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Föreliggande studie tillämpar diskursanalys i syfte att förstå var det råder samstämmighet eller konflikt kring huruvida Sverige ska sälja, spara eller annullera överskottet på utsläppsrätter inom EU:s och FN:s utsläppshandel. Genom kritisk diskursanalys har vi kategoriserat och kodat tio riksdagsdebatter mellan åren 2010 och 2014, i vilka en ekologisk diskurs och en ekonomisk diskurs kämpar om tolkningsföreträde. Bortsett från samstämmigheten att handel med utsläppsrätter – vilken kan ses som ekologisk modernisering – är ett viktigt verktyg för att minska klimatförändringar; råder öppen kamp kring hur ett överskott på utsläppsrätter ska hanteras. Kampen har delats in i sju kategorier baserat på huruvida: 1) ett beslut om annullering kan tas direkt eller om det krävs en utredning först, 2) en annullering är en symbolisk handling eller styrs av marknadens logik, 3) en försäljning leder till ökade utsläpp, 4) på vilket sätt överskottet ska fungera som förhandlingsstrategi under klimatmöten, 5) Sverige förlorar sitt klimatanseende vid en försäljning av överskott på utsläppsrätter, 6) utsläppshandeln i högre grad borde styras av politiker eller marknadsmekanismer, och slutligen 7) huruvida överskott på utsläppsrätter bör ses som ett lyxproblem. Eftersom det ännu inte finns en fixerad diskursiv entydighet angående hur överskott på utsläppsrätter ska hanteras, menar vi att ingen av diskurserna kan ses som helt hegemonisk. Den ekonomiska diskursen har dock patent på rationaliteten eftersom den, till skillnad från den ekologiska diskursen, har accepterat ekomodernismen. Om den ekonomiska diskursen blir hegemonisk är det sannolikt att ytterligare överskott på utsläppsrätter säljs.Nyckelord: klimatförändringar, EU-ETS, Kyotoprotokollet, ekologisk modernisering, diskursiv kamp. / The following study uses insights derived from discourse analysis to examine whether there is consensus or conflict regarding if Sweden should sell, save or invalidate the surplus of allowances within the emissions trading systems of the EU and the UN. Through critical discourse analysis, we have categorized and coded ten parliamentary debates between the year of 2010 and 2014, in which an ecological discourse and an economic discourse can be derived. Aside from the consistency that the emissions trading systems – which can be seen as ecological modernization - is an important tool to mitigate climate change; an open struggle can be seen regarding how a surplus of allowances should be governed. The struggle has been divided into seven categories based on whether: 1) a decision of invalidation can be taken directly or if an investigation is necessary, 2) an invalidation is a symbolic act or controlled by the logic of the market, 3) a sale directly leads to an increased amount of emissions, 4) in what way the surplus of allowances should serve as a negotiating strategy during international climate meetings, 5) Sweden’s climate profile will be lost in case of a sale, 6) the emissions trading systems to a higher rate should be controlled by politicians or mechanisms of the market, and finally 7) whether the surplus of allowances should be seen as a luxury problem. Since there is not yet a fixed unity regarding how surplus of allowances should be governed, we argue that none of the discourses can be seen as completely hegemonic. However, the economic discourse have positions on rationality due to that it, unlike the ecological discourse, has accepted the ecological modernisation. If the economic discourse becomes hegemonic it is likely that additional surplus of allowances will be sold.Key words: climate change, EU-ETS, the Kyoto Protocol, ecological modernisation, discursive struggle.

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De flesta forskare är överens att den mänskliga påverkan på klimatet i form av växthusgaser är ett faktum. För att minska den mänskliga påverkan har ett system med utsläppsrätter för att reglera utsläppen införts. Tanken är att utsläppen ska minskas successivt av alla inblandade och att detta ska redovisas inom varje land i särskilda rapporter. Inom redovisningen av företags finansiella status såsom årsredovisningar finns det i dagsläget ingen reglering som styr om och hur dessa utsläppsrätter ska redovisas. IASB utreder redovisningspraxis för att kartlägga vilka metoder som används. Genom denna kartläggning undersöker de om det är genomförbart att ge ut finansiella rapporteringskrav för ett potentiellt stort antal system och förbättra jämförbarheten. Liknande studie har gjorts i Europa av PwC och IETA år 2007. Denna studie behandlar hur företag i Sverige valt att redovisa sina utsläppsrätter. En genomgång av de 267 företag som omfattas av handelssystemet för utsläppsrätter i Sverige och innehållsanalys av deras årsredovisningar för år 2014 har gjorts. Därefter har strax över 20 procent av företagen granskats ytterligare för att utreda varför företagen valt att redovisa sina utsläppsrätter på visst sätt. Den insamlade data har sedan analyserats mot tidigare forskning och finansiella redovisningsteorier som behandlar oreglerade finansiell rapportering. Det som har framkommit i studien är att av de företag i Sverige som redovisar utsläppsrätter, redovisar de flesta sina utsläppsrätter framförallt som immateriella tillgångar eller omsättningstillgångar. Tidigare forskning ihop med teorierna kan förklara dessa val av redovisningspraxis som ett nationellt mönster som förmodat skapats i brist på internationell vägledning och med grund i IFRIC 3 för de av företagen som redovisat sina utsläppsrätter som immateriella tillgångar. De utav företagen som har valt att redovisa sina utsläppsrätter som omsättningstillgångar kan förklaras av avsikten med utsläppsrätterna. I studien uppmärksammas även de företag som valt att inte redovisa sina utsläppsrätter som valt att ha upplysningar som beskriver deras utsläpp på annat vis. Företags val av redovisningsmetod av utsläppsrätter förklaras av institutionell teori för företag som redovisat sina utsläppsrätter som immateriella tillgångar och som en överlappning mellan intressentteorin och legitimitetsteorin för de företag som inte redovisar sina utsläppsrätter men har upplysningar om utsläpp. Studiens resultat påvisar både skillnader och likheter med tidigare undersökning av hur stora företag i EU redovisar sina utsläppsrätter och kan därför påvisa att IASB torde kunna utge finansiella rapporteringskrav av utsläppsrätter som redan stämmer överens med redovisningspraxis idag. Detta behöver dock undersökas vidare för att kunna generaliseras till alla länder som omfattas av EU ETS. / Most scientist agree that human influence on the climate in terms of greenhouse gas emissions is a fact. To reduce the human impact, a system of emission rights to regulate emission have been introduced. The idea is that emissions should be reduced gradually by all involved entities and that this should be recognized in every country in special reports. In recognition of the company’s financial status, such as annual reports, there is currently no state regulations governing whether and how there emission rights should be reported. IASB is investigating accounting practices to identify the methods used. Through this survey they try to identify the feasibility of issuing financial reporting requirements for a potentially large number of systems and improve comparability. Similar studies have been made in Europe by PwC and IETA in 2007. This study discusses how companies in Sweden chosen to report their emission rights. A review of the 267 companies covered by the emission trading scheme in Sweden and content analysis of their financial statements for 2014 have been made. Subsequently about 20 percent of the companies have been further examined to determine why companies have chosen to report their emission rights in a certain way. The collected data were analyzed against past research and financial accounting theory such as unregulated financial reporting theory. What has been found in this study is that among companies in Sweden that do report their emission rights, the majority reported their allowances primarily as intangible assets or current assets. Previous research together with the theories can explain the choice of accounting practices as a national pattern that supposedly been created by a lack of international guidance and due to IFRIC 3 for those companies that reported their emission rights as intangible assets. Those companies that have chosen to report their emission rights as current assets can be explained by the intent of the allowances. The study also addresses the companies that have chosen not to declare their allowances and have chosen to have disclosures that describes their emission in other ways. Companies’ choice of accounting method of allowances is explained by institutional theory for the companies that reported their emission rights as intangible assets and an overlap between stakeholder theory and legitimacy theory for companies that do not report their emission rights but have emission disclosures. The study’s results demonstrate both similarities and differences with the precious survey of how large entities in the EU report their emission right and could thereby demonstrate that the IASB should be able to issue financial reporting requirements of allowances that already is consistent with the accounting practices today. This needs to be investigated further in order to be generalized to all countries covered by the EU ETS.

Im ersten Teil meiner Arbeit habe ich den molekularen Mechanismus beschrieben, mit dem endogene neuronale Vorläuferzellen antitumorigen gegen Gliomstammzellen wirken. Unsere Forschungsgruppe hat in bereits veröffentlichten Arbeiten gezeigt, dass neuronale Vorläuferzellen zu experimentellen Gehirntumoren migrieren und Tumorzelltod induzieren können. In der nun vorliegenden Arbeit zeige ich, dass die neuronalen Vorläuferzellen nicht nur benefiziell gegen die Hauptpopulation der Tumorzellen wirken, sondern darüber hinaus auch die kleinere Population der sehr aggressiven Tumorstammzellen – mittels Sekretion von BMP7 – supprimieren. Insgesamt zeigt meine Arbeit, dass neuronale Vorläuferzellen die Pathogenität der Gliomstammzellen unterdrücken. Im zweiten Teil meiner Arbeit habe ich einen zellautonomen Mechanismus untersucht, der Gliomzellen in vitro und in vivo vermehrt expandieren lässt. Meine Ergebnisse zeigen, dass die Familie der ets-Transkriptionsfaktoren Gliomzellen zur Proliferation anregen, indem sie die Expresion eines Eisentransporters (dem Transferrin-Rezeptor-1) induzieren und damit die intrazelluläre Akkumulation von Eisenionen begünstigen. Die Veränderung des Redox-Gleichgewichts in den Gliomzellen regt die Tumore zu verstärkter Sekretion von Glutamat an. Dadurch werden die Gliome sehr zytotoxisch und induzieren Zelltod in den Zellen des tumorumgebenden Parenchyms. Das untergegangene Nervengewebe schafft damit den Platz, den der Tumor zur Expansion braucht. Insgesamt zeigt meine Arbeit, dass die ets1-induzierte CD71 Expression nicht nur das Tumorwachstum befördert, sondern auch den Platz zum Tumorwachstum schafft. / In my first part,Gliomas cells with stem-like properties (GSCs) control tumor growth and recurrence. Here, I showed that endogenous neural precursor cells (NPCs) perform an anti-tumor response by specifically targeting GSCs: In vitro, NPCs predominantly expressed BMP7; BMP7 was constitutively released from neurospheres and induced canonical BMP-signaling in GSCs. Exposure of human and murine GSCs to neurosphere-derived BMP7 increased GSC differentiation, attenuated GSC-marker expression, GSC self-renewal and the ability for tumor initiation.This anti-tumor response of NPCs protect the brain from gliomas by releasing BMP7, which acts as a paracrine tumor suppressor that represses proliferation, self-renewal and tumor-initiation of GSCs. In the 2nd part, Transferrin receptors (TfR) are overexpressed in brain tumors, but the pathological relevance has not been fully explored. Here, I showed that TfR is an important downstream effector of ets transcription factors that promotes glioma proliferation and increases glioma-evoked neuronal death. TfR mediates iron accumulation and reactive oxygen formation and thereby enhanced proliferation in clonal human glioma lines. TfR-induced oxidant accumulation modified cellular signaling by inactivating a protein tyrosine phosphatase (low-molecular-weight protein tyrosine phosphatase), activating mitogen-activated protein kinase and Akt and by inactivating p21/cdkn1a and pRB. Inactivation of these cell cycle regulators facilitated S-phase entry. Besides its effect on proliferation, TfR also boosted glutamate release, which caused NMDA mediated reduction of neuron cell mass. Overall my results indicate that TfR promotes glioma progression by two mechanisms, an increase in proliferation rate and glutamate production, the latter mechanism providing space for the progressing tumor mass.

Le cancer papillaire de la thyroïde (CPT) est la tumeur endocrine la plus fréquente. Des anomalies moléculaires activant la voie des MAPK (Mitogen-Activated Protein Kinases) sont identifiées, de façon mutuellement exclusive, dans environ 70% des cas. Il s’agit de réarrangements chromosomiques, le plus souvent de type RET/PTC (10%), de mutations ponctuelles activatrices des trois isoformes de l’oncogène RAS (H, N et K-RAS) (10%), ou de l’oncogène B-RAF (50%). La mutation « hot spot » B-RAFV600E est la plus fréquemment identifiée, elle est associée à une plus grande agressivité clinique (diagnostic à un stade tardif, risque de récidives et de décès accru). Ces évènements moléculaires ont pour conséquence commune l’activation de la voie des MAPK, se traduisant en aval par la phosphorylation de MEK (Mitogen-activated Extracellular signal-Regulated Kinase) puis de ERK (Extracellular signal-Regulated Kinase). Cette dernière est régulée négativement par des phosphatases, appartenant à la famille des Dual Specificity Phosphatases (DUSPs), d’expression ubiquitaire, et en particulier de deux phosphatases spécifiques de ERK, l’une cytoplasmique (DUSP6) et l’autre nucléaire (DUSP5). Nous avons fait l’hypothèse que ces phosphatases pouvaient être soit des gènes suppresseurs de tumeurs (leur perte d’expression conduisant à une augmentation de phosphorylation de ERK et une prolifération accrue), soit des marqueurs du degré d’activation de la voie MAPK dans le cadre d’une boucle de rétrocontrôle négatif. Ceci nous a conduits à analyser la régulation et l’expression de ces phosphatases dans trois modèles : la lignée cellulaire PCCL3 (thyroïde de rat), exprimant l’un des trois principaux oncogènes mutés dans les CPT (RET/PTC3 ou H-RASV12 ou B-RAFV600E) sous le contrôle d’un promoteur inductible par la doxycycline, des lignées cellulaires humaines dérivant de CPT et des CPT humains. (...) / Papillary thyroid cancer (PTC) is the most common endocrine malignancy. Mutually exclusive and activating alterations of the MAPK pathway (Mitogen-Activated Protein Kinases) are identified in 70% of cases. Common mutations found in PTCs are point mutation of the B-RAF (50%) and RAS genes (10%) as well as RET/PTC chromosomal rearrangements (10%). The hot spot B-RAFV600E mutation is the most frequently alteration identified and is connected with agressive clinical characteristics (high stage at diagnosis, high recurrence risk and death). These molecular events lead to constitutive activation of the MAPK pathway, resulting in MEK (Mitogen-activated Extracellular signal-Regulated Kinase) and ERK (Extracellular signal-Regulated Kinase) phosphorylation. ERK is negatively regulated by phosphatases and among them, Dual Specificity Phosphatases (DUSPs), ubiquitary expressed, in particular two ERK-specific phosphatases DUSP5 (nuclear) and DUSP6 (cytosolic). We hypothesized that these phosphatases could have tumor supressor properties (i.e. their loss would be associated with an increase in MAPK pathway activation) or may serve as a surrogate marker of MAPK pathway activation in the context of a negative feedback loop. We analysed regulation and expression of both phosphatases in 3 models: three PCCL3 cell lines (rat thyroid cells) expressing one of the most common oncogene identified in PTCs (RET/PTC3 or H-RASV12 or B-RAFV600E) under the control of a doxycycline-inducible promoter, human PTC-derived cell lines and human PTC. We demonstrated that MAPK pathway activation was correlated with induction of DUSP5 and DUSP6. These phosphatases are involved in a negative feedback loop that contributes to a tight regulation of phospho-ERK levels. DUSP5 and DUSP6 mRNA are overexpressed in human PTCs, especially in B-RAF mutated tumors suggesting a higher MAPK signaling output in these agressive PTCs. Silencing of DUSP5 and/or DUSP6 by small interfering RNA does not affect proliferation of human B-RAFV600E thyroid carcinoma-derived cell lines, suggesting the lack of tumor suppressor gene role. Compensatory changes in expression of DUSPs when a specific one is inactivated may explain this lack of effect. On the opposite, a DUSP6 pharmacological inhibitor induced a concentration dependent decrease in proliferation of human B-RAFV600E cells, suggesting « off-target » effect of this inhibitor. In a second part, we analysed the regulation of DUSP5 expression, which is a target of the MAPK pathway activation. We demonstrated, using pharmacological inhibitors, that DUSP5 is an early response gene, regulated mostly by the MAPK pathway, at the transcriptional level. Two contiguous CArG boxes that bind serum response factor (SRF) were found in a 1Kb promoter region, as well as several E twenty-six transcription factor family binding sites (EBS). These sites potentially bind Elk-1, a transcription factor activated by ERK1/2. Using wild type or mutated DUSP5 promoter reporters, we demonstrated that SRF plays a crucial role in serum induction of DUSP5 promoter activity, the proximal CArG box being important for SRF binding in vitro and in living cells. Moreover Elk-1 was bound in vitro to a promoter region containing the proximal CArG box and a putative EBS. Its specific binding to SRF was necessary to elicit promoter response to dominant positive Elk-VP16 and to enhance the response to serum stimulation. Altogether our results suggest that the MAPK pathway is more active in B-RAFV600E PTC than in PTC with other genetic alteration and could explain their clinical agressivity. DUSP5 and DUSP6, as well as phosphorylated MEK, are markers of activation of the MAPK pathway. Neither phosphatase has tumor suppressor properties in our thyroid cancer cell models. Our results suggest redundancy and functional compensation among DUSPs. (...)

Getinge AB is a global medical technology company. This master’s thesis is based on the outflow of capital equipments from Getinge’s factory in Växjö to four different sales and service units. The purpose of this thesis is to give Getinge a deeper insight of why the customers and the own organization do not know when they can expect their products. This makes most requests urgent and thus prohibits them from using the best environmental and cost efficient modes of transportation. Two sub-problems have been created in order to investigate this. Sub-problem 1 originates from an organizational perspective. The aim of this problem is to examine the possibilities to achieve less urgent transportations by improving the communication between sales and service units, factories and logistics services. This is evaluated based on semi-structured interviews containing both qualitative and quantitative questions with employees rep- resenting the different functions at the company. It appeared that different phrases, explaining the same thing, were used internally leading to confu- sion. Further, the different functions have harmonized follow-up sessions but do not share the information between each other. The resulting information vacuum creates trust issues and unnecessary time margins and buffers. Sub-problem 2 concerns the trade-off between the economic and environmen- tal impacts in relation to the Greenhouse Gas Protocol Scope 3. This trade- off is evaluated by a multi-objective optimization model, where emissions are priced based on the EU ETS market valuation. Current research argues that the choice of transportation mode is the simplest emissions abatement option in terms of implementation. This study indicates that it is possible for Getinge, in the short-term, to decrease costs and emissions by just chang- ing between current transportation modes. However, a long-term strategy should include evaluation of consolidations, alternative fuels and electrified vehicles since the cost of decreasing one kilogram of emissions by changing between current transportation modes will increase. Finally, increased transparency and communication between sales and ser- vice units, factory and logistics services could be achieved via a one point of contact solution. This could avoid unnecessary time margins and buffers and hence open up the possibility of better over all lead time utilization. This could make it easier to use more environmental friendly transportation modes and thus lower emissions and costs, while still satisfying the customers.

[pt] Tendo em vista mudanças significativas no varejo causadas pelo crescimento de compras online no Brasil, este estudo tem como objetivo facilitar um relevante lead time e um forte grau de assertividade na previsão de demanda do Omnichannel de uma empresa do setor. Com a crescente relevância do Omnichannel, é importante compreender as necessidades dos consumidores tradicionais e digitais, integrar suas experiências e oferecer múltiplos canais de compra. Nesse contexto, a previsão de demanda é crucial para apoiar as decisões estratégicas, táticas e operacionais da organização. A utilização de séries temporais hierárquicas auxilia na precisão das previsões e, portanto, na tomada de decisões, permitindo gerar estimativas coerentes ao longo dos múltiplos níveis hierárquicos. Dessa forma, neste estudo, combinando as metodologias de previsão de séries temporais ETS, ARIMA e SARIMAX, com métodos de reconciliação Bottom-up, Top-down, MinTrace Combinação Ótima (OLS) e MinTrace WLS Struct, doze modelos foram gerados. Baseado nas principais abordagens de séries temporais hierárquicas, com uma sequência de sete passos, os modelos foram comparados, por meio de métricas de avaliação de desempenho, para identificar qual deles melhor se encaixa na série trabalhada. Ao final do estudo, o modelo SARIMAX com Bottom-up se mostrou a combinação mais adequada para a série em análise. A abordagem alcançou um MAPE de 22 por cento no nível mais agregado da hierarquia, reduzindo em cinco pontos percentuais o MAPE original da empresa, além de apresentar a melhor colocação na combinação das métricas comparativamente. / [en] In light of recent changes in retail caused by the growth of online shopping in Brazil, this study aims to enable a substantial lead time and a high degree of accuracy of the Omnichannel demand forecast for a retail company. As Omnichannel success continues to expand, it becomes increasingly important tounderstand the needs of both traditional and digital consumers, integrate their experiences and offer multiple purchase channels. In this context, demand forecasting is crucial for identifying market trends, growth opportunities, potentialstrategies and supporting strategic, tactical and operational decisions. The use of Hierarchical Time Series improves forecasts accuracy and, therefore, assists in decision-making, allowing the development of consistent estimations acrossmultiple hierarchical levels. Thus, this study combines the time series forecast generation methodologies ETS, ARIMA and SARIMAX, with Bottom-up, Top-down, MinTrace Optimal Combination (OLS) and MinTrace WLS Struct reconciliation methods, resulting in the generation of twelve models. Based on the main theories of Hierarchical Time Series and following a 7-steps sequence, the models were compared using performance evaluation metrics to identify the best fit for the investigated series. The research concludes that the SARIMAX model,together with the Bottom-up strategy, proves to be the most appropriate composition for the Hierarchical Time Series under analysis, as it demonstrates the best performance across the evaluation metrics, reaching a MAPE of 22 percent at the most aggregated level of the hierarchy and reducing the original company forecasting MAPE by five percentage points.

The European Union Emission Trading System (EU ETS) is the cornerstone of the EU's transition to climate neutrality by 2050. Significant carbon price increases and ambitious changes to the ETS make phase four (2021-2030) uncharted territory. This thesis exploratively investigates how the EU Emission Trading System (ETS) currently affects Swedish firms’ competitive position within the European Union and how these firms respond to the carbon price. This is done through a qualitative approach with a thematic analysis of findings from interviews with nine Swedish firms within the sectors: Combined Power and Heat generation (CHP), Electricity production, Mining & Refining, and Smelting of iron and steel and of ferroalloys. Our findings show unanimous support for the Emission Trading System as an instrument to reduce carbon emissions, yet significant differences in each firm's response to the carbon price. Uncertainty related to future price development is found to cause difficulties in pricing among firms within the CHP sector. In contrast, firms with free allocation of EU Allowances have limited financial impact. Across the board, the ETS drives clean technology innovation by making fossil technology less appealing. Nonetheless, two instances of competitive losses stemming from system design were recognised: 1) Swedish CHP producers bear emission costs that other European producers do not, as a result of Sweden’s opt-in of the CHP sector, potentially causing carbon leakage within the EU; 2) The maintained division between the manufacturing of iron pellets (NACE 07.10) and sinter (NACE 24.10) keeps benchmarks for sinter high, resulting in less incentive for abatement efforts within EU. This thesis adds to the existing literature by identifying skewness in the harmonisation of the EU ETS and investigating signals to which the firms respond. / Europeiska unionens system för handel med utsläppsrätter (EU ETS) är hörnstenen i EU:s övergång till klimatneutralitet till 2050. Betydande koldioxidprishöjningar och ambitiösa förändringar av ETS innebär att fas fyra (2021-2030) är outforskat territorium. Denna avhandling undersöker explorativt hur EU:s system för handel med utsläppsrätter (ETS) för närvarande påverkar svenska företags konkurrensposition inom EU och hur dessa företag reagerar på koldioxidpriset. Detta görs genom ett kvalitativt angreppssätt med en tematisk analys av resultat från intervjuer med nio svenska företag inom sektorerna: Kraft och Värmeproduktion (CHP), Elproduktion, Gruvindustrin, samt Smältning av järn och stål samt ferrolegeringar. Våra resultat visar enhälligt stöd för systemet för handel med utsläppsrätter som ett instrument för att minska koldioxidutsläppen, men ändå betydande skillnader i varje företags svar på koldioxidpriset. Osäkerhet relaterad till framtida prisutveckling visar sig orsaka svårigheter i prissättningen bland företag inom kraftvärmesektorn. Medan företag med gratis tilldelning av EU-utsläppsrätter har begränsad ekonomisk inverkan. Överlag driver ETS ren teknologiinnovation genom att göra fossil teknik mindre tilltalande. Icke desto mindre erkändes två fall av konkurrensförluster till följd av systemdesign: 1) Svenska kraftvärmeproducenter bär utsläppskostnader som andra europeiska producenter inte, som ett resultat av Sveriges val av kraftvärme-sektorn, vilket potentiellt orsakar koldioxidläckage inom EU; 2) Den bibehållna uppdelningen mellan tillverkning av järnpellets (NACE 07.10) och sinter (NACE 24.10) håller riktmärkena för sinter högt, vilket resulterar i mindre incitament för minskningsinsatser inom EU. Denna avhandling kompletterar den befintliga litteraturen genom att identifiera skevheter i harmoniseringen av EU ETS och vilka styrsignaler som företagen reagerar på.

Le blocage du processus de maturation est un élément central de l’oncogenèse des LAL-Tcomme en témoigne la forte corrélation observée entre le stade d’arrêt de maturation et le type d’oncogène dérégulé. Une meilleure compréhension des mécanismes moléculaires responsables de l’arrêt de différenciation est une piste de choix dans la recherche de thérapie« différenciante ». Les LAL-T qui expriment les oncogènes TLX1/HOX11 et TLX3/HOX11L2correspondent à des lymphoblastes T ayant arrêté leur développement au stade cortical « préalphabeta». A ce stade, les thymocytes expriment une chaine TCRβ mais n’expriment pas la protéine TCRα. Une analyse moléculaire du locus TCRα montre que ce dernier n’est pas réarrangé dans ces LAL-T. Notre hypothèse est que les oncoprotéines TLX1 et TLX3bloquent l’expression et le réarrangement du locus TCRα et ainsi sont directement impliqués dans l’arrêt de la différentiation au stade pré-αβ. La mise en route des réarrangements aulocus TCRα est sous le contrôle d’un élément de régulation de la transcription situé en 3’ dulocus : l’enhancer alpha (Eα) dont l’activation nécessite les facteurs de transcription ETS1,RUNX1 et LEF1. Nous avons montré que l’expression de TLX1/3 réprime l’activité transcriptionnelle de l’enhanceosome Eα, que cette répression est dépendante de l’homéodomaine et qu’elle est spécifique et dose dépendante. De plus, nous avons mis en évidence que cette répression exercée par TLX1/3 est possible par une interaction protéine/protéine mise en évidence par Co-IP avec ETS1. Nous avons montré par EMSA que ETS1recrute TLX1/3 au niveau de Eα et confirmé ces résultats in vivo par la technique de ChIP.Par ailleurs, par une approche fonctionnelle de ‘knockdown’, nous avons utilisé des lentivirus contenant des vecteurs shRNAs de TLX1 et TLX3 afin d’éteindre leur expression dans les lignées cellulaires LAL-T qui l’exprime (respectivement ALL-SIL et DND-41). Ces expériences nous ont permis d’observer qu’au sein de ces lignées LAL-T TLX+, la down-régulation des oncogènes TLX1/3 est accompagnée d’une réactivation de l’Eα, traduite par la présence d’expression de transcrits germinaux du TCRα. L’ensemble de nos résultats suggère que TLX1/3 sont impliqués dans l’inhibition du locus TCRα et, par conséquence dans l’arrêt de différenciation observé dans ces leucémies / Acute lymphoblastic leukemias (ALL) are characterized by multi-step oncogenic processesleading to a cell differentiation arrest. Improved understanding of the underlying molecular mechanisms is a prerequisite for targeted therapeutic approaches. In T lineage ALLs, over expressionof the orphan homeobox factors, TLX1 or TLX3 is associated with a corticalthymic maturation arrest. We demonstrate that both TLX1 and TLX3 proteins interact withETS1, an essential component of the TCRα gene-enhanceosome, resulting in repression ofenhancer activity, blocked TCR-Jα rearrangement, and auto-extinction of clones with a TCRαenhancer driven TLX1-TCRδ chromosomal translocation. Our results identify novel functionsfor homeodomain proteins during T-cell development and imply that TLX1/3 exert an ETS1-dependent block to αβ T-cell maturation in T-ALLs, there fore representing promising targets for differentiation therapy