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1
Schmidt-Mende, Jan Georg. "Bone marrow apoptosis in myelodysplastic syndromes." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=96939781X.
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Shinde, Sneha. "Role of EZH2 in myelodysplastic syndromes." Thesis, King's College London (University of London), 2015. https://kclpure.kcl.ac.uk/portal/en/theses/role-of-ezh2-in-myelodysplastic-syndromes(323849bf-af95-47e6-8b6d-3393585bfe87).html.
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Occurrence of mutations in the Polycomb (PcG) gene; EZH2 (Enhancer of Zeste Homologue 2) represent a new class of molecular lesions associated with instability in the epigenome of patients with Myelodysplastic Syndrome (MDS). Detection of microdeletion at 7q36.1 or 7q Copy Neutral Loss of Heterozygosity [CN (LOH)] led to the identification of EZH2 mutations. EZH2 is the catalytic component of Polycomb Repressive Complex 2 (PRC2) that trimethylates lysine 27 of histone 3 (H3K27) resulting in gene silencing and recruitment of the sister complex i.e. Polycomb Repressive Complex 1 (PRC1) to target genes. Discovery of EZH2 mutations have shed light on the involvement of other PcG and PcG interacting proteins i.e. Jumonji (jmj) family of demethylases and DNA methyltrasferase 3A (DNMT3A) in MDS. Investigation of Single Nucleotide Polymorphism (SNP) array abnormalities and mutational analysis of these genes have not been ascertained and therefore I examined cytogenetic aberrations affecting twelve Polycomb (PRC1) and seventeen Jumonji genes using high density SNP 6 arrays. SNP6 data analyzed in this study was generated by our group for previous research projects. I visualised this data using CHromosome Analysis Suite (Chas) from Affymetrix and identified five PRC1 genes (BMI1, PHC1, PHC2, RING1A and RING1B) in 17/91 (19 %) patients with either Copy Number Variations (CNVs) like deletions or amplifications or CN (LOH). Interestingly, the frequency of SNP6 aberrations was high (two times) in Jumonji genes as compared to PRC1. 29/91 patients (31 %) showed either CNVs or CN (LOH) in fifteen (JMJD3, JMJD4, JMJD1B, JMJD2A, JARID2, JMJD1C, JARID1B, JMJD2C, UTX, JARID1C, JARID1A, JMJD2D, JHJD1A, JARID1D and JHJD1B) Jumonji genes. Mutational analysis of patients with SNP6 aberrations was carried out using Sanger or 454 sequencing but no mutations were detected in either the PRC1 or Jumonji genes. To elucidate changes in gene expression as a result of amplification or deletion of genomic material, qPCR was performed on 22/29 patients for thirteen Jumonji genes. Gene expression of JARID1A, JARID1C and UTX were modulated concomitant to the CNVs. Deletion of JARID1A locus was associated with reduced gene expression (p value < 0.0001) in two patients while trisomy of JARID1C (n=1) and UTX (n=2) were associated with increased expression (p value < 0.0001) of both the genes. Mutational analysis of PRC2 core components (SUZ12, EED, EZH1) and DNMT3A was carried out in a cohort of 61 MDS patients previously sequenced by our group for EZH2 mutations to examine their mutational overlap. 10/61 patients had heterozygous DNMT3A mutations (clone size 20-44 %) with two patients showing mutations at the R882 site. Interestingly, these mutations were seen predominantly (n= 6) in patients with monosomy 7/del 7q however only one patient had both DNMT3A (R882H) and EZH2 (V626M) mutations suggesting that there is no specific association between mutations of the two genes. In contrast, PRC2 genes were not mutated in this cohort emphasizing the importance of EZH2 mutations alone in MDS pathogenesis. Therefore I examined the functional consequences of the commonly occurring EZH2 (R690C/R690H) and DNMT3A (R882H) mutations in myeloid cell lines. To achieve this, numerous attempts were made to clone DNMT3A R882H mutation into p3XFLAG-myc-CMV-26 to allow transfection and in vitro assessment of the mutant in myeloid cells but all attempts to ligate the plasmid failed and therefore work on DNMT3A was discontinued. EZH2 (R690C/R69H) and Flag tagged wild type EZH2 were constructed in p3XFLAGmyc- CMV-26 vector using a PCR based cloning strategy and transfected into K562 cells. Western blot analysis at 72 hr post transfection, showed elevated levels of both R690C/R690H mutants and Flag tagged wild type EZH2 but no alterations in its target H3K27me3 levels. Affymetrix Human Transcriptome 2.0 gene expression profiling was used to identify modulation of gene signature as result of elevated EZH2 levels and MLLT10 gene was found to be up regulated in cells transfected with Flag-tagged wild type EZH2 (2.3 fold) as well as R690C/ R690H (3.6 – 4.6 fold) mutants. In contrast, PML (promyelocytic leukaemia) (2.16 fold) and FANCL (Fanconi Anaemia, Complementation Group L) (2.18 fold) genes were up regulated exclusively in cells over expressing the Flag tagged wild type EZH2. To compare this gene signature to gene expression changes as a result of EZH2 knock out (KO), shRNA mediated inhibition of EZH2 was carried out in myeloid cells and 95 % KO of both EZH2 and H3K27me3 levels were observed at Day 7 post transduction. Microarray gene expression profiling identified BCL2 (-2.14 fold), FLT1 (-4.03 fold), HOXA10 (-2.2 fold), CD44 (-8.2 fold), CD83 (-2.1 fold), TLSP (-3.24 fold), IFI16 (-3.11 fold) and PAG1 (-3.37 fold) inhibition in cells transduced with shRNA against EZH2 compared to the scrambled and wild type K562 cells. There were no overlapping genes in K562 cells with EZH2 KO and EZH2 mutants R690C/R690H. The differences in expression profiling could be due to the difference in H3K27me3 levels modulated by EZH2. Comparison of gene signature obtained by EZH2 KO on patient samples carrying the R690H mutation, showed contrasting results i.e. up regulation of HOXA10, FLT1, PAG1B, EZH1 and TLSP compared to patients with wild type EZH2 suggesting that EZH2 R690C/R690H mutants do not mimic the transcriptional changes seen in EZH2 KO. This strongly suggests the presence of other mechanisms to compensate for the loss of EZH2 in myeloid cells. However the results obtained here should be examined in additional other myeloid cell lines to validate the findings obtained in K562 cells.
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Abrahamson, Gail Mathilde. "The molecular genetics of the myelodysplastic syndromes." Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293790.
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梁杏媚 and Hang-mei Polly Leung. "Cellular and molecular aspects of myelodysplastic syndromes." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1994. http://hub.hku.hk/bib/B31211628.
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Leung, Hang-mei Polly. "Cellular and molecular aspects of myelodysplastic syndromes /." [Hong Kong : University of Hong Kong], 1994. http://sunzi.lib.hku.hk/hkuto/record.jsp?B13781455.
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Lord, Allegra. "Epigenetics of TET2 Loss in Myelodysplastic Syndromes." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17467483.
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Myelodysplastic syndromes (MDS) are a class of myeloid malignancy characterized by peripheral blood cytopenias and impaired hematopoietic differentiation. Our understanding of the molecular basis of MDS has improved enormously in recent years due to clinical research efforts to characterize the spectrum of acquired mutations found in patients. This work has revealed that mutations in TET2 are common lesions in MDS and other myeloid malignancies. TET2 function has only recently been elucidated: TET proteins convert 5’-methylcytosine (mC) first to 5’-hydroxymethylcytosine (hmC), apparently the first step in an active DNA demethylation program that leads to the replacement of 5-mC with unmodified cytosine. My thesis work focuses on a characterization of TET2 loss on DNA methylation, and on how TET2 mutations impact patient response to treatment with hypomethylating agents.
We examined DNA methylation in a matched set of TET2-WT and -mutant MDS samples, and found that loss of TET2 results in global hypermethylation. This global increase is due to gains in intragenic methylation, specifically localized to intron-exon boundaries. We then used clonal TF1 cell lines with CRISPR/Cas9-engineered TET2 mutations to examine global DNA hydroxymethylation. Loss of TET2 results in a global loss of 5-hmC. By aligning our methylation data with hydroxymethylation data from TET2-WT cells, we were able to identify direct TET2 targets. Because changes in mC/hmC with loss of TET2 appeared to localize to intron-exon boundaries, we investigated the effect of aberrant methylation on mRNA splicing in our TF1 cell system. TET2 loss resulted in an overall increase in exon skipping, consistent with published data on the effect of methylation on splicing, and hypermethylated regions were enriched for alternate splicing events. These findings suggest that the alterations in hematopoietic differentiation seen in TET2-mutant models are due to shifts in the expression of different mRNA isoforms rather than wholesale changes in gene expression. Our data show that loss of TET2 function results in region-specific gains in DNA methylation, and that these alterations affect mRNA splicing by promoting exon skipping. Finally, we have found that presence of TET2 mutations are positively associated with response to HMA therapy.Medical Sciences
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Williams, Jenna. "The characterisation of telomere dynamics in Myelodysplastic syndromes." Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/56965/.
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The Myelodysplastic syndromes (MDSs) are comprised of a heterogeneous group of clonal disorders characterised by ineffective haematopoiesis. Although 30 to 35% of MDS cases progress to Acute Myeloid Leukaemia (AML), the majority of patients die from blood related ailments caused by progressive bone marrow failure. Large-scale genomic rearrangements are a key feature of MDS, with different aberrations conferring specific risks of progression. Telomere erosion, dysfunction and fusion, creating cycles of anaphase bridging breakage and fusion is a mechanism that has the potential to drive genomic instability in many tumour types including MDS. The key aim of this project was to examine the role that telomere dysfunction may play in the generation of genomic rearrangements observed in MDS/AML. High resolution Single Telomere Length Analysis (STELA) revealed telomere shortening when compared to age-matched individuals in two cohorts of MDS and AML patients; this included large-scale telomeric deletion events observed within the MDS cohort. A PCR based telomere fusion assay detected telomere-telomere fusion events at a frequency that was consistent with sporadic fusion arising as a consequence of large-scale deletion. Telomerase activity was up-regulated in AML which may contribute to the reduction of deletion and fusion events in these cells. Sequence analysis revealed that telomere fusion was associated with microhomology and sub-telomeric deletion; this profile was consistent with error-prone Ku-independent alternative end joining processes. Telomere length at diagnosis irrespective of conventional markers appeared to influence the overall survival of MDS patients, but this was not apparent in AML. More importantly, telomere length was able to refine favourable prognostic markers, specifically good risk cytogenetics, uni-lineage cytopenia and low-risk IPSS (International Prognostic Scoring System) scores of which MDS patients bearing shorter telomeres for their respective age displayed reduced overall survival. This may be a particularly important finding given the heterogeneous clinical outcomes observed within low-risk MDS patients.
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Machado, Diogo Alcino de Abreu Ribeiro Carvalho. "Myelodysplastic Syndromes - Therapeutic options in high-risk patients." Dissertação, Instituto de Ciências Biomédicas Abel Salazar, 2009. http://hdl.handle.net/10216/52785.
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Machado, Diogo Alcino de Abreu Ribeiro Carvalho. "Myelodysplastic Syndromes - Therapeutic options in high-risk patients." Master's thesis, Instituto de Ciências Biomédicas Abel Salazar, 2009. http://hdl.handle.net/10216/52785.
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Seal, Sudeshna. "Role of Flice inhibitory protein (FLIP) in myelodysplastic syndromes /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/8632.
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Tehranchi, Ramin. "Apoptosis in myelodysplastic syndromes : effects of hemopoietic growth factors /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-045-1/.
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Pradhan, Anjala Vinayak. "Genes differentially expressed in adult familial myelodysplastic syndromes (MDS)." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418063.
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Chowdhury, Onima. "Characterisation and targeting of stem cells in myelodysplastic syndromes." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:741c2079-c6b3-46dc-b4d2-5708693e6cb3.
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Understanding which cells within a cancer are responsible for its initiation and propagation is vital if we are to achieve cure. If cancer stem cells are the only population able to sustain a tumour long term, designing therapeutic strategies to target this population will give medical science the best chance of long-term cure. Significant controversy remains over the existence of cancer stem cells, predominantly due to the lack of a sensitive human cancer stem cell assay. This thesis investigates whether two haematological malignancies, myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) can only be driven by rare and distinct cancer stem cells. We have demonstrated that low and intermediate-1 risk MDS is driven solely by the stem cell (Lin- CD34+ CD38- CD90+ CD45RA-) by developing a novel genetic approach, tracing all somatic mutations and karyotypic abnormalities back to this population. Prior to this study, very little was known about the clonal architecture of CMML. By performing detailed phenotypic, functional, molecular and genetic analysis of patients with CMML, we were able to demonstrate that the most likely candidate driver cell in these patients was also the stem cell rather than any of the down-stream progenitors. Currently, effective therapeutic strategies for MDS or CMML are very limited. Allogeneic stem cell transplantation is the only potential cure and not suitable for most patients. Cancer stem cells, including MDS stem cells are known to be highly quiescent and selectively resistant to therapy. Having demonstrated that both MDS and CMML were driven by stem cells, we developed a novel therapeutic targeting strategy. Using the thrombopoietin receptor agonist, Romiplostim, we were able to activate stem cells and enhance their subsequent sensitivity to chemotherapy dramatically. This approach may facilitate improved remission rates and prevent cancer stem cell driven relapse in many diseases.
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Schmidt-Mende, Jan Georg. "Apoptosis in the myelodysplastic syndromes : protective effect of G-CSF/." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-471-6/.
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Palau, de Miguel Anna. "Polycomb Repressive Complex 1 functions in differentiation and myelodysplastic syndromes." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/400293.
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Polycomb proteins are important epigenetic regulators involved in the maintenance of stemness and differentiation. In this thesis, I focused on the role of some Polycomb Repressive Complex 1 (PRC1) components. On the one hand, I studied the role of Cbx8 PRC1 component protein in the differentiation of mouse embryonic stem cells (mESCs). On the other hand, I analyzed the role of PRC1 components in a hematological disease-related context which implies a defect in differentiation, the myelodysplastic syndrome (MDS). Specifically, I focused on RING1A PRC1-component function in this disease.
Our previous data showed that upon addition of retinoic acid (RA) during 3 days to E14 mouse ESC cell line, by which cells were prompted into the neuronal lineage, Cbx8 was upregulated both at mRNA and protein level. We performed a genome-wide chromatin immunoprecipitation of endogenous Cbx8 coupled to direct massive parallel sequencing (ChIP-seq) to assess the binding sites of Cbx8 genome- wide using IgG and Cbx8 ChIP in untreated mESC as negative controls. Our analysis identified 171 high confidence peaks. To our surprise, by crossing our data with previously published microarray analysis, we showed that several differentiation genes transiently recruit Cbx8 during their early activation. Depletion of Cbx8 by 2 different shRNA partially impaired the transcriptional activation of these genes as well as diminish Cbx8 recruitment to its target genes. Both interaction analysis, as well as chromatin immunoprecipitation experiments supported the idea that activating Cbx8 acts in the context of an intact PRC1 complex. Prolonged gene activation resulted in eviction of PRC1 despite persisting H3K27me3 and H2A ubiquitination. The composition of PRC1 is highly modular and changes when embryonic stem cells commit to differentiation. We further demonstrated that the exchange of Cbx7 for Cbx8 is required for the effective activation of differentiation genes. Taken together, our results establish a function for a Cbx8-containing complex in facilitating the transition from a Polycomb- repressed chromatin state to an active state.
In order to characterize the function of PRC1 in the pathogenesis of MDS we used publicly available expression datasets of PRC1 components from MDS patients and during normal myeloid differentiation to identify and quantify the level of relevant PRC1 complexes. From this data mining we selected four PRC1 components (CBX6, BMI1, RING1A and CBX7) and two PRC2 components (EZH2 and ASXL1) for further analysis. To study these PRC components we wished to use cell lines that are MDS-related. For this reason, we extensively characterized 5 MDS/AML derived cell lines by conventional cytogenetics, single nucleotide polymorphism arrays, mutational panel of 83 MDS/AML relevant genes and immunoprofile. After this study, we selected SKK-1 cell line as the most suitable model to study the function of the selected PRC1 components. Based on the finding that RING1A is highly expressed in hematopoietic stem cells and further overexpressed in patients with high risk MDS, we have analyzed the role of RING1A in cells. We found that RING1A inhibits differentiation in MDS-derived AML cells and in primary human hematopoietic stem cells (HSCs). We further provide first evidence that pharmacological inhibition of RING1A could be therapeutic strategy by showing that the treatment of HSCs favors differentiation.Les proteïnes Polycomb són importants reguladors epigenètics implicats en el manteniment de la pluripotència i la diferenciació. En aquesta tesi, m'he centrat en el paper d'alguns components del Polycomb Repressive Complex 1 (PRC1). D'una banda, he estudiat el paper de la proteïna Cbx8, component del PRC1, en la diferenciació de les cèl·lules mare embrionàries de ratolí (mESCs). D'altra banda, he analitzat el paper dels components del PRC1 en un una malaltia hematològica que implica un defecte en la diferenciació, la síndrome mielodisplàstica (SMD). En concret, m'he centrat en la funció de RING1A, component del PRC1, en aquesta malaltia. Les nostres dades anteriors van mostrar que després de l'addició d'àcid retinoic (RA) durant 3 dies a la línia cel·lular de mESCs Cbx8 es sobreexpressava, tant a nivell d'ARNm com de proteïnes. Vam realitzar una immunoprecipitació de cromatina del Cbx8 endogen a nivell de tot el genoma seguit de seqüenciació massiva (ChIP-seq) per avaluar els punts d'unió de Cbx8 en tot el genoma utilitzant els ChIPs IgG i Cbx8 de mESC sense tractar com a controls negatius. La nostra anàlisi va identificar 171 pics d'alta confiança. Sorprenentment, en creuar les nostres dades amb l'anàlisi de microarrays publicat prèviament, es va demostrar que diversos gens de diferenciació transitòriament recluten Cbx8 durant la seva activació primerenca. El knockdown de Cbx8 per 2 shRNA diferents va afectar parcialment l'activació transcripcional d'aquests gens, així com va disminuir el reclutament de Cbx8 als seus gens diana. Tant l’anàlisi d'interacció per espectrometria de masses com els experiments de immunoprecipitació de la cromatina van donar suport a la idea que l'activació de Cbx8 actua en el context d'un complex PRC1 intacte. L’activació gènica prolongada va resultar en l’expulsió de PRC1 amb un H3K27me3 i H2AK119ub persistents. La composició del PRC1 és altament modular i canvia quan les cèl·lules mare embrionàries es diferencien. A més, vam demostrar que es requereix l'intercanvi de Cbx7 per Cbx8 per a l'activació efectiva dels gens de diferenciació. En conjunt, els nostres resultats estableixen una funció per a un complex que conté Cbx8 a l'hora de facilitar la transició d'un estat de cromatina reprimida per Polycomb a un estat actiu. Per tal de caracteritzar la funció de PRC1 en la patogènesi de SMD vam utilitzar dades d’expressió públicament disponibles de pacients amb SMD i durant la diferenciació mieloide normal per tal d’identificar i quantificar el nivell dels components de PRC1. A partir d'aquesta anàlisi es van seleccionar quatre components del PRC1 ( CBX6, BMI1, RING1A i CBX7) i dos components del PRC2 (EZH2 i ASXL1) per al seu posterior estudi. Vam decidir treballar amb línies cel·lulars relacionades amb MDS per tal d’estudiar aquests components PRC. Per aquesta raó, hem caracteritzat àmpliament 5 línies cel·lulars de leucèmia mieloide aguda (LMA) derivades de síndromes mielodisplàstiques (SMD) per citogenètica convencional, single nucleotide polymorphism arrays, un panell mutacional de 83 gens relacionats amb SMD /LMA i immunofenotip. Després d'aquest estudi, vam seleccionar la línia cel·lular SKK-1 com el model més adequat per estudiar la funció dels components PRC1 seleccionats. Basant- nos en la troballa que RING1A està altament expressat en cèl·lules mare hematopoètiques i a més es sobreexpressa en pacients de SMD amb alt risc, hem analitzat la funció de RING1A. Vam trobar que RING1A inhibeix la diferenciació de la línia cel·lular de SMD/LMA i en cèl·lules mare hematopoètiques primàries. Proporcionem a més la primera evidència que la inhibició farmacològica de RING1A podria ser una estratègia terapèutica ja que el tractament en cèl·lules mare hematopoètiques afavoreix la diferenciació.
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Montoro, Gómez Mº Julia. "Improvement strategies for the prognostic evaluation of myelodysplastic syndromes patients." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/668204.
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Los síndromes mielodisplásicos (SMD) suponen un grupo heterogéneo de enfermedades mieloides con diferentes manifestaciones clínicas y pronósticos que van desde pacientes asintomáticos y con una expectativa de vida larga, hasta aquellos con citopenias severas y un riesgo incrementado a evolucionar a una leucemia mieloide aguda. El tratamiento de estos pacientes se ha basado en el IPSS (International Prognostic Scoring System), siendo conservador en aquellos pacientes de bajo riesgo: IPSS bajo e intermedio-1 (IPSS < 1.5 puntos), e intensivo en los SMD de alto riesgo: intermedio-2 y alto (IPSS > 1.5 puntos). Por lo tanto, una valoración adecuada del pronóstico en los pacientes con SMD en fundamental. La presencia de enfermedades autoinmunes (EA) ha sido descrita en los SMD, sin embargo, la incidencia y el impacto pronóstico de las EA en estos pacientes es desconocida. Por otra parte, recientemente se ha publicado el IPSS revisado (IPSS-R), en el cual el punto de corte que mejor divide a los pacientes en alto y bajo riesgo se desconoce. Con todo lo anterior, en el primer trabajo hemos analizado la prevalencia, las características clínicas y el impacto pronóstico de las EA en los pacientes con SMD, y hemos demostrado que la presencia de las EA es frecuente en los SMD y, lo que es más importante, confieren un impacto pronóstico adverso en estos pacientes. En el segundo trabajo, hemos analizado cuál es el punto de corte del IPSS-R que mejor estratifica a los SMD en pacientes de alto y bajo riesgo, siendo el punto de corte de 3 puntos el más adecuado. De acuerdo a nuestros resultados, los pacientes con SMD y EA y aquellos con un IPSS-R > 3 puntos, deberían considerarse de alto riesgo y por lo tanto considerarlos candidatos a recibir tratamientos intensivos.Myelodysplastic syndromes (MDS) comprise a heterogeneous group of myeloid disorders with heterogeneous clinical manifestations and outcomes, ranging from those asymptomatic patients with long-life expectancy, to those with profound cytopenias and high risk of evolution to an acute myeloid leukemia. Treatment options have been based on risk prognostic stratification according to the International Prognostic Scoring System (IPSS), being conservative in the low-risk group: IPSS low and intermediate-1 (IPSS < 1.5 points), whereas intensive in the high-risk group: intermediate-2 and high (IPSS > 1.5 points) patients. Therefore, a proper prognostic assessment is mandatory in MDS. Autoimmune disorders (AD) have been described in MDS, however, its real incidence and prognostic effects in these patients are not completely understood. Moreover, a revised IPSS (IPSS-R) has been recently published and which is the best cut-point that stratifies patients into low and high-risk group has not been established. Against this background, in the first work we have analyzed the prevalence, clinical characteristics and outcomes of AD in MDS patients, and we have demonstrated that AD are a common feature in MDS and what is more important, present a worse prognostic impact in these patients. In the second work, we have analyzed in a large cohort of MDS patients which is the best IPSS-R threshold that divides MDS in low vs high-risk groups, being 3 points the best cut-point. According to our results, MDS with AD and those with an IPSS-R > 3 points should be considered as high-risk patients and therefore considered treatment with intensive regimens.
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Champion-Suntharalingam, K. M. "Aspects of molecular analysis in myeloproliferative disorders and myelodysplastic syndromes." Thesis, Anglia Ruskin University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342919.
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Stenson, Laura. "Unravelling haematopoietic stem cell dysfunction in isolated Del(5q) myelodysplastic syndromes." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:5eab7859-53fa-4a55-a04c-eecc3ca19a7e.
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Myelodysplastic syndromes (MDS) represent a heterogeneous group of haematological malignancies. A subgroup of MDS patients are characterized by heterozygous deletion of the long arm of chromosome 5, Del(5q), as the only karyotypic abnormality. The commonly deleted region (CDR) on chromosome 5 contains approximately forty-two genes and haploinsufficiency of one or more of these genes is thought to be the basis for Del(5q) MDS pathogenesis. The 5q deletion originates in the Hematopoietic Stem Cell (HSC) compartment and Del(5q) HSCs have a clonal advantage, outcompeting healthy HSCs in the bone marrow of patients. Although they have a competitive advantage in situ, Del(5q) HSCs perform poorly in functional stem cell assays in vitro and in vivo. A mouse model of Del(5q) MDS, the Cd74-Nid67 model, carries a heterozygous deletion of eight genes located within the CDR. Cd74-Nid67 haploinsufficiency causes macrocytic anaemia and bone marrow dysplasia in mice. However, the impact of Cd74-Nid67 haploinsufficiency on HSC function has not previously been investigated. The results presented, herein, demonstrate that haploinsufficiency of Cd74-Nid67 has a significant impact on HSC self-renewal and repopulation potential. Furthermore, two genes within this region, Rps14 and Rbm22, are identified as likely candidates responsible for Cd74-Nid67 HSC dysfunction. Finally, we demonstrate that Cd74-Nid67 HSC dysfunction is driven by a P53-dependent mechanism. This study provides important insights into the mechanistic basis for disease development and propagation, which may facilitate the development of improved therapeutic avenues for Del(5q) MDS patients.
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Goulard, Marie. "The bone marrow microenvironment in myelodysplastic syndromes : functional and molecular study." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC302.
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Les syndromes myélodysplasiques (MDS) sont un groupe de pathologies myéloïdes caractérisées par une hématopoïèse inefficace. Le rôle du microenvironnement médullaire (MM) dans l’histoire naturelle de ces pathologies reste incertain. Des anomalies du MM ont été décrites au cours des myélodysplasies et des modèles murins récemment publiés font penser qu’une altération du MM pourrait jouer un rôle dans le déclenchement et/ou l’évolution de ces maladies.Nous avons tenté de développer un modèle in vivo récapitulant l’histoire naturelle des myélodysplasies par des xénogreffes chez des souris NSG et NSG-S. Le faible taux de prise de greffe nous a amenés à développer un modèle in vitro de co-culture en 2D. Ce modèle est une bonne alternative pour les études de nouvelles stratégies thérapeutiques pour les patients atteints de myélodysplasies.Au cours de ce travail, nous avons également réalisé une étude systématique du stroma médullaire de patients atteints de syndromes myélodysplasiques dans le but d’identifier les anomalies fonctionnelles et moléculaires des cellules souches mésenchymateuses (CSMs), cellules centrales du MM pour leur interaction avec les cellules souches hématopoïétiques (CSHs).Les CSMs de MDS ont une clonogénécité diminuée. Nous n’avons pas observé de modification significative de leurs capacités de différenciation en ostéoblastes, adipocytes et chondrocytes ni dans leur capacité à supporter une hématopoïèse normale. Les CSMs de MDS présentent des modifications au niveau épigénétique et transcriptionnel pouvant expliquer l’altération des relations observées grâce à de l’imagerie enregistrée entre les CSMs de MDS et les CSHs dans un modèle de co-culture en 3D.Ces résultats montrent que les CSMs de MDS ont des modifications fonctionnelles et moléculaires et que ces anomalies perturbent leur relation avec les CSHsMyelodysplastic syndromes (MDS) are a heterogeneous group of clonal myeloid pathologies characterized by an impaired hematopoiesis. The role of the bone marrow microenvironment (BMM) remains unclear in the natural history of these diseases. Abnormalities of the BMM have been observed in myelodysplasia and a recent published murine model implies that alterations of the BMM could play a role in the trigger/progression of these diseases.Firstly, we tried to develop an in vivo model of MDS in NSG and NSG-S mice. The low rate of engraftment pushed us to develop a 2D co-culture model in vitro. This model is a good alternative to test new therapeutic strategies for MDS patients.In this study, we analysed mesenchymal stromal cells (MSCs) from the bone marrow of pretreated MDS patients in order to identify the functional and molecular abnormalities in those cells of the BMM, central for their interactions with the hematopoietic stem cells (HSCs).MDS MSCs have an impaired clonogenic capacity. We didn’t observed modifications of their differentiation toward osteogenic, adipogenic and chondrogenic pathways and capacity to support of a normal hematopoiesis. MDS MSCs display epigenetic and transcriptomic modifications that could explain the alteration of the relationships between these cells and HSCs observed in imagery in a 3D co-culture model.These results showed that MDS MSCs have functional and molecular abnormalities and that these alterations could impair their relationship with HSCs
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Booth, Christopher. "Collaboration of Ezh2 and Runx1 inactivating mutations in malignant haematopoiesis." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:3f3b18b1-5875-42ed-b025-cf0dd457b99f.
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Extensive efforts have shed light on the identity and biology of cancer stem cells, required and sufficient for the propagation of hematological malignancies and solid tumours. Much less is understood about the closely related issue as to the identity and properties of the normal stem and progenitor cells targeted by oncogenic lesions, and how the nature of the targeted cell might impact on the biology and clinical picture of the resulting cancer. To address this, we developed a mouse model allowing targeted inactivation of Ezh2 and Runx1 to different haematopoietic compartments. Inactivating mutations of EZH2 and RUNX1 frequently co-occur in haematological malignancies with markedly different phenotypes including myelodysplastic syndrome (MDS) and early thymic progenitor (ETP) leukaemia. Inactivation of Ezh2 and Runx1 in adult haematopoietic stem cells (HSCs) resulted in perturbed haematopoiesis leading to development of an MDS-like disease. Unexpectedly, this MDS phenotype could be fully reproduced when Ezh2 and Runx1 inactivation was targeted to multipotent progenitors (MPPs) using Flt3-Cre. Furthermore, the disease was transplantable by MPPs, but not more committed progenitor populations, demonstrating that MDS tumour propagating potential is not exclusive to intrinsically self-renewing HSCs. Targeting Ezh2 and Runx1 inactivation to early lympho-myeloid progenitors did not result in an MDS phenotype. These mice showed a marked expansion of ETPs within the thymus, combined with a block in thymocyte differentiation. These expanded ETPs displayed transcriptional features characteristic of ETP leukaemia, a treatment-resistant acute leukaemia subtype hypothesised to originate from ETPs. Combination of inactivation of Ezh2 and Runx1 in ETPs with the constitutively activating Flt3-ITD signalling mutation resulted in an aggressive lympho-myeloid acute leukaemia, which could be propagated by the expanded ETP population. These findings demonstrate the potential of lympho-myeloid progenitors such as ETPs to become leukaemia stem cells which propagate a disease retaining lympho-myeloid features. We used this novel ETP leukaemia model to explore therapeutic targeting of Ezh2-inactivated ETP leukaemias using inhibitors of the bromodomain and extra terminal (BET) proteins. Aberrant transcription resulting from epigenetic changes induced by Ezh2 loss could be reversed by BET inhibitors, and these compounds showed therapeutic efficacy against both mouse and human ETP leukaemias in vitro and in vivo.
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Robu, Carmen Mariana. "Study of marrow microenvironment and focal adherences in myelodysplastic syndromes and leukemias." Phd thesis, Université Jean Monnet - Saint-Etienne, 2012. http://tel.archives-ouvertes.fr/tel-00955168.
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Myelodysplastic syndromes (MDS) are regarded as clonal disorders of haematopoietic stem cells (HSC). Recent evidence demonstrates that stromal microenvironment, in addition to HSC defects, plays a particular role via its direct contact with haematopoietic precursor cells (HPC). This thesis aims at evaluating the putative growth deficiencies of mesenchymal stromal cells (MSC) from MDS individuals compared with normal controls, exploring their adhesion profile, assessing the adhesion process-involved molecular substrates, and establishing correlations with their growth patterns and HPC dysfunctions. Functional assays revealed that MSC from MDS are intrinsically pathological, show a continuous decline of proliferation over a 14-day culture and a reduced clonogenic capacity in the absence of signals from HPC. MSC growth defects significantly correlate with decreased CD44 and CD49e expression. Moreover, stroma-dependent adhesion mechanisms control HPC clonogenic potential and CD49e might be one of the molecules involved in this process. Qualitative and quantitative abnormalities of focal adhesion (FA) proteins paxillin and pFAK [Y397] and of two regulatory proteins, HSP90αβ and p130CAS were identified via immunofluorescence analysis. Paxillin, pFAK [Y397] and HSP90αβ increased expression, besides its stronger nuclear colocalization in MSC from RAEB correlates with a consistent proliferative advantage and has a negative impact on HPC clonogenic capacity. These results open interesting opportunities, e.g. HPC-to-MSC interactions involve FA proteins signalling, and, as FAK is an HSP90αβ-client protein, it may enhance the utility of HSP90αβ inhibitors as adjuvant therapy in MDS
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Offman, Judith Muriel. "DNA mismatch repair deficiency in therapy related acute myeloid leukaemia / myelodysplastic syndrome." Thesis, University College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411977.
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Ochi, Yotaro. "Combined Cohesin-Runx1 Deficiency Synergistically Perturbs Chromatin Looping and Causes Myelodysplastic Syndromes." Kyoto University, 2020. http://hdl.handle.net/2433/258999.
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Cullen, Matthew John. "The use of flow cytometry in the diagnosis of the Myelodysplastic Syndromes." Thesis, University of Leeds, 2016. http://etheses.whiterose.ac.uk/13713/.
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The Myelodysplastic Syndromes (MDS) are a biologically and clinically heterogeneous group of bone marrow haematopoietic cell disorders that result in ineffective haematopoiesis. Unlike most forms of haematological malignancy, the diagnosis of MDS remains heavily reliant on subjective morphological interpretation which can result in inaccurate and missed diagnoses. The use of flow cytometric immunophenotyping offers a potential solution to aid in the diagnosis of MDS, and numerous flow cytometric scoring schemes have been already been proposed and tested. However, most flow cytometric scoring schemes are user-defined, with simple schemes lacking diagnostic sensitivity, whilst the more comprehensive schemes may be unfeasible to implement in a large-scale diagnostic setting. The use of machine learning classifiers offered a more subjective approach to the use of flow cytometric data. Therefore, we have tested a series of classifiers both by combining simple immunophenotypic and demographic features, and by utilising a 2 tube-immunophenotyping panel which contained a large array of numerical and immunophenotypic attributes which had been identified as being abnormal in MDS patients. We have shown that machine learning classifier-based approaches could reproducibly identify patients with definite abnormalities in MDS, and those with normal haematopoietic populations in non-diagnostic, reactive conditions. The classifiers further offered the ability to aid in the triage of patients unlikely to be MDS by providing the basis to a diagnostic confidence score. The application of multiple classifiers also identified a grey-area of MDS patients who were consistently misclassified and who may prove to be challenging to diagnose by flow cytometry, due to an absence of aberrant immunophenotypic features. Finally, we have also shown that a combination of immunophenotyping and targeted gene mutation analysis provides the potential to identify non-diagnostic cases which may progress to MDS. It is in a combination of these two techniques where the future of MDS diagnosis may lie.
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Khan, Rasheed. "DNA methylation and 5-azacytidine in myelodysplastic syndromes : pharmacodynamic, mechanistic and clinical studies /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-419-8/.
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Asimakopoulos, Fotios A. "Molecular analysis of chromosome 20q deletions associated with myeloproliferative disorders and myelodysplastic syndromes." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388490.
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Matos, Sarah Sofia Mealhada Cardoso de. "" Identification of the Genomic Breakpoints of a Novel Chromosome Translocation in Myelodysplastic Syndrome "." Dissertação, Instituto de Ciências Biomédicas Abel Salazar, 2011. http://hdl.handle.net/10216/57120.
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Wang, Xiaofeng. "Population pharmacokinetics and exposure toxicity analysis of Vatalanib in patients with myelodysplastic syndromes." Diss., University of Iowa, 2013. https://ir.uiowa.edu/etd/4972.
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Vatalanib is a novel, potent, orally bioavailable angiogenesis inhibitor which can block all known vascular endothelial growth factor (VEGF) receptor tyrosine kinases. It has been shown to have potential in treating hematological malignancies, including myelodysplastic syndromes (MDS). Previous studies have revealed substantial pharmacokinetic variability that is further increased by auto-induction of its metabolism. And safety and tolerability are of great importance for such anti-angiogenic treatment. Therefore, the objectives of thesis was to characterize the pharmacokinetics and auto-induction process of vatalanib using population pharmacokinetic approaches, and to evaluate the relationship between systemic exposure to vatalanib and its toxicity in order to achieve optimal therapy in the treatment of MDS with standard fixed vatalanib doses.
In this thesis, we characterized the time dependent pharmacokinetics of vatalanib employing both the standard two-stage approach with maximum a posteriori Bayesian estimation method in Chapter 2 and the nonlinear mixed effects modeling approach in Chapter 3 with sparse sampling data from a phase II clinical study, in which adult MDS patients received vatalanib orally once daily on a 28-day cycle of therapy. A one compartment model with a time dependent oral clearance term and lagged first order absorption was determined to be the best structural model for both approaches. The mean parameter estimates from both approaches were similar, probably due to similar model structure and the same underlying model assumptions. The mean apparent oral clearance was estimated to increase to approximately 2-fold after the enzyme auto-induction. The relationship between pharmacokinetic parameters and subject specific covariates was assessed using simple linear regression analysis in Chapter 2. In Chapter 3, graphical exploration, generalized additive models, and stepwise forward addition and backward elimination approaches were utilized for covariate modeling. Results from both chapters revealed that none of the available covariates was found to significantly influence the pharmacokinetics of vatalanib.
Finally, exposure toxicity analysis was carried out to characterize the relationship between the systemic exposure to vatalanib and its toxicity. Both simple logistic regression and multinomial logistic regression approaches were utilized. Results from both analyses showed no correlation between the vatlanib exposure and the magnitude of its toxicity.
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Rhyasen, Garrett W. "IRAK Family Kinases as Therapeutic Targets for Myelodysplastic Syndrome and Acute Myeloid Leukemia." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1406810785.
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Matos, Sarah Sofia Mealhada Cardoso de. "" Identification of the Genomic Breakpoints of a Novel Chromosome Translocation in Myelodysplastic Syndrome "." Master's thesis, Instituto de Ciências Biomédicas Abel Salazar, 2011. http://hdl.handle.net/10216/57120.
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Arruda, Daisy Maria Meireles. "Aloimmunity against HLA class I antigens in patients with myelodysplastic syndrome and aplastic anemia." Universidade Federal do CearÃ, 2005. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=38.
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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel SuperiorMyelodysplastic syndrome (MDS) and aplastic anemia (AA) are two of the hematological disorders which present peripheral cytopenias, with extensive clinical manifestations that vary from slight anemia to severe pancytopenia; the latter requiring continuous transfusional reposition of red cell (RC) and platelet concentrates (PC), which can induce aloimunization in patients. Such patients can develop a post-transfusional refractory state, rendering further transfusions unviable. The objective of the present study was to investigate the incidence of anti-HLA antibodies in politransfused patients, and correlate the aloimmunity levels to the clinical profiles of MDS and AA patients. A total of 110 politransfused patients (70 with MDS, and 40 with AA) have been included in the study, with the MDS patients being subclassified into four clinical diagnostic categories: refractory anemia (RA), ringed-sideroblastic refractory anemia (RSRA), refractory anemia with excess blasts (RAEB) and refractory anemia with excess blasts in transformation (RAEB-t). Blood serum samples from these patients were treated with dithiothreitol for the detection of anti-HLA class I antibodies, using the complement-dependent cytotoxicity test (CDC), in a panel of lymphocytes constituted on the basis of the frequency of HLA antigens in our population (PRA). The results showed that a larger number of AA patients were aloimmunized than MDS patients (45% v 28.6%), with the aloreactivity being higher in AA patients who received higher mean transfusions of PC, than in MDS patients who received higher average number of EC transfusions. The degree of aloimmunization was different in the two disorders, and was generally related to: the number of transfusions received, the application of un-deleukocytised PC and EC, and the type of immunosuppressant drugs used in treatment [Cyclosporin (CsA) and/or antiglobulin (ALG) therapy significantly reduced aloimmunization, but corticoids alone were not sufficient]. The highest degree of aloimmunity (Grade 4) was observed only in MDS females, particularly in those who had multiple births. Persistent IgG was also associated with Grade 4 aloimmunity. These results reveal that significant numbers of MDS and AA patients, if politransfused with un-deleukocytised PC and EC and un-treated with immunosuppressants CsA and/or ALG, can develop anti-HLA antibodies and become refractory to further transfusions. Such aloimmunized patients can also become potentially unsuited to receive bone marrow transplants from HLA-matched donors.
As SÃndromes MielodisplÃsticas e Anemia AplÃstica sÃo desordens hematolÃgicas que apresentam citopenias perifÃricas, com desenvolvimento de caracterÃsticas clÃnicas extensas, com manifestaÃÃes clÃnicas variÃveis que vÃo desde uma leve anemia atà uma pancitopenia severa, necessitando, nos Ãltimos casos, de reposiÃÃo transfusional contÃnua de concentrados de hemÃcias (CH) e de plaquetas (CP), tornando-os alvos à aloimunizaÃÃo pÃs-transfusional e desenvolvimento do estado de refratariedade Ãs transfusÃes. Este estudo objetivou determinar a incidÃncia de anticorpos anti-HLA de classe I em pacientes politransfundidos e correlacionar a aloimunidade ao perfil clÃnico dos pacientes de SMD e AA. 110 pacientes foram incluÃdos nesta pesquisa (70 portadores das SMD e 40 de AA), com os portadores das SMD classificados em quatro sub-grupos clÃnicos: anemia refratÃria (AR), anemia refratÃria sideroblÃstica em anel (ARSA), anemia refratÃria com excesso de blastos (AREB) e anemia refratÃria com excesso de blastos em transformaÃÃo (AREB-t). Soros dos pacientes foram tratados com Dithiothreitol (DTT) para a pesquisa de Acs contra os Ag HLA de classe I, usando a tÃcnica de âcitotoxicidade dependente do complementoâ (CDC), no painel de linfÃcitos baseado na frequÃncia dos Ags HLA da nossa populaÃÃo (PRA). Os resultados demonstraram que os pacientes portadores das SMD desenvolveram um menor grau de aloimunizaÃÃo (28,6%), que os pacientes de AA (45%). A alorreatividade foi mais freqÃente nos portadores de AA que tinham recebido maiores mÃdias transfusionais de CP, em relaÃÃo aos pacientes de SMD que receberam maior nÃmero de transfusÃes com CH. O grau de alorreatividade se manifestou diferente nestas duas doenÃas e, de forma geral, se relacionou com: o maior nÃmero mÃdio de transfusÃes, a aplicaÃÃo de preparaÃÃes nÃo desleucotizadas de CH e CP e o uso de imunossupressores (ciclosporina e/ou soros anti-leucocitÃrios). Somente o uso de corticÃide nÃo foi suficiente para reduzir a aloimunizaÃÃo. O mais alto grau de alorreatividade (PadrÃo 4) nas SMD foi evidenciado somente em mulheres, principalmente nas multÃparas. IgG persistente esteve mais presente no PadrÃo 4. Estes dados revelam que alguns pacientes das SMD e AA podem desenvolver anticorpos anti-HLA, se forem politransfundidos com hemoconcentrados nÃo desleucotizados e sem o tratamento com os imunossupressores CsA e/ou GAL. Tal alorreatividade poderà tornar o paciente refratÃrio Ãs futuras transfusÃes e dificultar, em princÃpio, recebimento do transplante de medula Ãssea de doadores HLA compatÃveis.
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Ohmori, Seiichi. "Myelodysplastic syndrome(MDS)の造血障害に関する研究." Kyoto University, 1993. http://hdl.handle.net/2433/168850.
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本文データは平成22年度国立国会図書館の学位論文(博士)のデジタル化実施により作成された画像ファイルを基にpdf変換したものであるKyoto University (京都大学)
0048
新制・論文博士
博士(医学)
乙第8218号
論医博第1437号
新制||医||568(附属図書館)
UT51-93-J541
(主査)教授 内山 卓, 教授 淀井 淳司, 教授 大熊 稔
学位規則第4条第2項該当
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Basiorka, Ashley. "Changing the Pathobiological Paradigm in Myelodysplastic Syndromes: The NLRP3 Inflammasome Drives the MDS Phenotype." Scholar Commons, 2017. http://scholarcommons.usf.edu/etd/6613.
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Note: Portions of this abstract have been previously published in the journal Blood, Basiorka et al. Blood. 2016 Oct 13, and has been reproduced in this manuscript with permission from the publisher.
Myelodysplastic syndromes (MDS) are genetically diverse hematopoietic stem cell malignancies that share a common phenotype of cytological dysplasia, ineffective hematopoiesis and aberrant myeloid lineage maturation. Apoptotic cell death potentiated by inflammatory cytokines has been considered a fundamental feature of MDS for over two decades. However, this non-inflammatory form of cell death cannot account for the inflammatory nature of these disorders. We report that a hallmark of lower-risk (LR) MDS is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptosis, a caspase-1-dependent programmed cell death induced by danger-associated molecular pattern (DAMP) signals. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPC) overexpress pyroptosis-related transcripts, inflammasome proteins and manifest activated NLRP3 inflammasome complexes that direct caspase-1 activation, IL-1β and IL-18 maturation and pyroptotic cell death. Using the S100A9 transgenic (S100A9Tg) mouse model that phenocopies human MDS, we demonstrated that forced expression of S100A9 was sufficient to drive pyroptosis in vivo, implicating pyroptosis as the principal mechanism of HSPC cell death in S100A9Tg mice. The lytic cell death releases intraceullar contents that include alarmins and catalytically active ASC specks, which can propagate bystander inflammation. Notably, MDS mesenchymal stromal cells (MSC) and stromal-derived linages were found to predominantly undergo pyroptosis, with marked activation of caspase-1 and NLRP3 inflammasome complexes. These findings may account for the clusters of both HSPC and stromal cell death previously described in the bone marrows of patients with MDS.
Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPC and bone marrow (BM) plasma. Further, both somatic gene mutations and S100A9-induced signaling activate NADPH oxidase (NOX), generating reactive oxygen species (ROS) that initiate cation influx, cell swelling and β-catenin activation. Accordingly, ROS and active β-catenin were significantly increased in MDS BM mononuclear cells (BM-MNC) and S100A9Tg mice compared to normal controls, as well as in human cell lines harboring gene mutations and in murine models of gene mutation knock-in or gene loss. ROS and β-catenin nuclear translocation were significantly reduced by NLRP3 or NOX inhibition, indicating that S100A9 and somatic gene mutations prime cells to undergo NOX1/4-dependent NLRP3 inflammasome assembly, pyroptosis and β-catenin activation. Together, these data explain the concurrent proliferation and inflammatory cell death characteristic of LR-MDS.
Given that loss of a gene-rich area in del(5q) disease results in derepression of innate immune signaling, we hypothesized that this genetic deficit would trigger assembly of the NLRP3 inflammasome complex, akin to the pathobiological mechanism characteristic of non-del(5q) MDS. To this end, we utilized two distinct murine models of del(5q) disease, namely in the context of Rps14 haploinsufficiency and concurrent loss of mDia1 and microRNA (miR)-146a. In both models, pyroptosis was not evident in the HSPC compartment; however, early erythroid progenitors displayed high fractions of pyroptotic cells. This was associated with significant increases in caspase-1 and NLRP3 inflammasome activation, ROS and nuclear localization of β-catenin, which was extinguished by inflammasome or NOX complex inhibition. These data suggest that early activation of the inflammasome drives cell death and prevents terminal maturation of erythroid precursors, accounting for the progressive anemia characteristic of del(5q) disease, whereby hematopoietic defects are primarily restricted to the erythroid compartment. Importantly, these data implicate a similar pathobiological mechanism in del(5q) MDS as is observed in non-del(5q) patients.
The identification of the NLRP3 inflammasome as a pathobiological driver of the LR non-del(5q) and del(5q) MDS phenotype allows for novel therapeutic agent development. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppresses pyroptosis, ROS generation and nuclear β-catenin in MDS, and are sufficient to restore effective hematopoiesis. In del(5q) murine models, inhibition of the NLRP3 inflammasome significantly improved erythroid colony forming capacity by a mechanism distinct from that of lenalidomide, highlighting the translational potential for targeting this innate immune complex in this subset of MDS. Thus, alarmins and founder gene mutations in MDS license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention.
Furthermore, aggregated clusters of the NLRP3 adaptor protein ASC [apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (CARD)] are referred to as ASC specks. During pyroptosis, ASC specks are released from dying cells and function as DAMP signals that propagate inflammation. In this way, specks are a surrogate marker for NLRP3 inflammasome activation and pyroptotic cell death. Given that pyroptosis is the predominant mechanism of cell death in MDS and ASC specks are readily quantified by flow cytometry, we hypothesized that BM or peripheral blood (PB) plasma-derived ASC specks may be a biologically rational biomarker for the diagnosis of MDS.
The percentage of ASC specks were significantly increased in MDS BM plasma compared to normal, healthy donors, which was validated by confocal microscopy. PB plasma-derived ASC specks were significantly greater in LR- versus HR-MDS, consistent with the greater extent of cell death and myeloid-derived suppressor cell (MDSC) expansion in LR disease. As hyperglycemia induces NLRP3 inflammasome activation, plasma glucose levels were measured to adjust for this confounding variable. Subsequently, the percentage of glucose-adjusted, PB plasma-derived ASC specks was measured in a panel of specimens of varied hematologic malignancies. The corrected percentage of ASC specks was significantly increased in MDS compared to normal donors and to each other malignancy investigated, including other myeloid and lymphoid leukemias, myeloproliferative neoplasms and overlap syndromes, like chronic myelomonocytic leukemia (CMML). These data indicate that the glucose-adjusted ASC speck percentage is MDS-specific and may be a valuable diagnostic biomarker. At a cutoff of 0.039, the biomarker minimizes misclassification error and achieves 95% sensitivity and 82% specificity in classifying MDS from normal donors, other hematologic malignancies and T2D. Lastly, the biomarker declined with treatment response to lenalidomide in LR-MDS patients, but not to erythropoietin stimulating agent (ESA) or hypomethylating agent (HMA) therapy. As such, the percentage of ASC specks represents the first biologically rational, diagnostic biomarker for MDS that can be implemented with current diagnostic practices to reduce diagnostic error.
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Fegas, Rebecca K. "GERIATRIC ASSESSMENT VARIABLES ADD PROGNOSTIC VALUE TO THE INTERNATIONAL PROGNOSTIC SCORING SYSTEM FOR MYELODYSPLASTIC SYNDROME." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/528170.
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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.Background: The International Prognostic Scoring System (IPSS) for myelodysplastic syndrome (MDS) is commonly used to predict survival and assign treatment. We explored whether markers of frailty add prognostic information to the IPSS in a cohort of older patients. Design, Setting, Participants: Retrospective cohort study of 114 MDS patients ≥ age 65 who presented to Dana‐Farber Cancer Institute between 2006‐2011 and completed a baseline quality of life questionnaire. Measurements: We evaluated questions corresponding to frailty and extracted clinical‐ pathologic data from medical records. We used Kaplan‐Meier and Cox proportional hazards models to estimate survival. Results: 114 patients consented and were available for analysis. The median age was 72.5 years, and the majority of patients were white ( 94.7%), male ( 74.6%), and over half had a Charlson comorbidity score < 2. Few patients ( 23.7%) had an IPSS score consistent with low‐risk disease and the majority received chemotherapy. In addition to traditional prognostic factors (IPSS score and history of prior chemotherapy or radiation), significant univariate predictors of survival included low serum albumin, Charlson score, the ability to take a long walk, and interference of physical symptoms in family life. The multivariate model that best predicted mortality included low serum albumin (HR=2.3; 95%CI: 1.06‐5.14), previous chemotherapy or radiation (HR=2.1; 95%CI: 1.16‐4.24), IPSS score (HR=1.7; 95%CI: 1.14‐2.49), and ease taking a long walk (HR=0.44; 95%CI: 0.23‐0.90). Conclusions: In this study of older adults with MDS, we found that markers of nutritional status and self‐reported physical function added important prognostic information to the IPSS score. More comprehensive risk assessment tools for older patients with MDS that include markers of function and frailty are needed.
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Mcgraw, Kathy Lynn. "Interrogation of EpoR Fidelity in Myelodysplastic Syndrome Hematopoiesis and Stabilization by the Immunomodulatory Agent, Lenalidomide." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4726.
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Myelodysplastic syndromes (MDS) include a spectrum of stem cell malignancies characterized by ineffective hematopoiesis and predisposition to acute myeloid leukemia (AML) transformation. Patients are predominantly older (greater than 60 years old), with progressive cytopenias resulting from ineffective and cytologically dysplastic hematopoiesis. MDS subtypes are classified by morphologic features and bone marrow blast percentage, as well as cytogenetic pattern, as is the case for deletion 5q MDS. Interstitial deletion of the long arm of chromosome 5, del(5q), is the most common chromosomal abnormality in patients with MDS, and the 5q- syndrome, represents a distinct subset of del(5q) MDS characterized by an isolated deletion, megakaryocyte dysplasia, hypoplastic anemia, and an indolent natural history. MDS risk stratification is most commonly based on the International Prognostic Scoring System (IPSS) with survival outcomes ranging from a few months to many years based on risk factors. There are several therapeutic options for MDS including hematopoietic growth factors, immunosuppressive therapy, azanucleosides, and allogeneic stem cell transplant, however, there is still a need for more effective treatment options, particularly targeted therapeutics. One of the most effective treatments for MDS is selective for del(5q) MDS, and is the second generation immunomodulatory agent, lenalidomide (LEN).
LEN is an analog of the known teratogen, thalidomide, and has broad biological effects including selective cytotoxicity to del(5q) clones, activation of T-cells, and expansion of erythroid precursors. In patients with del(5q) MDS, LEN is effective in up to 75% of patients, however, 50% of patients will become resistant within 2-3 years of treatment response. Studies in normal hematopoietic progenitors have shown that LEN induces expansion of the primitive erythroid precursors, which our laboratory has shown is accompanied by sensitization of progenitors to ligand induced erythropoietin receptor (EpoR) signaling. This sensitization is evidenced by increased and prolonged activation of the Signal Transducer and Activator of Transcription 5 (STAT5), compared to Epo stimulation alone. Although EpoR signaling is augmented by LEN, the exact mechanisms by which this is mediated to result in erythroid expansion are not fully characterized. In del(5q) MDS, we have shown that LEN selectively suppresses del(5q) clones via inhibition of the haploinsufficient phosphatases Cdc25c and PP2a, as well as stabilizing the human homolog of the murine double minute-2 protein (MDM2) to decrease expression of the tumor suppressor, p53, however, the mechanisms of action of LEN in non-del(5q) MDS remains elusive.
Although most anemic MDS patients have normal or elevated endogenous levels of Epo, as well as comparable levels of progenitor EpoR density relative to healthy individuals, the biologic pathology underlying the impaired EpoR signaling in MDS is poorly defined. Recent reports have shown that membrane microdomains are important for T-cell, c-kit, and integrin signaling, however, there have been no reports on EpoR membrane localization. Lipid rafts are discrete membrane entities that provide platforms by which receptors aggregate and initiate downstream signaling. Furthermore, reports have indicated that there is a decrease in lipid raft density in GM-CSF primed MDS neutrophils, that consequently impaired production of reactive oxygen species (ROS) after fMLP stimulation, suggesting a role of rafts in MDS disease biology. Based on the role of rafts in signaling, and potential role in MDS pathogenesis, we sought to determine whether there was specific membrane localization of EpoR to the raft fractions, and whether disruption of rafts in MDS erythroids could impair EpoR signaling. To address this, we first examined the membrane localization of EpoR on the cell surface. We show here that EpoR translocates to lipid rafts in both erythroid progenitor cell lines as well as primary progenitor cells after stimulation by Epo. Furthermore, we found that Epo stimulation increases the assembly of lipid rafts, as well as the aggregation of rafts on the cell surface. Epo stimulation not only promoted the recruitment of EpoR into the raft fractions, but also downstream signaling intermediates such as Janus kinase 2 (Jak2), STAT5, and Lyn kinase. Moreover, a negative regulator of EpoR signaling, the CD45 tyrosine phosphatase, was redistributed outside of raft fractions after Epo stimulation, potentially enhancing receptor signal competence. Furthermore, disruption of lipid rafts by depletion of membrane cholesterol with MâCD (methyl-β-cyclodextrin) inhibited EpoR signaling in both cell lines and primary bone marrow progenitor cells. Additionally, we found that inhibition of Rho-associated, coiled-coil containing protein kinase (ROCK) and/or Ras-related C3 botulinium toxin substrate 1 (Rac1), blocked the recruitment of the receptor into the raft fractions indicating a critical role of these GTPases, and associated proteins, in the transport and localization of EpoR into raft microdomains.
We next asked whether LEN could alter lipid raft assembly in erythroid precursors in the absence of Epo. LEN not only induced raft formation and aggregation but also increased F-actin polymerization. Similar to Epo stimulation, LEN alone was able to induce the recruitment of EpoR, Jak2, and STAT5 into raft fractions. Additionally, CD45 was redistributed outside of raft fractions after LEN treatment. Similarly, inhibition of ROCK blocked LEN induced raft formation and F-actin polymerization, indicating that LEN utilized effectors shared by Epo. Furthermore, LEN was able to increase raft density in raft deficient primary MDS erythroid progenitors. These data demonstrate that LEN may enhance erythroid expansion via induction of EpoR signaling competent raft platforms, to enhance survival and differentiation transcriptional response.
Recently, ribosomal protein (RP), S-14, gene (RPS14) haplodeficiency was found to be a key determinant of the hypoplastic anemia in del(5q) MDS. Allelic loss of RPS14 compromises ribosome assembly, thereby causing nucleolar stress and release of free RPs that bind to and promote the degradation of MDM2, the principal negative regulator of p53. As a result, the accumulation of RPs causes lineage restricted stabilization of p53 in erythroid precursors. Our laboratory and colleagues confirmed that cellular p53 expression levels were elevated in del(5q) erythroid precursors, and that LEN decreased expression in responding patients. However, at the time of LEN treatment failure, p53 expression was again elevated at levels exceeding those at baseline. These results suggest that LEN is initially able to reverse p53 accumulation levels and that this action may be a mechanism by which LEN is selectively cytotoxic to del(5q) clones. Subsequent studies showed that LEN inhibits the cereblon E3 ubiquitin ligase complex, the newly discovered target of LEN. Cereblon has been reported to be the principal protein involved in thalidomide induced teratogenicity. Furthermore, the cytotoxic activity of LEN in multiple myeloma is dependent on cereblon. Our laboratory found that LEN inhibits the auto-ubiquitination of MDM2, thereby stabilizing the protein, and promoting ubiquitination of and ultimately the degradation of p53. Additionally, we found that LEN blocked the binding of free ribosomal proteins to MDM2, which are liberated from the nucleosome by ribosomal stress from RPS14 haploinsufficiency, consequently stabilizing the E3-ubiquitin ligase and fostering p53 degradation.
In non-del(5q) MDS there is no cytotoxicity of MDS clones by LEN, suggesting an alternative method of erythropoiesis rescue. Although we know that LEN promotes the formation of signaling platforms, and recruitment of EpoR, we wished to determine whether there was an effect of LEN on EpoR expression, as EpoR expression is controlled through ubiquitination and proteasomal degradation. Treatment of erythroid progenitor cell lines and primary erythroid precursors with LEN increased cellular expression of Jak2-associated EpoR in a concentration dependent manner. There was no change in mRNA expression, supporting a post transcriptional mechanism. We then investigated whether receptor up-regulation was limited to EpoR, or included other cytokine receptors. We found that LEN induced expression of another Jak2 associated Type I receptor, IL3-R, but did not alter cellular expression of c-kit, a Type II cytokine receptor. Because Type I cytokine receptor turnover is regulated by a shared E3-ubiquitin ligase, and LEN inhibited both MDM2 and cereblon, we evaluated the effects of LEN on the E3-ubiquitin ligase, Ring Finger Protein-41 (RNF41), which regulates steady state or ligand independent, Jak2 associated Type I receptor internalization. We found that LEN inhibited the ubiquitination activity of RNF41, ultimately stabilizing EpoR membrane residence and increasing expression.
In summary, MDS patients display ineffective hematopoiesis likely in part to decreased lipid raft assembly. Stimulation by Epo, or treatment by LEN, not only induced raft formation, but also induced the recruitment of both growth factor receptor, and downstream signaling intermediates into raft fractions to enhance EpoR signal fidelity. We have shown here two methods by which LEN may augment EpoR signaling. First, LEN increases lipid rafts and promotes recruitment of signaling effectors. Second, LEN increases and stabilizes the expression of EpoR through inhibition of the E3 ubiquitin ligase, RNF41. Therefore, we suggest here that LEN may have broad E3 ubiquitin ligase inhibitory effects. These data also indicate that lipid raft upregulation by LEN is mediated through GTPases, suggesting that GTPase activation may also occur via inhibition of specific E3 ubiquitin ligases, a question to be addressed in future studies.
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Marley, Stephen Bernard. "The effects of cytokines on normal and myelodysplastic marrow in long-term bone marrow culture." Thesis, University of Nottingham, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.358091.
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Fern, Lorna A. "Possible molecular mechanisms in the development of therapy related acute myeloblastic leukaemia and myelodysplastic syndrome." Thesis, University of Nottingham, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403385.
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Ibrahim, Rawa. "The role of Toll/interleukin-1 receptor adaptor protein in the pathogenesis of myelodysplastic syndromes." Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/53969.
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Hematopoiesis is a process essential for the maintenance of cells that mediate many vital functions such as the production of red blood cells necessary for transportation of oxygen and the removal of carbon dioxide from the body. It is also required for the production of platelets which are necessary for clotting, and the various types of white blood cells that make up the innate and adaptive immune systems that protect against viral, microbial, and parasitic infections. The cell responsible for the generation of all the downstream effector cells, the hematopoietic stem cell (HSC), is generated during embryogenesis. Through a series of symmetric and asymmetric cell divisions, the HSC is capable of maintaining all the cells of the hematopoietic hierarchy throughout the lifespan of an organism. A variety of genetic and epigenetic cues are necessary to maintain homeostasis, and perturbations in these cues lead to the development of hematopoietic malignancies and myelodysplastic syndromes. In recent years the innate immune pathway has emerged as an important player in hematopoietic homeostasis.
This dissertation examines the role of dysregulation of innate immune signaling in the development of the myelodysplastic syndromes, one of the most common hematological malignancies. Using a murine bone marrow transplantation assay, I show that overexpression of the innate immune signaling adaptor, TIRAP, results in perturbations in normal hematopoiesis. Overexpression of TIRAP in the hematopoietic compartment results in an inability to produce mature hematopoietic cells, leading to pancytopenia and bone marrow failure (BMF). TIRAP-induced BMF is a result of both autonomous and non-autonomous effects mediated by the cytokine IFNγ. Interestingly, in an environment depleted of IFNγ, TIRAP-transplanted mice develop a myeloproliferative neoplasm suggesting that TIRAP activates both myelosuppressive pathways (through IFNγ) as well as myeloproliferative pathways. IFNγ acts in a paracrine manner inhibiting osteoclast proliferation and maturation in the bone marrow microenvironment, thus disrupting the HSC niche. In summary, this thesis shows the importance of immune regulation in hematopoietic homeostasis. Furthermore, it shows how defects in the hematopoietic stem/progenitor compartment can translate into a defect in the stem cell niche, contributing further to marrow failure and disease progression.Medicine, Faculty of
Graduate
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Castro, ClÃudio CÃsar Monteiro de. "AvaliaÃÃo da funÃÃo miocÃrdica de pacientes com sÃndrome mielodisplÃsica pelo ecocardiograma convencional com doppler e pelas novas tÃcnicas de doppler tecidual e speckle-tracking." Universidade Federal do CearÃ, 2012. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=7902.
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A SÃndrome MielodisplÃsica à uma hemopatia clonal de alta prevalÃncia em idosos Anemia à uma caracterÃstica marcante dessa doenÃa Pacientes com dependÃncia de suporte transfusional tem pior prognÃstico Depois das complicaÃÃes relacionadas à prÃpria doenÃa as complicaÃÃes cardiovasculares sÃo a principal causa de morte Novas tÃcnicas ecocardiogrÃficas como o Doppler tecidual e speckle-tracking podem ser Ãteis na anÃlise da funÃÃo cardÃaca nesse grupo Neste estudo foi avaliado um grupo de 34 pacientes e 14 controles saudÃveis emparelhados por sexo e idade sendo submetido à ecocardiograma convencional Doppler tecidual e avaliaÃÃo da deformaÃÃo miocÃrdica (strain) Os pacientes foram subdivididos entre dependentes (13) ou nÃo de suporte transfusional (21) e comparados aos controles Dentre os 13 pacientes do grupo dependentes havia 10 com sobrecarga de ferro (ferritina >1.000 ng/mL) Os pacientes dependentes de suporte transfusional apresentaram maiores volumes diastÃlico e sistÃlico do ventrÃculo esquerdo em relaÃÃo aos controles (p = 0,047 e 0,039) O volume do Ãtrio esquerdo indexado foi maior no grupo de dependentes em relaÃÃo ao grupo controle (p = 0,003) A funÃÃo diastÃlica do ventrÃculo esquerdo (VE) por Doppler convencional e tecidual (razÃo E/A e razÃo E/Eâ) foi normal no grupo de pacientes e nÃo apresentou diferenÃa significante entre os grupos (p = 0,15 e 0,90) Na avaliaÃÃo da funÃÃo sistÃlica do VE por fraÃÃo de ejeÃÃo e por deformaÃÃo miocÃrdica (strain longitudinal global) nÃo houve desvio da normalidade nem diferenÃas entre os grupos (p = 0,71 e 0,097) A espessura do septo interventricular foi maior nos pacientes com ferritina > 1.000 ng/mL (p = 0,012) O nÃvel de hemoglobina mas nÃo o de ferritina apresentou correlaÃÃo com os volumes esquerdos (Ãtrio: r = -0,53 e p = 0,013 / ventrÃculo: r = -0,4 e p = 0,019) Nossa amostra nÃo apresentou disfunÃÃo global nem sistÃlica nem diastÃlica mesmo à anÃlise por novas tÃcnicas de ecocardiograma como Doppler tecidual e deformaÃÃo miocÃrdica (strain) O nÃvel de hemoglobina menor que 8 g/dL foi marcador precoce de pior funÃÃo ventricular nos nossos pacientes com SÃndrome MielodisplÃsicaMyelodysplastic syndrome is a clonal disorder of hematopoietic tissue highly prevalent on elderly Anemia is one of most striking feature of this disorder Patients with transfusional dependence have a poor prognosis Following complications related to the own illness cardiovascular complications are the leading cause of death New echocardiographic techniques such as Tissue Doppler and speckle-tracking may be useful on assessment of the myocardial function in these patients A group with 34 patients and 14 healthy controls matched by sex and age was subjected to conventional echocardiography Tissue Doppler and assessment of myocardial deformation (strain) Patients were divided between those with (13) or without (21) transfusional dependence and compared to controls In the group of transfusional dependence there were 10 subjects with iron overload (serum ferritin levels > 1.000 ng/mL) Those with transfusion dependence had bigger left systolic and diastolic ventricular volumes than controls (p = 0,047 and 0,039) The indexed left atrium volume was larger on those with transfusion dependence compared to controls (p = 0,003) The left ventricular diastolic function assessed by tissue and conventional Doppler (E/A and E/Eâ ratios) was normal in the patient group and has not difference between them (p = 0,15 and 0,9) On the assessment of the systolic left ventricular function by ejection fraction and myocardial deformation (global longitudinal strain) there was no difference between groups or from reference values (p = 0,71 and 0,097) The interventricular septum thickness was larger in the group with serum ferritin > 1.000 ng/mL than patients with ferritin < 1.000 ng/mL (p = 0,012) The hemoglobin level but not ferritin showed linear correlation with the left volumes (atrium: r = -0,53 with p =0,013 / ventricle: r = -0,4 with p = 0,019) Our sample doesnât show diastolic nor systolic global dysfunctions yet with new techniques of tissue Doppler and myocardial deformation (strain). Hemoglobin below 8 g/dL was an early marker of worst ventricular function in our patients with myelodysplastic syndrome
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Okyere, Benjamin. "Evaluation of the actin architecture in dysplastic megakaryocytes expressing the NUP98-HOXD13 leukemic fusion gene." Thesis, Virginia Tech, 2013. http://hdl.handle.net/10919/23738.
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Some myelodysplastic syndrome (MDS) patients present with macrothrombocytopenia due to impaired megakaryocyte (MK) differentiation. Transgenic mice that express the NUP98-HOXD13 (NHD13) fusion gene is a model for MDS and recapitulates the key features of MDS. The study investigated the hypothesis that expression of NHD13 disrupts actin architecture during MK differentiation leading to macrothrombocytopenia. To test the hypothesis, sternums were stained with hematoxylin and eosin, and evaluated by light microscopy to analyze MK morphology in vivo. NHD13 bone marrow (BM) contained many dysplastic MK. BM from wild type (WT) and NHD13 mice were also flushed, cultured in media supplemented with thrombopoietin only or with estrogen to induce proplatelet formation, and MK harvested after 5 days. Harvested MK and BM cores were processed and analyzed by transmission electron microscopy (TEM) to detail the ultrastructural features. TEM of MK revealed that NHD13 leads to formation of an irregular demarcation membrane system and fewer proplatelets. Cultured WT and NHD13 MK were also cytospun onto glass slides, labeled with fluorescent-tagged F-actin, α/β-tubulin and myosin IIa, and their cytoskeleton compared. Interestingly WT MK had actin either distributed evenly or predominantly in the periphery of the cytoplasm, NHD13 MK displayed only the former phenotype. Additionally, proplatelets lacked actin cytoplasmic extensions. The results from the present thesis demonstrate actin expression and architecture are impaired in dysplastic MK expressing the NHD13 leukemic fusion gene and leads to macrothromcytopenia. Understanding the molecular mechanisms of abnormal MK differentiation in MDS is important as many MDS patients die of hemorrhagic complications.Master of Science
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Wallrabenstein, Till [Verfasser]. "Clinical characterization and prognostic impact of SF3B1 and TP53 gene mutations in myelodysplastic syndromes / Till Wallrabenstein." Ulm : Universität Ulm, 2018. http://d-nb.info/1172351635/34.
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Watkins, Fiona. "An Investigation into the Molecular Pathogenesis of the Myelodysplastic Syndromes (MDS), in Particular the 5q- Syndrome." Thesis, Open University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.520781.
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Osório, Catarina Raquel de Sousa. "Angiogenic profile in Myelodysplastic Syndromes and genetic characterization of the endothelial compartment - biologic and clinic relevance." Dissertação, Faculdade de Medicina da Universidade do Porto, 2006. http://hdl.handle.net/10216/22115.
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Osório, Catarina Raquel de Sousa. "Angiogenic profile in Myelodysplastic Syndromes and genetic characterization of the endothelial compartment - biologic and clinic relevance." Master's thesis, Faculdade de Medicina da Universidade do Porto, 2006. http://hdl.handle.net/10216/22115.
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Tsutsumi, Ikuyo. "Impact of oral voriconazole during chemotherapy for acute myeloid leukemia and myelodysplastic syndrome: a Japanese nationwide retrospective cohort study." Kyoto University, 2020. http://hdl.handle.net/2433/245837.
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AlAhmad, Adnan [Verfasser], and Nikolaus [Akademischer Betreuer] Müller-Lantzsch. "The Antibody Repertoire of Patients with Paroxysmal Nocturnal Hemoglobinuria and Myelodysplastic Syndrome / Adnan AlAhmad. Betreuer: Nikolaus Müller-Lantzsch." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2011. http://d-nb.info/105109545X/34.
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Masuda, Kenta. "PAS positivity of erythroid precursor cells is associated with a poor prognosis in newly diagnosed myelodysplastic syndrome patients." Kyoto University, 2018. http://hdl.handle.net/2433/233844.
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Martino, Samuela [Verfasser], Ulrich [Gutachter] Germing, and Udo [Gutachter] Boeken. "Myelodysplastic Syndromes: evaluation of different prognostic scores in patients treated with chemotherapy / Samuela Martino ; Gutachter: Ulrich Germing, Udo Boeken." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2016. http://d-nb.info/111930055X/34.
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Hishita, Terutoshi. "Caspase-3 activation by Iysosomal enzymes in cytochrome c-independent apoptosis in a myelodysplastic syndrome(MDS)-derived cell line P39." Kyoto University, 2001. http://hdl.handle.net/2433/150164.
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Lim, Raelene. "Analysis of Madm, a novel adaptor protein that associates with Myeloid Leukemia Factor 1." Curtin University of Technology, School of Biomedical Sciences, 2003. http://espace.library.curtin.edu.au:80/R/?func=dbin-jump-full&object_id=14294.
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Myeloid Leukemia Factor 1 (Mlf1) is the murine homolog of MLF1, which was identified as a fusion gene with Nucleophosmin (NPM) resulting from the (3;5)(q25.1;q34) translocation associated with acute myeloid leukemia and myelodysplastic syndrome (Yoneda-Kato et al., 1996). Mlf1 was independently isolated using cDNA representational difference to identify genes up-regulated when an erythroleukemic cell line underwent a lineage switch to display a monoblastoid phenotype (Williams et al., 1999). Mlf1 has been shown to enhance myeloid differentiation and suppress erythroid differentiation; however, its mechanism of action is unknown. A yeast two hybrid screen was employed to identify Mlf1-interacting proteins. This screen isolated a number of known protein, as well as several novel molecules, that bound Mlf1. One of these was 14-3-3ξ, a member of a family of molecules that bind phosphoserine motifs and regulate the subcellular localization of partner proteins. Mlf1 contains a classic RSXSXP sequence for 14-3-3 binding and associated with 14-3-3ξ; via this phosphorylated motif (Lim et al., 2002). The aim of this thesis was to characterise a novel Mlf1-interacting protein that had some homology to protein kinases and was named Mlf1 Adaptor Molecule (Madm). Adaptor proteins are molecules that possess no enzymatic or transcriptional activity, but instead mediate protein-protein interactions. Madm is encoded by a gene consisting of 18 exons and promoter analysis suggested Madm expression might be widespread; indeed Northern blotting of adult tissues and in situ hybridization of embryos demonstrated ubiquitous Madm expression. Significantly, the Madm protein sequence is highly conserved across diverse species.Madm formed dimers and although it contains a kinase-like domain, the protein lacks several critical residues required for catalytic activity, including an ATP-binding site. Purification of recombinant Madm revealed that the protein was not a kinase; however, studies in mammalian cells showed that Madm associated with a kinase and that Madm was phosphorylated on serine residues in vivo and in vitro. Madm also contains a nuclear localization sequence and nuclear export sequence and was shown to localise to both cytoplasm and nucleus by subcellular fractionation and confocal microscopy. The presence of two nuclear receptor binding motifs (consensus MILL) suggests that Madm may have a functional role in the nucleus. Madm co-immunoprecipitated with Mlf1 and co-localized in the cytoplasm. In addition, the Madm-associated kinase phosphorylated Mlf1 on serine residues, including the RSXSXP motif. In contrast to wild-type Mlf1, the oncogenic fusion protein NPM-MLF1 did not bind 14-3-3i; and localized exclusively in the nucleus. Although Madm co-immunoprecipitated with NPM-MLF1 the binding mechanism was altered. As Mlf1 is able to reprogram erythroleukemic cells to display a monoblastoid phenotype and potentiate myeloid maturation (Williams et al., 1999), the effects of Madm on myeloid differentiation was investigated. However, unlike Mlf1, ectopic expression of Madm in M1 myeloid cells suppressed cytokine-induced differentiation.
In summary, the data presented in this thesis reports on the cloning and characterization of a novel adaptor protein that is involved in the phosphorylation of the proto-oncoprotein MIM. Phosphorylation of Mlf1 is likely to affect its interaction with other proteins, such as 14-3-3~. Complex formation, therefore, may well alter the localization of Mlf1 and Madm, and influence hematopoietic differentiation.