derived from patients with different hematological disorders. The extent to which MSCs derived from AML patients are altered remains unclear. The aim of this study was to detect changes occurring in MSCs obtained from human bone marrow in patients with AML by comparing their function and gene expression pattern with normal age-matched controls.
MSCs expanded from patients diagnosed with acute leukemia were observed to have heterogeneous morphological characteristics compared to the healthy controls. Immunohistochemistry and flow data confirmed the typical cell surface immunophenotype of CD90+ CD105+ CD73+ CD34- CD45-, although MSCs from two patients with AML revealed reduced surface expression of CD105 and CD90 antigens respectively. Differentiation assays demonstrated the potential of MSCs from AML patients and healthy donors to differentiate into bone, fat and cartilage. However, the ability of MSCs from AML samples to support hematopoietic function of CD34+ progenitors was found to be impaired while the key hematopoietic genes were found to be differentially expressed on AML-MSCs compared to nMSCs.
These studies indicate that there exist differences in the biologic profile of MSCs from AML patients compared to MSCs derived from healthy donors. The results described in the thesis provide a formulation for additional studies that may allow us to identify new targets for improved treatment of AML.
34
Chim, Chor-sang James. « Study of gene promoter methylation in acute promyelocytic leukaemia ». Hong Kong : University of Hong Kong, 2002. http://sunzi.lib.hku.hk/hkuto/record.jsp?B25256725.
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Ihme, Erika Ruth Susann [Verfasser]. « Characterization of the Leukemia Initiating Cell in Human Acute Myeloid Leukemia / Erika Ruth Susann Ihme ». Ulm : Universität Ulm, 2016. http://d-nb.info/1126036323/34.
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Möllgård, Lars. « Drug resistance in acute myeloid leukemia : pharmacokinetic and in vitro studies / ». Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4661-2/.
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Benajiba, Lina. « Identification and Characterization of New Therapeutic Targets in Acute Myeloid Leukemia ». Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS173.
Texte intégralRésumé :
La leucémie aiguë myéloïde (LAM) est une pathologie hématologique dont le pronostic reste très défavorable, malgré les progrès réalisés dans la compréhension des mécanismes physiopathologiques sous-tendant son développement. Identifier de nouvelles stratégies anti-leucémiques représente donc une étape clé dans la concrétisation des avancées thérapeutiques. Grâce à la combinaison de plusieurs approches de criblage génétiques et pharmacologiques, l’objectif de ma thèse a été de définir et valider de nouvelles cibles thérapeutiques dans les LAM. La première partie de ma thèse a eu pour but de transposer en clinique l’inhibition de la Glycogen Synthase Kinase 3 (GSK3). La stabilisation de la β-caténine secondaire à l'inhibition concomitante des deux paralogues de GSK3, représente un obstacle à l’utilisation clinique de cette classe thérapeutique. Mettant à profit la présence d'un «switch» Asp133 à Glu196 dans les domaines de liaison ATP de GSK3, nous avons identifié un inhibiteur sélectif du paralogue GSK3α et mené des études précliniques validant le BRD0705 comme nouveau traitement pro-différenciant dans les LAM. De plus, une combinaison de profilage métabolomique et d'approches de criblage haut débit à l’aide d’une banque de shRNA a permis d'identifier un nouveau lien entre EVI-1, la voie de la créatine kinase et la voie de signalisation GSK3. La deuxième partie de ma thèse a porté sur l'identification de nouvelles cibles thérapeutiques en utilisant une approche de criblage par banque de shRNA dans le modèle murin de LAM porteur de la translocation MLL-AF9. VCP, une AAA-ATPase, a ainsi été identifiée puis validée comme cible thérapeutique. Nous avons montré que VCP orchestre la génération d'une plateforme à ADN simple brin recouverte de RPA, ce qui entraîne l'activation de la kinase ATM et la HR. Dans leur ensemble, nos découvertes permettent une meilleure compréhension de la biologie des LAM et participeront ainsi à l’amélioration des traitements futurs de cette pathologieDespite the significant progress made in understanding Acute Myeloid Leukemia oncogenesis over the last decades, this disease remains devastating and the overall five-year survival does not exceed 17%. Developing new translational research strategies focused on the identification of druggable oncogenic targets is critical to continued progress in AML treatment. The goal of this work was to define and validate novel leukemia-specific dependencies using small-molecule inhibitors and RNA-interference-based high-throughput screening methods.The first part of my thesis work aimed at translating Glycogen synthase kinase 3 (GSK3) inhibition into the clinic. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, were a concern in the clinical translation of this target candidate. Specific knock-down of GSK3α or GSK3β alone does not increase β-catenin, thereby offering a conceptual resolution to GSK3 targeting. The design of selective ATP-competitive inhibitors posed a drug discovery challenge due to the high homology in the GSK3α and GSK3β ATP binding domains. Taking advantage of an Asp133 ® Glu196 “switch” in the GSK3 paralog hinge binding domains, we identified a first-in-class GSK3α selective inhibitor and conducted preclinical studies validating BRD0705 as a promising new differentiation therapy in AML. In addition, a combination of a metabolomic profiling and a pooled shRNA screening method identified a new interplay between the oncogene EVI-1, the creatine kinase pathway and GSK3 signaling. The second part of my studies focused on identification of new therapeutic targets using an in vivo pooled shRNA screening approach in the MLL-AF9-driven AML mouse model. VCP, an AAA-ATPase, was thus identified and validated as a top target. We demonstrated that VCP orchestrates RPA-coated-single-stranded-DNA platform generation, resulting in ATM kinase activation and subsequent HR. Taken together, our discoveries increased our understanding of AML biology and may therefore contribute to novel and more efficacious treatments for this highly aggressive and lethal disease
38
Mitchell, Shaneice Renee. « Preclinical evaluation of NAMPT inhibitor KPT-9274 in Acute Myeloid Leukemia ». The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1546527486477125.
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Jeon, Jae Yoon. « Preclinical and clinical development of kinase inhibitors in acute myeloid leukemia ». The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu158699311567933.
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Ristic, Marko. « ROS/SUMO relationship in the chemotherapeutic treatment of Acute Myeloid Leukemia ». Thesis, Montpellier, 2015. http://www.theses.fr/2015MONTT047.
Texte intégralRésumé :
Les leucémies aiguë myéloïde (LAM) sont un groupe d’hémopathies malignes, dont le traitement est généralement composé de deux génotoxiques : la cytarabine (Ara-C) et la daunorubicine (DNR). Nous avons montré que l’Ara-C et la DNR induisent la déconjugaison rapide de SUMO (Small Ubiquitin-related Modifier) de ses protéines cibles. Cette deSUMOylation est dûe à l'inactivation des enzymes E1 et E2 de SUMOylation par les espèces réactives de l'oxygène (ROS) produites par l’Ara-C et la DNR et est impliquée dans l'activation de l'apoptose. En outre, cet axe ROS/SUMO est anergisé dans les LAM chimiorésistantes. Cependant, il peut être réactivé par des pro-oxydants ou par inhibition de la voie SUMO par l'acide anacardique. Pour identifier les protéines contrôlées par l’axe ROS/SUMO nous avons effectué une approche de spectrométrie de masse quantitative (SILAC). Parmi les 1000 protéines SUMOylées identifiées, la plupart des 114 protéines qui perdent leur SUMOylation lors du traitement sont impliquées dans la régulation de l'expression des gènes. De plus, un ChIP-Seq avec des anticorps anti SUMO-2 a permis de montrer que les génotoxiques, en particulier la DNR, induisent une diminution massive de la présence de protéines SUMOylées sur la chromatine. La recherche de motifs au sein des séquences fixant SUMO a permis d’identifier le motif de liaison de CTCF à l’ADN. De plus, CTCF a été trouvé dans la SILAC comme l’une des protéines déSUMOylées par les traitements. En utilisant des données publiques de Chip-Seq pour CTCF, nous avons identifié 55 gènes qui fixent à la fois CTCF et SUMO et dont l’expression est régulée par les traitements. Dans la dernière partie de ce travail, nous avons étudié le groupe de 19 protéines dont la SUMOylation augmente suite aux traitements génotoxiques. Parmi ces protéines, nous avons trouvé diverses protéines centromériques, y compris CENP-B et CENP-C. En utilisant le PLA (Proximity Ligation Assay) nous avons pu montrer que CENP-B et CENP-C colocalisent avec SUMO et yH2AX après traitement. Cela suggère que la SUMOylation des protéines centromériques se produit sur les sites de cassure et pourrait jouer un rôle dans la réparation des dommages de l'ADNAcute Myeloid Leukemias (AML) are a group a severe hematological malignancies, which treatment is generally composed of two genotoxics: Cytarabine (Ara-C) and Daunorubicin (DNR). We have shown that these drugs induce the rapid deconjugation of the Small Ubiquitin-related Modifier (SUMO) from its target protein. This is due to the inactivation of SUMO E1 and E2 enzymes by Reactive oxygen species (ROS). This deSUMOylation participated in the activation of specific genes and is involved the induction of apoptosis. In addition, this ROS/SUMO axis is anergized in chemoresistant AMLs. However, it can be reactivated by pro-oxidants or inhibition of the SUMO pathway with anacardic acid, an inhibitor of the SUMO E1. To identify which proteins are regulated by this ROS/SUMO axis, we performed a quantitative mass spectrometry approach. Among the 1000 identified SUMO targets, most of the 114 proteins, which SUMOylation decrease upon treatment, are involved in the regulation of gene expression. In addition, we showed by ChIP-Seq with SUMO-2 antibodies that genotoxics, in particular DNR, induce a massive decrease of the presence of SUMOylated proteins on the chromatin. Motif search analysis of the SUMO binding sequences in these genes identified CTCF binding motif. Interestingly, CTCF was found in the SILAC as deSUMOylated by the drugs. Using publicly available ChIP-Seq data for CTCF, we found 55 genes which are occupied by both SUMO-2 and CTCF and which expression is regulated by the drugs. In the last part of this work, we got interested in the 19 proteins that get up-SUMOylated upon treatment. Among them, we found centromeric proteins, including CENP-B and CENP-C. Using Proximity Ligation Assay, we could show that CENP-B and CENP-C colocalize with both SUMO and yH2AX upon DNR treatment. Altogether, this suggests that centromeric protein up-SUMOylation occurs at sites of DNA damage and might play a role in DNA damage repair
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Li, Hubo. « Genome-Wide RNAi Screens for Novel Regulators of Acute Myeloid Leukemia ». Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:14226105.
Texte intégralRésumé :
Acute myeloid leukemia (AML) is a heterogeneous disease with complex molecular mechanisms. Recent advent of genomic technologies, such as copy number profiling, whole genome sequencing, and gene expression profiling has accumulated a plethora of large-scale data in AML cell lines and patient samples. However, the functional relevance of most genes identified by these methods has yet to be determined. To systematically characterize the genetic requirement in AML, we conducted genome-wide shRNA screens in 17 AML cell lines in parallel with 199 cell lines of other cancer types. We identified over 150 genes that were required for proliferation specifically by AML, but not other cancer cell lines. We further interrogated the requirements of primary screen hits in vivo with a secondary screen in a xenotransplantation model driven by the MLL-AF9 oncogenic fusion. Integrating both of the RNAi screens and additional gene expression data, we identified transcription factor ZEB2 as a top candidate for regulating AML proliferation. In human AML cells, ZEB2 inhibition impairs proliferation and promotes granulocytic differentiation. Mechanistically, we showed that ZEB2 interacts with the CtBP co-repressor complex, and transcriptionally represses genes involved in cell adhesion and migration. ZEB2’s relevance in AML is further demonstrated by its overexpression in MLL-rearranged AML, and by the epigenetic silencing of its negative regulators, miR-200 family microRNAs, in AML. Our results extend the role of ZEB2 beyond regulating epithelial-mesenchymal transition, and establish ZEB2 as a novel regulator of AML proliferation and differentiation.
MicroRNA-like off-target effect is a major caveat of RNAi screens, which often leads to false positive discoveries. However, systematic analysis of off-target effects in large-scale RNAi screen data can also lead to the discovery of microRNAs with functional relevance. By analyzing the off-target effects in our AML screen, we identified several microRNAs as candidate suppressors for AML proliferation. We show that miR-105, miR-140, miR-501, and miR-532 are novel regulators of the myeloid oncogene MYB. In particular, miR-105 inhibits AML cell growth and miR-532 is associated with myeloid differentiation. The combination of the ZEB2 and microRNA work emphasizes the power of RNAi screens in the exploration of novel cancer regulators.
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Mingay, Matthew. « Vitamin C induced epigenomic remodelling in IDH1 mutant acute myeloid leukemia ». Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/61020.
Texte intégralRésumé :
The genomes of myeloid malignancies are characterized by epigenomic abnormalities. Heterozygous, inactivating TET2 mutations and neomorphic IDH mutations are recurrent and mutually exclusive in acute myeloid leukemia genomes. Ascorbic Acid (vitamin C) has been shown to stimulate the catalytic activity of TET2 in vitro and thus we sought to explore its effect in a leukemic model expressing IDH1R132H. Vitamin C treatment induced a reduction in cell proliferation and an increase in the expression of genes involved in leukocyte differentiation in IDH1R132H expressing cells. Genome-wide assessment of 5mC and 5hmC revealed a set of vitamin C induced differentially methylated regions (DMRs), many of which displayed demethylation at myeloid enhancers and regions containing binding elements for the hematopoietic transcription factors RUNX1 and PU.1. We observed a significant loss of PU.1 DNA binding and an increase of RUNX1 binding that was accompanied by demethylation at RUNX1 binding sites within enhancers. Genome-wide profiling of histone modifications revealed a negative correlation between H3K4 methylation and DNA methylation at vitamin C induced DMRs. In addition, vitamin C induced an increase in H3K27ac flanking sites bound by RUNX1. Taken together our results suggest that vitamin C is able to stimulate epigenetic remodelling of transcription factor binding sites and regulatory elements to drive differentiation in a leukemic model.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
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Askew, David Stephen. « Characterization of novel myeloid differentiation antigen associated with acute myelogenous leukemia ». Thesis, University of British Columbia, 1985. http://hdl.handle.net/2429/26768.
Texte intégralRésumé :
A monoclonal antibody has been developed that detects a unique cell surface antigen (NHL-30.5) with a molecular weight of 180,000 expressed on the human acute promyelocytic cell line HL-60. In addition to HL-60 and other AML cell lines, the antibody reacts with a significant proportion of hemopoietic cells from 40/48 patients with acute myeloid leukemia (AML), and on a variety of other hematologic disorders characterized by the presence of immature myeloid blast cells. In contrast it does not react with normal mature hemopoietic cells, including lymphocytes, monocytes, granulocytes, erythrocytes, platelets, and splenocytes. Only one of 15 acute lymphoblastic leukemias has demonstrated reactivity (weakly) and all lymphoid cell lines tested have been uniformly negative. Reactivity with cells from patients in the chronic phase of chronic myeloid leukemia (CML) is also rare (7/26) and the number of NHL-30.5 positive cells is low (<20%). The acute phase of CML is strongly NHL-30.5-positive if the blast crisis is of the myeloid variant but is clearly negative in lymphoid blast crisis.
Analysis of normal differentiating bone marrow cells and mature peripheral blood mononuclear cells stained indirectly with the NHL-30.5 monoclonal antibody and FITC-second antibodies did not reveal a distinctly positive population. However, the cells with the highest fluorescence intensities (comprising 5% of the total population) sorted on a fluorescence activated cell sorter were highly enriched in both erythropoietic (CFU-E/BFU-E) and granulopoietic (CFU-C) progenitors. It therefore appears that the NHL-30.5 antigen is not an AML-associated marker but rather a normal myeloid differentiation antigen that is expressed on immature myeloid cells. Consistent with this hypothesis is the observation that a number of AML- derived cell lines that are blocked at an early stage of maturation lose NHL-30.5 expression when they are induced to terminally differentiate. These results support the concept that undifferentiated myeloid progenitors accumulate in AML patients due to a block in their capacity to differentiate into the stages characterized by loss of the NHL-30.5 antigen. The NHL-30.5 monoclonal antibody identifies a previously undescribed progenitor cell antigen and is potentially a useful reagent to differentiate myeloid leukemias from lymphoid leukemias, particularly in the acute phase of CML.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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Conrad, David Paul. « Development of Vesiculovirus-based Therapeutics for Acute Leukemia ». Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31743.
Texte intégralRésumé :
Outcomes for most patients with acute leukemia remain dismal. In-vitro, vesiculovirus members induced rapid apoptosis of acute leukemia cells. Intravenous injection of lymphoblastic leukemia cells infected ex-vivo with attenuated Vesicular Stomatitis Virus or Maraba Virus followed by gamma-irradiation, controlled leukemic progression in murine recipients. Essential properties of this autologous vaccine [immunotherapy by Leukemia-Oncotropic Virus (iLOV)] and the host’s immune system were characterized. iLOV durability was restricted to the leukemia used to manufacture the vaccine. At administration, virion cell-entry was required but vesiculovirus lifecycle completion was not essential. Apoptotic or necrotic leukemia cells, with/without co-injection of virus, were ineffective vaccines. Similarly ineffective were leukemia cells activated by, or injected with, Toll-like receptor agonists. Naïve recipients of adoptive splenocyte transfer from vaccine-treated immunocompetent donors were protected from leukemic challenge. Efficacy was notably diminished following matched allogeneic bone marrow transplantation; this correlated with isolated depletion of cytotoxic T-cells. iLOV was ineffective in athymic mice. Taken together, iLOV therapy relies on immediate spaciotemporal interactions between infected-dead/dying leukemia cells and the immune system; this promotes adaptive anti-tumor responses. Clinical translation could target patients in remission to control relapse.
During the above I discovered that under specific conditions, live vesiculovirus exposed to a precise window of UV fluence reproducibly generates unique “non-replicating rhabdovirus-derived particles” (NRRPs) that maintain cell-entry and cytopathic properties. A gamut of leukemia cells, including multidrug-resistant blasts, underwent rapid NRRPs-induced apoptosis. Normal cell lines and healthy bone marrow mononuclear cells were resistant, in part through interferon-mediated signaling responses. Administering NRRPs intravenously was curative in a murine acute leukemia model, versus uniform disease progression using maximal tolerated dose of replicating virus. Serum levels of an array of immunomodulatory cytokines were significantly elevated after injection of NRRPs. iLOV prepared with NRRPs protected recipients from otherwise lethal leukemia. Intracranial administration of NRRPs proved nonlethal as opposed to neurotoxic live vesiculovirus. Following treatment, neutralizing antibodies were diminished with NRRPs compared to replicating virus. Together, NRRPs exhibit enhanced therapeutic index over replication-competent vesiculovirus. Leukemocidal activity of NRRPs is exerted through a plurality of immune-related and direct cytotoxic effects. This novel approach now extends vesiculovirus-based therapeutics into upfront treatment for acute leukemia.
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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.
Texte intégralRésumé :
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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Dorrance, Adrienne M. « The role of the partial tandem duplication of the MLL (MLL PTD) in leukemogenesis ». Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1203712889.
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Gudgin, Emma-Jane. « Integrated epigenetic and genetic analysis of transcriptional dysregulation in acute myeloid leukaemia ». Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608093.
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Mak, Wan-ling Justina Crystaline, et 麥允齡. « The effects of a methionine aminopepitdase inhibitor fumagillin on leukemia cell growth in-vitro ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193534.
Texte intégralRésumé :
Acute Myeloid Leukaemia (AML) is a disease normally found in elderly patients, with the median age of presentation at about 68 years. At this age, many of the patients are frail and unlikely to respond well to intensive chemotherapy treatments. Conventional chemotherapy eradicates the proliferating leukaemic progenitors while leaving the quiescent leukaemic stem cells undisturbed. These quiescent LSCs are able to then bring about leukaemic relapse. Fumagillin is a natural metabolite from Asperigillus fumigatus that is generally used as an anti-microbial agent but it is also known to bind to intracellular MetAP-II and inhibit endothelial cell growth. Many cancers are found to have an over expression of MetAP-II.
In the past, MetAP-II inhibitors have been tested and shown success in angiogenesis inhibition and tumor reduction. The aim of this study is to observe whether methionine aminopeptidase-2 inhibitors can be used in the treatment of acute myeloid leukemia. The investigation included a dose response comparison of various AML cell lines to fumagillin treatment, cell proliferation assay, a colony forming unit assay, and cell cycle analysis of KG-1 cells following three days of fumagillin treatment. I have determined that fumagillin does indeed decrease the cellular proliferation of KG-1 in vivo and at 10μM, prevents colony formation in methylcellulose plating. There is an increase in cells found in the sub-G1 phase with fumagillin treatment, as analyzed by flow cytometry. It is interpolated that fumagillin treatment increases AML cell apoptosis, in addition to hindering its ability to grow in culture.published_or_final_version
Medicine
Master
Master of Medical Sciences
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Xiao, Kang. « Investigating the functional roles of Mcl-1 in apoptosis in mammalian cells / ». View abstract or full-text, 2009. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202009%20XIAO.
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Vangala, Rajani Kanth. « AML1/ETO Downregulates the Transcription Factor PU.1 in Acute Myeloid Leukemia ». Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-10271.
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