No description available.

No description available.

Interferons (IFNs) are a class of structurally related proteins first discovered to be produced by virus-infected cells. By now, several other inducing agents have been described. IFNs exert multiple effects on cells exemplified by the establishment of an antiviral state, inhibition of cell proliferation and alteration of different immune reactions. In the present thesis the inhibition of cellular growth concentrated on effects in the early cell cycle have been studied. The human glioma cell line 251 MG was found to be blocked in the S phase of the cell cycle upon addition of IFN both to exponentially growing and growth-factor depleted, synchronized cells. Thymidine kinase and DNA-polymerase activities were reduced in parallel with the S phase effect. 2-5 oligo Anucleotides transfected into glioma cells lead to inhibition of cell growth, exponentially growing cells being blocked in the S phase as during IFN treatment. In contrast, synchronized, restimulated cells were blocked in the cellcycle phase where they resided at the time of transfection. As 2-5 oligo A synthetase activity was induced in the middle of the Gl phase, these results might indicate that the kinetics of expression of oligonucleotides after IFN additiondetermines the type of cell cycle block obtained in differenttumor cells. IFN inhibited preferentially proteins originating from newly synthesized mRNA in Sw 3T3 cells, c-mvc did not seem to be included among these proteins. In both cell systems c-myc expression was unaltered after IFN treatment. In clone T1 selected from the the Sw 3T3 cell line , c-mvc expression was uncoupled to growth and seemed to be growth factor independent. The change in c-myc expression in clone T1 compared to SW 3T3 cells did not render the cells sensitive to IFN. Hence, c-myc regulation does not seem to be the mechanism by which IFN regulates cell growth in this system. The proliferation marker KI-67 antigen was shown not to be causatively involved in growth inhibition of IFN. The reduced levels of the antigen was proposed to be a secondary effect caused by the G0/G1 arrest. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1991, härtill 6 uppsatser</p> / digitalisering@umu

Albright’s hereditary osteodystrophy (AHO) is a rare inherited disease characterized by skeletal abnormalities, short stature, and, in some cases, resistance to parathyroid hormone, resulting in pseudohypoparathyroidism (PHP). Heterozygous inactivating mutations of the GNAS1 gene are responsible for reduced activity of the alpha subunit of the Gs protein (GSα), a protein that mediates hormone signal transduction across cell membranes. Gsα is also known to have oncogenic potentials, leading to the development of human pituitary tumors and Leydig cell tumors. Here, we report the 1st case, a 3.5-year-old girl, with classic AHO phenotype and PHP type 1A associated with a cerebellar pilocytic astrocytoma. Coincidence or genetic relationships of both diseases are discussed according to molecular findings and current literature. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

A disease has consequences not only for the afflicted person but also for those who interact with him or her. A low-grade glioma is a brain tumour whose regarding its psychosocial implications for adult patients and their next of kin has received little attention in the literature. In the light of this the overall aim of the present thesis was to provide increased knowledge about how patients with low-grade glioma and their next of kin experience and deal with everyday life. The methods of the studies were mainly qualitative. Thirty-nine patients and 28 next of kin were interviewed and all except one next of kin completed a quality of life questionnaire. The onset of low-grade glioma was described from the patients’ perspective as a process, either rapid (up to a few months) or prolonged over several years. This phase of low-grade glioma encompassed repeated visits to physicians and care institutions. The onset of low-grade glioma was accompanied by stress, anxiety and uncertainty in the case of both the patients and those nearest. The symptoms and problems the patients experienced covered a broad range of consequences, physical, psychological and social. The patients presented a wide range of ways to cope with illness-related problems. The next of kin were often deeply involved in the patients’ situation and many of them experienced extremely stressful emotions mainly in the early period of the illness. They had experience of positive encounters in health care but more often they had had a sense both of powerlessness and of being invisible and neglected. Relations and roles changed in ways that mostly were experienced as negative. Enabling strength in everyday life had to do with alleviation of strain and having a positive outlook upon life. By means of the questionnaire Subjective estimation of Quality of Life (SQoL) the patients and those nearest estimated their quality of life as being comparatively high. Only one variable, among the patients the absence of work/meaningful occupation and among the next of kin the absence of own children, being estimated at below 60% of the maximum score.

Comprendre comment le cerveau humain engendre les formes les plus élaborées de comportements est profondément lié à nos connaissances générales sur son organisation anatomique et fonctionnelle. Jusqu'à récemment encore, on pensait que les fonctions cognitives n'étaient rien d'autre que le sous-produit de l'activité neurale de régions corticales discrètes et hyper-fonctionnalisées. Les découvertes majeures obtenues ces dix dernières années dans le champ de la neuro-imagerie, et plus particulièrement de la connectomique, invitent cependant à complexifier nos représentations sur les liens qu'entretiennent structures et fonctions cérébrales. Le cerveau semble en effet être organisé en systèmes neurocognitifs complexes, hautement distribués et plastiques. C'est dans cet esprit qu'a été réalisé ce travail de thèse dont l'ambition première a été de repenser les modèles actuels de la cognition sociale, et en particulier ceux ayant trait à la fonction de mentalisation, à travers l'étude comportementale des patients porteurs d'un gliome diffus de bas-grade. Cette tumeur neurologique rare constitue un excellent modèle physiopathologique en vue du démasquage des structures maîtresses des systèmes cognitifs complexes, en ce qu'elle induit des phénomènes majeurs de réorganisation fonctionnelle, et s'infiltre préférentiellement le long de la connectivité axonale associative. Des corrélations anatomo-cliniques ont été réalisées suivant une approche topologique classique (analyse de groupe en régions d'intérêt, cartographie voxel-based lesion-symptom, stimulation électrique corticale intra-opératoire) mais également hodologique (degré de déconnection des faisceaux d'association, stimulation électrique de la connectivité axonale). Les résultats principaux de nos différents travaux nous permettent de jeter les premières bases d'un modèle à double voie dynamique (plastique) et hodotopique (contraint par la réalité anatomique) de l'organisation anatomo-fonctionnelle des processus de mentalisation. Spécifiquement, une voie dorsale, interconnectant le aires corticales fronto-pariétales « miroirs » via le système périsylvien de substance blanche associative (faisceau arqué et faisceau longitudinal supérieur latéral), sous-tendrait les processus perceptifs de « bas-niveau » nécessaires à l'identification préréflexive des états mentaux ; une voie cingulo-médiane, interconnectant les régions préfrontales médiales et rostro-cingulaires aux régions pariétales postérieures médiales via le faisceau cingulaire, sous-tendrait les processus de «haut-niveau » nécessaires aux inférences mentalistiques conscientes. Ces découvertes constituent une avancée substantielle en neurosciences sociales, ont des implications importantes pour la prise en charge clinique des patients, et peuvent permettre de mieux comprendre certaines psychopathologies caractérisées à la fois par un trouble de la mentalisation et des anomalies structurales de la connectivité associative (troubles du spectre autistique). / Understanding how the brain produces sophisticated behaviours strongly depends of our knowledge on its anatomical and functional organization. Until recently, it was believed that high-level cognition was merely the by-product of the neural activity of discrete and highly specialized cortical areas. Major findings obtained in the past decade from neuroimaging, particularly from the field of connectomics, prompt now researchers to revise drastically their conceptions about the links between brain structures and functions. The brain seems indeed organized in complex, highly distributed and plastic neurocognitive networks. This is in this state of mind that our work has been carried out. Its foremost ambition was to rethink actuals models of social cognition, especially mentalizing, through the behavioural study of patients harbouring a diffuse low-grade glioma. Because this rare neurological tumour induces major functional reorganization phenomena and migrates preferentially along axonal associative connectivity, it constitutes an excellent pathophysiological model for unmasking the core structures subserving complex cognitive systems. Anatomo-clinical correlations were conducted according to both a classical topological approach (region of interest analyses, voxel-based lesion-symptom mapping, intraoperative cortical electrostimulation) and a hodological approach (degree of disconnection of associative white matter fasciculi, intraoperative axonal connectivity mapping). The main results of our different studies enable us to lay the foundation of a dynamic (plastic) and hodotopical (connectivity) dual-stream model of mentalizing. Specifically, a dorsal stream, interconnecting mirror frontoparietal areas via the perisylvian network (arcuate fasciculus and lateral superior longitudinal fasciculus), may subserve low-level perceptual processes required in rapid and pre-reflective identification of mental states; a cingulo-medial stream, interconnecting medial prefrontal and rostro-cingulated areas with medial posterior parietal areas via the cingulum, may subserve higher-level processes required in reflective mentalistic inferences. These original findings represents a great step in social neuroscience, have major implications in clinical practice, and opens new opportunities in understanding certain pathological conditions characterized by both mentalizing deficits and aberrant structural connectivity (e.g. autism spectrum disorders).

Les gliomes sont les principales tumeurs primitives du cerveau affectant environ 4000 nouveaux patients par an en France. La moitié des gliomes est détectée au stade avancé de glioblastome (grade IV) tandis que 15% des tumeurs sont diagnostiquées au stade II de gliomes diffus dit de bas grade. Ces tumeurs affectent des patients jeunes et présentent des mutations caractéristiques, notamment une mutation pour l’enzyme IDH1 communément retrouvée dans les glioblastomes secondaires. Ces tumeurs de bas grade sont traitées par une chirurgie, idéalement en condition éveillée mais du fait de leur nature diffuse, la partie résiduelle progressera inexorablement vers un stade III ou IV avec une survie globale entre 5 ans et 15 ans après diagnostique. La progression tumorale est hautement variable et non prédictible d’un patient à l’autre. Des foyers de progression tumorale chez 20% des patients atteints de gliome diffus de bas grade ont été identifiés. Ces foyers montrent une densité cellulaire plus élevée ainsi qu’un Ki67 augmenté. Mon travail de thèse aura consisté à étudier les modifications cellulaires et moléculaires associées à ces foyers de progression tumorale. À partir du profil ARN des foyers et des territoires adjacents, j’ai pu mettre en évidence par des techniques haut-débit la baisse d’expression significative de gènes dans les foyers notamment de AGXT2L1/ETNPPL, carboxypeptidase E, EDNRB, SFRP2. J’ai émis l’hypothèse que SFRP2 et ETNPLL pourraient s’opposer à la prolifération cellulaire et que leur diminution dans les foyers ouvrirait la voie à la transformation tumorale. Une corrélation inverse entre la quantité d’ETNPPL enzyme et la survie de patients atteints d’hépatocarcinomes a été publiée. En limitant la quantité de précurseurs de phospholipides dans la cellule, ETNPPL pourrait agir comme un frein en s’opposant à la prolifération et de fait, sa diminution dans les foyers de transformation des gliomes pourrait lever cette inhibition. Mes travaux auront été innovants tant dans leur approche comparative des différents compartiments tumoraux pour chaque patient étudié et auront révélés ETNPPL comme corrélé à la gliomagenèse et potentielle cible thérapeutique. / Gliomas are the main primary brain tumours affecting around 4000 new patients in France each year. Half of gliomas are detected in the advanced stage of glioblastoma (grade IV) while 15% of tumours are diagnosed in stage II (diffuse low-grade gliomas-DLGG). These tumors affect young patients and bear characteristic mutations, including a mutation for the enzyme IDH1 commonly found in secondary glioblastomas. These low-grade tumours are treated by surgery, ideally in awake condition but due to their diffuse nature, the residual part will progress inexorably to stage III or IV with overall survival between 5 and 15 years after diagnosis. Tumor progression is highly variable and unpredictable from one patient to another. Foci of tumor progression have been identified in 20% of patients with DLGG. These foci show a higher cell density and an increased Ki67. My thesis work consisted in studying the cellular and molecular changes associated with tumor progression. From the RNA profile of the foci and adjacent territories, I was able to highlight through high-throughput techniques significant decrease in gene expression in the foci, particularly of AGXT2L1/ETNPPL, carboxypeptidase E, EDNRB, SFRP2. I hypothesized that SFRP2 and ETNPLL could oppose cell proliferation and that their decrease would pave the way for tumor transformation. An inverse correlation between the amount of ETNPPL and the survival of patients with hepatocarcinoma has been published. By limiting the amount of phospholipid precursors in the cell, ETNPPL could act as a brake against proliferation and indeed, its decrease in glioma transformation foci could remove this inhibition. My PhD work will have been innovative in the comparative approach of the different tumors’ compartments for each patient studied and will have revealed ETNPPL as correlated to gliomagenesis and as potential therapeutic target.

The glial cells of the brain and the peripheral nervous system retain the capacity to divide and proliferate throughout the lifespan of an individual and thereby have the propensity to give rise to the most adult neurological tumours. Among them, the tumours which arise from different kinds of glial cells are referred to as gliomas. Of the various types of gliomas, astrocytomas are the most common central nervous system neoplasms which make upto 60% of all the primary brain tumours. Being the most prevalent type, the WHO classifies them into grades ranging from I to IV based on their intensity of malignancy. Grade IV astrocytoma or Glioblastoma (GBM) is considered to be the most malignant form with a median survival of 14.6 months, in spite of all therapeutic modalities. GBM is further classified as primary and secondary GBM. Primary GBM manifests de novo without any early history of pre-malignant lesions, on the other hand secondary GBM arises progressively from lower grades over a period of 5-10 years. Like other malignancies, GBM also arises from various genetic and epigenetic variations. Epigenetic variations include all such mitotically and meiotically heritable traits that do not involve changes in DNA sequence. There are three major areas of epigenetics - DNA methylation, histone modifications and non-coding RNAs which are known to have profound effects on gene expression. A lot being known about the genetic derailments in GBM, in this study we looked into the epigenetic aspects of GBM. In our lab, we have carried out various high throughput studies, which unveiled the distorted landscape of DNA methylation and miRNA expression in GBM. This indicates that, in addition to the genetic mechanisms of gene alterations like mutations, copy number aberrations, protein coding genes are also affected by changes in methylation as well as by miRNA misregulation. The study has been divided into two parts. Part one of the study deals with the identification of chromobox homolog 7 (Cbx7), as a hypermethylated and downregulated gene in GBM. More importantly, Cbx7 is a member of the polycomb repressive complex and brings about its function through chromatin modifications. Here we have investigated the role of Cbx7 in gliomagenesis, and why it has to be silenced by methylation for tumorigenesis to ensue. In part two, we elucidated two unique ways of miRNA regulation in GBM. In the first section, we identified miR-326 as a PI3 kinase regulated miRNA and demonstrated its tumour suppressive role in GBM. In the other section, we analysed the copy number aberration data from TCGA and identified miR- 4484 as a miRNA subjected to deletion in GBM. We further went ahead to demonstrate its growth suppressive role in GBM. Part 1: Epigenetic regulation of the chromatin modifier Cbx7; chromobox homolog 7 DNA methylation is involved in the normal cellular control of expression and thereby plays a crucial role in maintaining the homeostasis of the cell. The phenomenon of DNA methylation keeps the various loci of the genome such as the germline specific genes and the repetitive transposable elements silenced, whereas the tumour suppressors and other growth modulator genes are spared from the methylation induced gene repression. One of the important steps that promote tumorigenesis is aberrant hypermethylation, which leads to the silencing of tumour-suppressor genes. Another important epigenetic phenomenon that affects the transcriptibility of the genome is histone modifications, which control the accessibility of the chromatin to the transcriptional machinery. In this section, we identified Cbx7, which happens to be an essential component of the chromatin modifying machinery, as an epigenetically regulated gene in GBM. We observed from the methylation array carried out in our lab, that Cbx7 was one of the highly methylated genes. We also validated that Cbx7 is downregulated in GBM and the same observation was further corroborated from other data sets. The hypermethylated state of Cbx7 was confirmed by DNA bisulphite sequencing and the expression levels of Cbx7 also got alleviated after 5-Aza-2′-deoxycytidine treatment, which is a DNA methylation inhibitor. This indicated that the down regulation of Cbx7 could be attributed to the methylation of its promoter region. In order to figure out the role of Cbx7 in GBM, we carried out transcriptome analysis of Cbx7 overexpressing cells compared to vector control condition by RNA sequencing. Gene ontology analysis revealed a significant enrichment of pathways involved in cell cycle, migration and invasion like processes. In fact, the exogenous overexpression of Cbx7 leads to cell death, reduced colony formation, retarded migration and invasion of cells. In order to explain the above phenotypes brought about by the exogenous expression of Cbx7, we further examined the RNA sequencing data and observed that many of the top most downregulated genes in Cbx7 overexpression state belonged to the Hippo signaling pathway. The effectors of the Hippo pathway, YAP and TAZ which essentially antagonize the pathway activity, are well known for their role in proliferation, migration and invasion in cancer. So we carried out a Gene Set Enrichment Analysis (GSEA) and found that there was a significant negative enrichment of YAP/TAZ targets in the Cbx7 regulated gene set. We validated some of these targets that were downregulated by Cbx7 overexpression. One of the most downregulated genes that we validated was Connective Tissue Growth Factor (CTGF), which also happens to be a bonafide target of YAP/TAZ. Independent downregulation of CTGF also resulted in reduced migration, thereby phenocopying the effects as were produced by Cbx7 overexpression. Moreover, we also observed that SAPK/JNK was the only kinase whose activity was abolished upon Cbx7 overexpression. Since CTGF is known to activate SAPK/JNK, we assessed the SAPK/JNK activity upon CTGF silencing. We found that levels of phospho-SAPK/JNK were significantly reduced in CTGF silenced condition. In addition to that, the inhibition of the SAPK/JNK by synthetic inhibitor also hampered the migration ability of the cells. We were also able to rescue the loss of migratory potential of glioma cells by the exogenous overexpression of CTGF in Cbx7 stable background. A similar rescue was also achieved by the overexpression of a constitutively active form of SAPK/JNK. This indicates that Cbx7 activates Hippo pathway to inhibit YAP/TAZ dependent transcription, resulting in the downregulation of CTGF, thereby inhibiting CTGF mediated activation of SAPK and thus resulting in the inhibition of glioma cell migration. PART 2: ROLE OF MIRNAS IN GLIOMA DEVELOPMENT AND PROGRESSION miRNAs are a class of small non-coding RNAs that are not translated into functional proteins but still contribute to numerous cellular processes, thereby adding yet another realm of regulation and control. miRNAs bring about gene regulation at the post-transcriptional level, either by degrading the mRNA or by translational repression and in this manner fine tune the expression of protein coding genes. miRNAs are often located in the most fragile sites of the genome which exposes them to grave genetic alterations, thus providing a circumstantial evidence of their etiological role in tumorigenesis. In a malignant state, miRNAs have been found to play pivotal roles in cellular transformation by altering various cellular phenotypes. Owing to their participation in diverse cellular functions, miRNAs have gained a strong foothold in gene regulation. Though a lot has been deciphered about the functional aspect of miRNAs, not much is known about the precise mechanisms which lead to their misregulation and therefore demands in-depth study. The expression of miRNAs can be modulated by a variety of genetic and epigenetic mechanisms. Section I: Role of miR-326 – a PI3 kinase regulated miRNA, in gliomagenesis The TCGA group in the year 2008 identified three major pathways which go disarray in GBM. These include the pro-tumorigenic receptor tyrosine kinase (RTK) pathway, and the p53 and the pRB tumour-suppressive pathways. The RTK signalling includes the PI3 kinase pathway, which is pivotal in gliomagenesis and many other cancers. This directed us to elucidate the set of miRNAs which are controlled by the aberrant functioning of the PI3 kinase pathway. We used synthetic inhibitor LY294002 to abrogate the PI3 kinase signalling and examined the miRNA profile in two glioma cell lines U87 and U251, which have an activated PI3 kinase pathway. Indeed the abrogation of the PI3 kinase pathway resulted in the modulation of a wide array of miRNAs. We validated miR-326 as one of the miRNAs that was upregulated upon PI3 kinase pathway abrogation. Furthermore, we observed that miR-326 was a down regulated miRNA in GBM and different glioma cell lines, as well as in many other publicly available data sets. We also observed that miR-326 is an intragenic miRNA and its host gene Arrestin β1 (ARRB1) also exhibited similar upregulation upon PI3K pathway inhibition. Over-expression of miR-326 resulted in various anti-tumorigenic affects like reduced proliferation, reduced migration and colony suppression. In order to find the targets of miR-326, we analysed the transcriptome by RNA sequencing upon pre-miR-326 transfection. We shortlisted and validated some of the genes which were getting regulated through miRNA over-expression and also explain the functional role of miR-326. Section II: Role of miR-4484 – a copy number deleted miRNA, in gliomagenesis In the TCGA study mentioned above, it was also unfurled that there are many genes in the RTK, p53 and pRB signalling pathways which are made dysfunctional through gene deletions and amplifications. We envisaged whether it is only the protein coding genes which are subjected to such regulations or the non-coding genes like miRNAs as well. In this pursuit, we identified miR-4484 as one of the miRNAs located in the deleted region of uroporphyrinogen III synthase (UROS) gene in the chromosome 11 of the GBM genome. As conceived, miR-4484 was observed to be a downregulated miRNA in association with its host gene UROS. We further elucidated that the downregulation was due to the co-deletion of a locus harbouring both the protein coding gene and the miRNA. In addition, upon over-expression of miR-4484, we observed reduced migration and colony formation, indicating its role as a tumour–suppressor. For seeking the targets of miR-4484, we extracted RNA from miR-4484 over-expression condition and subjected it to RNA sequencing. We shortlisted and validated some of the genes which were getting regulated through miRNA over-expression and possibly explain the functional role of miR-4484.

Les gliomes malins de l’enfant (GME), de pronostic sombre, se distinguent des gliomes malins de l’adulte (GMA) sur le plan biologique mais aussi clinique, avec des taux de réponse au témozolomide (chimiothérapie alkylante de référence chez l’adulte) moindres. L’efficacité du temozolomide est réduite par l’action de l’enzyme de réparation de l’ADN, l’O6-methylguanine-DNA-methyltransferase (MGMT), dont l’expression est fréquemment inhibée par méthylation du promoteur de son gène dans les GMA. En première partie, la mise au point d’une nouvelle technique de PCR spécifique de méthylation a montré une fréquence plus faible dans les GME (15%) vs les GMA (45%, p<0,001). En deuxième partie, l’hypoxie intra-tumorale et la dérégulation en amont de l’axe mTOR-HIF-1α, connus pour être impliqués dans la chimio-résistance, ont été étudiés dans les GME et ciblés par l’association rapamycin-irinotecan dans une étude in vitro, pour laquelle des lignées dérivées de GME ont été développées. / Pediatric malignant glioma (PMGs), are associated with a very dismal prognosis. They are distinct from their adult counterparts (AMGs), biologically but also clinically, with a lower response to temozolomide (the current reference alkylating chemotherapy) compared to AMGs. Temozolomide efficacy is reduced by the activity of the DNA repair enzyme, O6-methylguanine-DNA-methyltransferase (MGMT), whose expression is frequently silenced by promoter methylation. First, the development of a new methylation-specific PCR showed a lower frequency of MGMT methylation in PMGs (15%) vs AMGs (45%, p<0,001). Secondly, intra-tumor hypoxia and the upstream deregulation of mTOR-HIF-1α axis, well-known to be involved in chemo-resistance and the up-regulation of MGMT expression, were studied in a PMG cohort. The targeting of this axis was then studied in vitro using a therapy combining rapamycin and irinotecan. For this, pediatric patient-derived malignant glioma cell lines were developed.

Les cellules souches de gliomes (CSG), une sous-population de cellules tumorales, seraient en partie responsables de l’échec des traitements des gliomes de par leur résistance et leur capacité régénérative. Le mécanisme alternatif (ALT) de maintenance des télomères, basé sur la recombinaison homologue et non pas sur la télomérase, est détecté dans environ 30% des gliomes humains suggérant que des stratégies thérapeutiques spécifiquement dirigées contre ALT pourraient avoir un intérêt thérapeutique. Dans ce travail, nous avons poursuivi la caractérisation du premier exemple de CSG humaines ayant un phénotype ALT, les cellules TG20. Nous avons montré que malgré leur très fort taux de recombinaison, les télomères de ces cellules continuaient à assurer leur fonction de protection des chromosomes. Nous avons vérifié que les cellules TG20 conservaient leur capacité à générer des tumeurs intracérébrales après des transplantations sériées chez les souris immunodéprimées tout en gardant un phénotype ALT. Ces résultats confirment à la fois les propriétés de cellules souches cancéreuses des cellules TG20 et la capacité de ALT à assurer la maintenance des télomères nécessaire à l’autorenouvellement et au fort taux de prolifération des CSG in vivo. La greffe intracérébrale de cellules TG20 chez des souris immunodéprimées représente donc un bon modèle d’étude préclinique des gliomes ALT. Nous avons ainsi montré qu’un traitement précoce par un ligand des G-quadruplexes télomériques, 360B, juste après la greffe de cellules TG20, était capable d’inhiber le développement tumoral suggérant l’intérêt de l’utilisation de ligands des G-quadruplexes pour cibler spécifiquement les CSG ALT. Une étude des profils d'expression transcriptomique des cellules TG20 et de plusieurs lignées de CSG humaines exprimant la télomérase, nous a conduit à nous intéresser aux rôles de deux lysine acétyl transférases homologues, PCAF (P300/CBP Associated Factor) et GCN5 (General Control Nonderepressible 5) dans la régulation de la recombinaison télomérique des cellules ALT. Nous avons montré que les inhibitions de ces deux protéines ont des effets opposés sur le mécanisme ALT. Nous proposons qu’une balance d’expression de PCAF et GCN5 régule la maintenance des télomères dans les cellules ALT via le contrôle du turnover de TRF1 ce qui pourrait constituer la base d’une nouvelle stratégie thérapeutique vis-à-vis des gliomes ayant un phénotype ALT. / Glioma stem cells (GSC), a subpopulation of tumor cells, are partly responsible for the failure of treatment of gliomas because of their resistance and regenerative capacity. The mechanism of alternative lengthening of telomere (ALT), based on homologous recombination, is detected in approximately 30 % of human gliomas. Therefore, therapeutic strategies directed specifically against ALT may have a therapeutic value. In this work, we further characterized the first model of human ALT GSC, the TG20 cells. We showed that despite their very high rate of recombination, the telomeres were still capable of fulfilling their protective function of chromosomes. We verified that the TG20 cells retained their ability to generate intracerebral tumors after serial transplantations in immunocompromised mice, while preserving an ALT phenotype. These results confirm the cancer stem properties of TG20 cells and the ability of ALT to ensure telomeres maintenance, which is required for the self-renewal and the high proliferation rate of GSC in vivo. Intracerebral grafts of TG20 cells in immunocompromised mice represent thus a good preclinical model for studying ALT gliomas. We have shown that treatment with a ligand of telomeric G-quadruplexes, the 360B, at an early stage of TG20 tumor engraftment, was able to inhibit tumor growth, showing the interest of the use of G-quadruplex ligands to specifically target ALT GSC. Transcriptomic profiling of TG20 cells and several other GSC telomerase-positive lines, incited us to study the roles of two homologous lysine acetyl transferases, PCAF (p300/CBP Associated Factor) and GCN5 (General Control Nonderepressible 5), in the regulation of telomeric recombination in ALT cells. We showed that the inhibition of these two proteins has opposite effects on the ALT mechanism. We propose that a balance of expression of PCAF and GCN5 regulates the telomere maintenance in ALT cells by controlling the turnover of TRF1. This model could serve for the development of new therapeutic strategies targeting ALT gliomas.