Tesi sul tema "Leucémie aigüe lymphoblastique – Génétique"
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Montpellier, Bertrand. "Recombinaison V(D)J illégitime et développement de leucémies aigues lymphoblastiques T". Aix-Marseille 2, 2008. http://theses.univ-amu.fr.lama.univ-amu.fr/2008AIX22086.pdf.
Testo completoT-ALL is a lymphoid neoplasia that accounts for 10-15% of pediatric ALL and 25% of adult ALL. Alarmingly, and despite indisputable success achieved in treatments its incidence is increasing and its prognostic remains pejorative. Survival rate outcome depend notably on a better understanding in pathogenic mechanisms. In this context, the thesis work has been the following: 1) Based on the observation that rare chromosomal SJ keep on recombining in cis using V(D)J recombination, we hypothesized that episomal SJ (ESJ) still remain reactives and can undergo genomic reintegration. We show that mechanistically, ESJ efficiently rearrange in trans and that the cRSS, the sequences targeted in oncogenic chromosomal translocations, are good ESJ integration sites. Moreover, we demonstrate the presence of ESJ reintegration events in vivo and estimate their frequency to ~1/104-6. In conclusion, ESJ reintegration is a potential mechanism of oncogenic deregulation. 2) Conventional and illegitimate V(D)J recombination events (e. G. Translocations) are ordered during lymphocyte development. Based on our knowledge on chromosomal translocation mechanisms, we determine the kinetics of a subset of oncogenic activations acquired during the transformation process in a T-ALL patient’s leukemic cells. Moreover, we identified up to 10 independent oncogenic events in this patient, illustrating the multi-hit characteristic of T-ALL. Finally, the oncogenic event’s functional impact suggests that cMyc play an important role in the particularly aggressive features of the T-ALL developed by this patient
España, Alexandre. "Caractérisation des enhancers dérégulés dans la leucémie aiguë lymphoblastique de type T". Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0481.
Testo completoSeveral genetic abnormalities in T-cell acute lymphoblastic leukemia (T-ALL) affect transcription factors or epigenetic regulators and mainly block the differentiation of T cells, thus delimiting subgroups of AL-T with specific genetic expression profiles. The regulation of the expression of cell-type-specific genes requires the interaction of different types of cis-regulatory elements (promoters, enhancers, isolators, inactivators. Given the well-recognized role of epigenetic deregulation in leukemogenesis, it is likely that a significant fraction of oncogenic enhancers remains to be discovered and functionally evaluated, and this was the subject of my thesis work. We identified potential enhancers in subpopulations of healthy thymus cells and tumor cells of LAL-T patients and thus determined 17,406 potential enhancers deregulated in T-ALL. Enhancers close to a list of genes known to be altered in LAL-T and enhancers whose presence is correlated with the overexpression of close oncogenes (NKX3-1, NKX3-2, TAL1, MYC, LMO2, or JDP2) are among them. We have also identified a new enhancer of TAL1 that appeared following a monoallelic somatic mutation incorporating a MYB site. Additionally, two high-throughput screening strategies (CapSTARR-seq and CRISPRi) have been implemented to evaluate the activity and function of potential enhancers, as well as validate the oncogenic relevance of the NKX3-2 enhancer and the HHEX gene through a CRISPR/Cas9 approach
Rouault, Jean-Pierre. "Caractérisation structurale et fonctionnelle d'un nouveau gène antiprolifératif, BTG1". Lyon 1, 1992. http://www.theses.fr/1992LYO1T089.
Testo completoRegnat, Séverine. "Quantification du transcrit TEL-AML1 pour le suivi de la maladie résiduelle des enfants atteints de leucémie aigüe lymphoblastique avec t(12;21)". Paris 5, 1998. http://www.theses.fr/1998PA05P176.
Testo completoLardeur, Henic Nathalie. "Étude cytogénétique et moléculaire des hémopathies présentant un chromosome Philadelphie". Lille 1, 1997. http://www.theses.fr/1997LIL10214.
Testo completoBen, Abdelali Raouf. "Détection des anomalies génétiques dans les LAL-T : de la biologie à la clinique". Thesis, Paris 11, 2011. http://www.theses.fr/2011PA11T013.
Testo completoT-cell acute lymphoblastic leukemia (T-ALL) are lymphoid neoplasms characterized by theproliferation of malignant T lymphoblasts arrested at early stages of maturation. Maturation arrest in TALLmirrors normal lymphopoiesis. Thus we have shown that the myeloid transcription factor CEBPA,expressed only in the most immature thymic precursors (ETP), is commonly repressed byhypermethylation in T-ALL with the exception of the most immature subset. It is now widely acceptedthat T-ALL is a “multi-hits” disease where the type A oncogenes affect the differentiation while type Boncogenes are involved in cell cycle regulation, self-renewal and T-cell commitment. The Notchsignaling pathway, crucial for T cell development, is constitutively activated by the occurrence ofmutations in NOTCH1 and /or FBXW7 (N / F) genes in approximately 60% of T-ALL. The prognosticvalue of these mutations is controversial. In our study, we showed that N/F mutations are morefrequently observed in T-ALL arrested at a cortical stage of maturation and confer a good prognosiswhich seems to be influenced by the therapeutic regimen. In this large cohort of T-ALL we could alsodetermine the frequency of the CALM-AF10 oncogenic abnormality. The latter is very common in TALLdeveloped from ETP wich are of very poor prognosis. We have shown that this is the presence ofCALM-AF10 which confers the poor prognosis in this subtype of T-ALL. Contrary to the litterature wedid not find any prognostic value associated with the overexpression of ERG and BAALC genes. Thestudy of genetic abnormalities in T-ALL provides a better understanding of oncogenesis and identifyabnormalities with prognostic value. The interest of this work is to assist clinicians for an efficienttherapeutic stratification to overcome the poor outcome of T-ALL patients
Fakhoury, May. "Pharmacogénétique en pédiatrie : 1-Expression du complexe CYP3A/P-gp dans l'entérocyte humain : 2-Implications des polymorphismes pharmacogénétiques dans la prise en charge des leucémies aiguës lymphoblastiques". Paris 5, 2005. http://www.theses.fr/2005PA05P625.
Testo completoXenobiotic disposition in the organism is highly variable among individuals and due to the impact of age and pharmacogenetic polymorphisms. A- Fundamental pharmacology project concerning the expression of CYP3A/P-gp complex in the human duodenum : - throughout post-natal development (localization and mRNA expression) - during systemic inflammation (Crohn's disease). Clinical pharmacology and pharmacogenetic project in children with acute lymphoblastic leukemia (LAL) : - evaluation of the variability in thiopurine S-methyltransferase (TPMT) during maintenance therapy - estimation of the pharmacokinetic parameters of methotrexate (MTX) and the proposal of a limited sampling strategy (H24 and H48) - impact of genetic polymorphisms (metabolic enzymes and transport proteins of anti-neoplasic agents) on the occurrence of side effects: preliminary results of two hospitals, Robert Debré (France) and Hôtel-Dieu de France (Beirut)
Jamrog, Laura. "Impact des altérations génétiques de PAX5 sur le développement de la lignée lymphoïde B et dans la leucémogenèse des LAL-B". Electronic Thesis or Diss., Toulouse 3, 2021. http://www.theses.fr/2021TOU30306.
Testo completoThe PAX5 (Paired boX 5) gene encodes a key transcription factor crucial for B-cell differentiation. We showed that the two PAX5 isoforms are differentially regulated but have equivalent function during early B-cell differentiation. Indeed, PAX5A and PAX5B isoforms can both induce B-cell program but may have functional differences after B-cell activation. The tight control of their expression may thus reflect a way to finely tune PAX5 dosage during B-cell differentiation process. PAX5 is a well-known haploinsufficient tumor suppressor gene in human B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and is the main target of a wide diversity of somatic alterations in childhood and adult BCP-ALL, occurring in one third of sporadic cases. However, the role of PAX5 fusion proteins in BCP-ALL initiation and transformation is ill-known. We previously reported a new recurrent t(7;9)(q11;p13) chromosomal translocation in human BCP-ALL that juxtaposed PAX5 to the coding sequence of elastin (ELN). To study the function of the resulting PAX5-ELN fusion protein in BCP-ALL development, we generated a mouse model in which the PAX5-ELN transgene is expressed specifically in B cells. PAX5-ELN-expressing mice efficiently developed BCP-ALL phenotype with a penetrance of 80%. Leukemic transformation was associated with clonal Immunoglobulin gene rearrangement and recurrent secondary mutations in Ptpn11, Kras, Pax5, and Jak3 genes affecting key signaling pathways required for cell proliferation. Our functional studies demonstrated that PAX5-ELN impairs B-cell development in vitro and in vivo and induces an aberrant expansion of the pro-B cell compartment at the preleukemic stage. Our molecular and computational approaches identified PAX5-ELN-regulated candidate genes that establish the molecular bases of the preleukemic state to drive BCP-ALL initiation. In conclusion, our study provides a new in vivo model recapitulating the multistep leukemogenesis process of human BCP-ALL and strongly implicates PAX5 fusion proteins as potent oncoproteins in leukemia development. Furthermore, there is increasing evidence for an inherited genetic basis of susceptibility to childhood BCP-ALL. In this context, four unrelated families with childhood BCP-ALL expressing heterozygous PAX5 germline point mutations were recently reported: the recurrent mutation PAX5 G183S affecting the octapeptide domain of PAX5 has been described in three families while PAX5 R38H affecting its DNA-binding paired domain has been identified in another one. We strengthen the hypothesis of inherited character of familial BCP-ALL with the description of three novel familial BCP-ALL cases in related patients that express the germline PAX5 R38H mutation. To uncover the intrinsic effect of PAX5 R38H mutant in B-cell development, we performed in vitro, and in vivo functional assays combined with a gene expression analysis, based on a retroviral complementation approach. Our results indicated that PAX5 R38H mutant acts as a strong hypomorphic variant that fails to drive B-cell differentiation and does not exert a dominant-negative effect on wild-type PAX5. Syngeneic transplantation of PAX5 R38H-expressing cells demonstrated maintenance of engraftment capacity and led to development of BCP-ALL phenotype in mice. Our transcriptomic analysis of these PAX5 R38H-expressing cells showed that PAX5 R38H drastically alters the pattern of expression of PAX5 target genes but also revealed a distinct molecular signature specific to PAX5 R38H. Together with previous unrelated family study, our observations allow to establish the recurrence of the germline PAX5 R38H mutation associated with BCP-ALL. Our data also highlight the importance of transcriptional dysregulation in leukemogenesis of familial BCP-ALL, particularly of genes involved in B-cell differentiation
Jakobczyk, Hélène. "Rôles de RUNX1 dan la pathogenèse des leucémies aiguës lymphoblastiques à réarrangement ETV6-RUNX1". Thesis, Rennes 1, 2018. http://www.theses.fr/2018REN1B033.
Testo completoB-cell precursor acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer. In this type of leukemia, one of the most common genetic abnormalities is the ETV6-RUNX1 rearrangement. This malignancy is described as a two "hits" model. The first event occurs mainly in utero and generates the fusion gene ETV6-RUNX1. The second event consists in the acquisition of additional genetic abnormalities after birth. These aberrant genomic modifications have been described as resulting from abnormal activity of the RAG recombinase. Our work consisted initially in completing the leukemogenesis model. In continuing our study of ETV6-RUNX1 B-ALL, we focused on the role of RUNX1, an upregulated gene in this type of leukemia. All results confirm the predominant role of RUNX1 in hematopoiesis and leukemogenesis thanks to its ability to associate with proteins with different functions and its involvement in the transcription of key genes in hematology. Our results therefore open new perspectives in understanding the control of transcriptional activity of RUNX1 and its role in malignant hematology
Goepp, Marie. "Dissection fonctionnelle des spécificités et des redondances des facteurs de transcription de la famille Ikaros dans les lymphocytes T". Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ043/document.
Testo completoThe lkaros transcription factor family is made of the proteins lkaros, Helios, Aiolos and Eos. They are expressed during the development and regulate the differentiation of lymphocytes B and T. These proteins present a strong homology between their nucleic and protein sequences and are involved the appearance of T or B lymphoblastic leukaemia. However these factors present strong differences in their profiles of expression, their functions and their target genes. An immature T cell line, deficient for lkaros, allows us to study the functional and molecular differences of members of the family. There-expression of lkaros, Aiolos and Helios allows the differentiation and the decrease of the proliferation of these cells. I also showed that the various members of the family had different capacities to activate or repress certain target genes. An exchange of the protein sequences coding for the DNA binding domain (DBD), shows that the functional specificity is partially determined by the DBD domain, but also by the other regions of lkaros and Aiolos
Koubi, Myriam. "PLZF et les protéines du groupe Polycomb : interaction et implication dans la différenciation hématopoïétique normale et pathologique". Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM5066/document.
Testo completoPolycomb group (PcG) proteins are epigenetic factors which play a major role in maintaining epigenetic silencing via histone modifications at the chromatin level. EZH2 is a key regulator that catalyzes the trimethylation of H3K27, which is a repressive mark. During my PhD, I was interested in the acute myeloid leukemia (AML) model in which, unlike other myeloid malignancies, EZH2 or other PcG protein mutations are very rare (˂1%). Studies have shown that in this type of leukemia, many of EZH2 target genes are deregulated although its repressive activity is still present highlighting possible EZH2 recruitment defects. Among the transcription factors that regulate the association of PcG proteins to chromatin, the transcription factor PLZF is an interesting candidate. Indeed, the laboratory has demonstrated an interaction between PLZF and the Polycomb protein BMI -1 and showed that the genomic distribution of PLZF is consistent with that of some Polycomb components. The aim of my thesis was therefore to determine in which extent PLZF is involved in the recruitment or activity of EZH2
Simand, Célestine. "Fonction d’Ikaros dans la transformation des progéniteurs des cellules B1". Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ097.
Testo completoMurine B cell development comprises 2 main B cell lineages, B1 and B2, with distinct progenitors, functions and localization. The transcription factor Ikaros, encoded by the Ikzf1 gene, is a major regulator of lymphopoiesis and plays a crucial role in B2 cell differentiation. However, the role of Ikaros in B1 cell differentiation is unclear. Genetic alterations of IKZF1 are a hallmark of high-risk B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Considering that lymphopoiesis takes place in distinct fetal and adult waves, with B1 cell lymphopoiesis predominating in fetuses and neonates and B2 cell progenitors predominating in adults, some pediatric BCP-ALL cases may originate from B1 cell progenitors. Using a mouse model with a conditional deletion of Ikzf1 in B cell progenitors (Ikzf1f/f Mb1-Cre), we show that Ikaros is critical for normal B1 cell differentiation, similarly to B2 cell differentiation. Using the BCR-ABL oncogene, we show that B1 progenitor can induce BCP-ALL in the murine model and that Ikaros has a tumor suppressor function in these cells. Further studies are required to determine if B1 cell progenitors can contribute to B1-like BCP-ALL in human
Cayuela, Jean-Michel. "Inactivation du locus MTS dans les leucémies aigues lymphoblastiques de la lignée T : implication de la recombinaison V-(D)-J". Paris 7, 1999. http://www.theses.fr/1999PA077257.
Testo completoVallée, Audrey. "Études transcriptionnelle et fonctionnelle du gène CD9 dans les leucémies aigües lymphoblastiques de la lignée cellulaire B chez les enfants à remaniement TEL/AML1". Rennes 1, 2011. http://www.theses.fr/2011REN1S047.
Testo completoThe translocation (12;21) resulting in a TEL/AML1 fusion transcript is the most common chromosomal rearrangement occurring in childhood B-lineage acute lymphoblastic leukemia (B-ALL). However the molecular basis underlying leukemogenesis and late relapse remain poorly understood. In a transcriptomic profiling study characterizing TEL/AML1-positive B-ALL, we previously identified 14 genes linked related to five biological processes. CD9, which belongs to the mobility pathway, was one of the genes identified. While it is an important marker of cancer progression in solid tumours, the role of CD9 has never been investigated in B-ALL. First, our analysis of CD9 transcriptional regulation suggests that in TEL/AML1 positive patients, the downregulation of CD9 could be due to a miRNA regulation. This result has to be confirmed by a functional analysis of the identified miARN. We then performed a functional analysis of the CD9 protein and our data show, using blasts derived from B-ALL patients and cell lines, that CD9 has a negative impact on cell adhesion and that it plays a major role in the CXCL12 induced migration pathway. We also show for the first time using confocal imaging, that there is a close relationship between CD9, actin and CXCR4 in the formation of long actin extensions induced by the CXCL12 signal. We conclude that CD9 may be an important player in the actin rearrangement in response to CXCL12 for ALL cells. These results raise the possibility that CD9 confers particular motility properties to blasts of ALL, which has important implications for the clinical outcome of TEL/AML1-positive patients
Davi, Frédéric. "Réarrangements des gènes des récepteurs à l'antigène dans les lymphocytes normaux et tumoraux chez l'homme". Poitiers, 1994. http://www.theses.fr/1994POIT2310.
Testo completoGolfier, Jean-Baptiste. "Présentation initiale et devenir des leucémies aigües lymphoblastiques de l'enfant de forme hyperleucocytaire". Paris 7, 1997. http://www.theses.fr/1997PA07B020.
Testo completoGuillard, Claire. "Evaluation pronostique initiale de quarante-six leucémies aiguës lymphoblastiques de l'enfant : caryotypes exclus". Bordeaux 2, 1988. http://www.theses.fr/1988BOR25344.
Testo completoVillacreces, Arnaud. "L'hypoxie contribue à la quiescence et la chimiorésistance des cellules initiatrices de leucémie aigüe lymphoblastique". Thesis, Bordeaux, 2014. http://www.theses.fr/2014BORD0126/document.
Testo completoOur group showed that severe hypoxia (0.1% O2) induces G0 cell-cycle-arrest of human CD34+ cells and of murine FDCP-mix Cells. Few studies explored the existence of quiescent Leukemia Initiating Cells (LIC) in ALL and their role in primary chemoresistance and relapses. Our project is focused on the effect of very low O2 concentrations in the maintenance of quiescent LIC in ALL, that could be responsible of a percentage of relapses. Indeed in bone marrow niches, where hematopoietic stem cells and probably LIC are located, the O2 concentrations are below 0.1%.In the present study we used the NALM-6 ALL cell line to explore the effects of culture at 0.1% O2 on their survival, cell cycle and chemoresistance. Our results evidence that a 7 days culture of NALM-6 cells at 0.1% O2: - inhibits their proliferation without major cell death; - reveals a restricted LIC population of quiescent and chemoresistant LIC; - maintains quiescent chemoresistant LIC that induce leukemia when injected in immunodeficient mice. We investigated the relationships between severe hypoxia and some characteristics of ALL primary cells obtained from patients: existence and role of quiescent chemoresistant LICs in ALL relapses; location of these residual cells inside the bone marrow of engrafted mice. Our results suggest that some ALL relapses could be due to the long term persistence of “quiescent / dormant” LIC in hypoxic bone marrow niches. This model is of interest for exploring the in vitro and in vivo (xenograft) mechanisms of chemoresistance in ALL and the role of the bone marrow environment in this phenomenon
Carlier, Marie-Christine. "Étude du suivi sérologique des virus des hépatites A et B chez les enfants leucémiques traités par les protocoles EORTC n°58831 et n°58832". Lyon 1, 1988. http://www.theses.fr/1988LYO1T051.
Testo completoCharrad, Rachida-Sihem. "Différenciation des blastes de patients atteints de leucémie aiguë myéloblastique par la molécule d'adhérence CD44". Paris 11, 2001. http://www.theses.fr/2001PA11T010.
Testo completoBeillard, Emmanuel. "Développement de nouvelles méthodes de PCR (Polymerase Chain Reaction) pour le diagnostic et le suivi de la maladie résiduelle dans les leucémies aigue͏̈s : l'exemple du gène Mixed Lineage Leukemia (MLL)". Aix-Marseille 2, 2003. http://www.theses.fr/2003AIX20654.
Testo completoKaushik, Anna-Lila. "Rôle du facteur de transcription Lyl-1 au cours du développement hématopoïétique chez la souris". Paris 11, 2009. http://www.theses.fr/2009PA112056.
Testo completoIn the mouse, the first wave of hematopoietic precursor generation, which occurs in the yolk sac (YS) from 7. 5 days post-coitus (dpc), gives rise to erythroid and myeloid cells. A second generation event takes place in the Aorta, Gonads and Mesonephros region (AGM) from 9 dpc and gives rise to HSC. Tal-1/scl and Lyl-1 genes, two related basic helix-loop-helix transcription factors were initially identified in T-cell acute lymphoblastic leukaemia. Tal-1/SCL is required for hematopoietic precursors generation in both the YS and AGM. We previously showed, using lyl-1lacZ mice, that Lyl-1 is expressed by AGM-HSC, as is Tal-1/SCL. Unlike Tal-1/SCL, the Lyl-1/-Gal protein seems absent from YS blood islands whereas Lyl-1 mRNA is expressed. We precise Lyl-1 expression and function during hematopoietic ontogeny. We confirm that Lyl-1/-Gal is absent from YS hematopoietic precursors, but becomes expressed in myeloid cells upon differentiation. Lyl-1 disruption increases YS monopotent macrophages progenitors and immature myeloid cells. In contrast, intra-embryonic myeloid differentiation is normal. Lyl-1 thus appears to regulate the production of the first YS macrophages. In the intra-embryonic compartment, Lyl-1 mutant harbor a reduced number of AGM-HSC. The respective contribution generation and expansion to the establishment of the AGM-HSC pool is currently unknown. A defective HSC generation or an impaired amplification may thus be responsible for the decreased HSC pool in Lyl-1 mutants. Using two different approaches to discriminate the two mechanisms, we show that Lyl-1 is not involved in HSC generation, but controls AGM-HSC amplification
Ben, Mami-Tabka Naïra. "Cellules dendritiques et leucémies lymphoïdes". Aix-Marseille 2, 2007. http://www.theses.fr/2007AIX20656.
Testo completoBonnet, Raphaël. "Étude et prédiction des rechutes de leucémie aiguë lymphoblastique T pédiatrique". Electronic Thesis or Diss., Université Côte d'Azur, 2021. http://www.theses.fr/2021COAZ6020.
Testo completoLeukemia is one of the most common pediatric cancers. T-Cell Acute Lymphoblastic Leukemia (T-ALL) is a subtype of ALL characterized by rapid and uncontrolled proliferation of T lymphoblasts in the bone marrow and blood. T-ALL accounts for approximately 15 % of all cases of ALL. Chemotherapy treatments have greatly evolved and are increasingly effective. Thus, nowadays, 80 to 85 % of young patients can heal from this pathology. Despite tremendous progress, a large proportion of relapsed T-ALL is still a therapeutic dead end that results in death in more than half of the relapsed cases.Except for the recently identified Early-T-Precursor (ETP) subtype, no correlation has been established between subtypes and the risk of relapse. Furthermore, while cytogenetic classifications of T-ALL exist, the genetic aberrations listed are of limited prognostic value. In T-ALL only the assessment of the response to treatment after induction, the minimal residual disease, can be used to assess the risk of relapse. In patients who relapse, the resistance of the leukemic cells calls for the use of new chemotherapies, an increase in the doses administered and, most often, an allogeneic hematopoietic stem cell transplant. These even more intense treatments, which also affect the cells of the immune system, are the cause of numerous complications that can lead to the death of the patient.During my thesis I worked on the identification of a new prognostic factor allowing the evaluation of the risk of relapse as soon as the diagnosis is made in order to identify patients at risk as early as possible and to treat them better. Through the study of gene expression profiles at diagnosis as well as information on the clinical outcome of these patients in a learning cohort, we set up a gene dependency network associated with the development of relapse. In this network, I identified 2 genes whose expression at diagnosis predicts the risk of relapse. The prognostic power of these genes was validated on 2 independent cohorts, and to validate their value with the analysis methods available in the biology laboratory on an additional group of patients by qPCR. In parallel, in order to identify new therapeutic targets, I analyzed the transcriptome of 8 patients with T-ALL, 3 of them at diagnosis and 5 at relapse, using a multimodal approach at the single-cell level (scRNA-seq, CITE-seq, TCR-seq). I was able to account for the inter- and intra-individual transcriptomic heterogeneity of this pathology and to study the order of appearance of several oncogenic events within the different samples. Further analysis allowed me to infer the activation of different transcription factors as well as the interactions of leukemia cells with other types of immune cells, actors of the anti-leukemia response.All these results lead to a better understanding of the molecular mechanisms involved in the development and resistance of relapsed ALL, which is now a major challenge to improve the prognosis of these patients. The use of computational methods as well as the access to a growing number of data could allow a new milestone in the treatment of pediatric T-ALL
Schneider, Pascale. "Invasivité et agressivité des leucémies aigües lymphoblastiques de l'enfant : rôle de l'angiogénèse et des métalloprotéases". Rouen, 2009. http://www.theses.fr/2009ROUENR09.
Testo completoLes leucmies aigües lymphoblastiques reprsentent la 1ère pathologie maligne de l'enfant. Les lymphoblastes ont des caractristiques leur permettant de migrer de la MO vers le sang périphrique et les organes extra-mdullaires. Ces atteintes extra-mdullaires sont l'un des éléments qui aggravent le pronostic de la maladie. Nous anons donc étudié chez des patients des marqueurs biologiques impliqués dans les phénomènes d'invasivité cellulaire, comme le système uPA/uPAR, le CXCL-12 et son récepteur et les métalloprotéases matricielles, ainsi que leurs répercussions pronostiques. L'autre partie de notre travail a porté sur les facteurs d'angiogène impliqués dans les LAL. Après les tumeurs solides, le rôle de l'angiogenèse a été exploré également dans les hémopathies. Notre travail confirme la présence d'une angiogenèse dans les LAL. II faut définir les patients pouvant bénéficier de traitements anti-angiogéniques
Pandrau, Dominique. "Étude de la prolifération et de la différenciation in vitro des précurseurs leucémiques lymphoïdes B de l'enfant". Lyon 1, 1993. http://www.theses.fr/1993LYO1T056.
Testo completoJacquy, Caroline. "Détection de la maladie résiduelle par techniques de biologie moléculaire dans les lymphomes et la leucémie aigüe lymphoblastique". Doctoral thesis, Universite Libre de Bruxelles, 2001. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/211523.
Testo completoDendale, Joëlle. "Etude des fonctions gonadiques de garçons atteints de L. A. L. Et traités par les protocoles de l'E. O. R. T. C : 58831, 58832 et 58881". Montpellier 1, 1992. http://www.theses.fr/1992MON11180.
Testo completoSaudemont, Aurore. "Développement d'une approche de thérapie génique des leucémies aiguës myéloblastiques". Lille 2, 2004. http://www.theses.fr/2004LIL2S010.
Testo completoIL12 and CD154 gene transfer in leukemic cells can induce an efficient antileukemic immunity in the aggressive DA1-3b-C3H/Hej mouse model of acute myeloid leukemia (AML). However, induced antileukemic immunity may result in persistence of a minimal residual leukemic disease (MRD) in mice in long-term remission. We sequentially quantified MRD using BCR/ABL real-time PCR in C3H/Hej mice, vaccinated with irradiated mouse leukemic DA1-3b cells transduced with IL12 or CD154 and challenged with lived 104 DA1-3b cells, during immune response and one year after vaccination. We showed that median number of leukemic cells in spleen decreased 30 days after challenge, and stabilized to only 90 cells in 35% of mice on day 90. After one year, 13 of 52 (25%) mice in remission were found positive for MRD with a median number of cells not statistically different to that found on day 90. Dormant leukemic cells isolated from spleen were able to grow in vitro and showed significant increased B7-H1 expression positively correlated with time of remission. Increased B7-H1 expression was able to inhibit antileukemic CTL activity in vitro and in vivo blocking of B7-H1 prolonged survival of mice. B7-H1 seems to be involved in long term persistence of MRD at low level in AML, suggesting a possible mechanism of tumor escape to whole cell vaccine strategies
Bernard, Natacha. "Mise au point d'un modèle de leucémie aigue͏̈ lymphoblastique de type B, chimiquement induite chez le rat pour l'étude d'agents leucémogènes : application aux champs magnétiques de 50 Hz". Paris 5, 2004. http://www.theses.fr/2004PA05P638.
Testo completoB acute lymphoblastic leukemia is the most common type of leukemia among children. However the causes of this disaese are not totally understood. At this time, no induced model of this type of leukemia exists. We therefore, decided to settle an induced model of B acute lymphoblastic leukemia in rats. The induction was obtained using butylnitrosourea, a nitrosourea compound reported as a leukemogenic agent. We characterized the leukemia obtained in our experiment. 65% of the rats developped B acute lymphoblastic leukemia. In a second time, using this model (320 rats), we tested, the effect of 50Hz magnetic fields (MFs), with or without harmonics of 150, 250 and 350Hz. Indeed, MFs are suspected to have an effect on children leukemia development. No effect of MF exposure, with or without harmonics, was detected, neither on survival, nor on the incidence of total leukemia, nor on the type of leukemia obtained
Kosmider, Olivier. "Coopération d'événements oncogéniques dans un processus leucémique murin". Paris 7, 2007. http://www.theses.fr/2007PA077092.
Testo completo3 month after birth, Spi-1 transgenics mice present an anemia and a hepatoslenomegaly due to the proliferation of proerythroblastic cells (HS1) blocked in their erythroid differentiation process and dependent on erythropoietin (Epo) for their growth and survival. In a second step, leukemic proerythroblasts (HS2 cells) appear in mice. These HS2 cells are also blocked in their differentiation process but are independent on Epo for their growth and proliferation. Moreover, HS2 cells are able to induce tumors into nude mice. Here, we have shown that two kind of mutation of the SCF receptor Kit (KitD814Y and KitD818Y) are found in 85% of these leukemic cells. Mutated forms of Kit cooperate with Spi-1 overexpression to transform a proerythroblastic cell into a malignant one. The mutant form KitD814Y is unsensible to the inhibitory effect of Gleevec (Imatinib Mesylate) which is the compound used in the treatment of disease implicating some mutated form of Kit. Here we repport that Semaxinib (SU5416), intially described as a VEGF-Receptor inhibitor, may act as a therapeutic agent targeting oncogenic Kit mutants resistant to Gleevec. Finally, we have also studied the interactions between the Epo receptor and the SCF receptor in HS1 preleukemic cells. We have shown that these receptors are able to activate similars and disctincts signalling pathways which may implicate Lyn, a kinase which belong to the SrcKinase Family
Bayet, Manon. "Modélisation de la leucémie aiguë lymphoblastique B induite par la mutation PAX5 P80R". Electronic Thesis or Diss., Université de Toulouse (2023-....), 2024. http://www.theses.fr/2024TLSES005.
Testo completoThe team is interested in alterations in transcription factors involved in acute leukemia, including PAX5, which is essential for B-cell development. This is why the PAX5-ELN transgenic mouse model was generated, which expresses the oncogenic fusion protein during B-cell development, and recapitulates the multi-step process of B-ALL (Jamrog L et al., PNAS, 2018). I was involved in identifying the cells at the origin of-B-ALL and characterizing their functional and molecular properties. Our work indicates that at pre-leukemic stage, PAX5-ELN induces the emergence of an aberrant population of B-progenitors with an abnormal self-renewal property. This population is enriched in quiescent cells resistant to chemotherapeutic agents, activating a molecular stem cell program and supporting long-term leukemic initiation. This work is the subject of a recent publication signed by myself as second author (Fregona V, Bayet M et al., J Exp Med, in press). In parallel, my thesis focused on modeling the initiation and leukemic transformation induced by the PAX5P80R mutation, a frequent initiating alteration in patients. I used fetal liver cells derived from Pax5-/- mouse embryos to select lymphoid progenitors not committed to the B lineage. After transduction with CTL, PAX5 Wt or PAX5P80R retroviruses, I showed that PAX5P80R does not restore efficiently definitive commitment of cells to the B lineage. Transplantation experiments have shown that PAX5P80R induces aberrant engraftment potential followed by the development of B-ALL. This leukemic transformation is associated with the selection of clones carrying additional mutations affecting the JAK/STAT signaling pathway. Our analyses identified Hif2 as a potential candidate for leukemogenesis. Finally, pharmalogical screening of Hif inhibitors revealed Acriflavine as an interesting compound targeting leukemic cells. Thus, the modeling of B-ALL by the PAX5P80R mutation provides the team with a new tool to mimic the multi-step process of B-ALL, and to decipher the biological mechanisms by which the mutation leads to tumor transformation. This work is the subject of a manuscript in preparation which I have signed as first author (Bayet M, Fregona V, et al., in preparation). The PAX5-ELN and PAX5P80R models not only make it possible to study the various stages of B leukemogeneis, but also serve as a basis for the development of small molecule screening on primary cells. I therefore set up a miniaturized and robust protocol by FACS to screen chemical compounds targeting pre-leukemic cells. Our multiparametric approach enables us to simultaneously assess the effect of compounds on pre-leukeic cells and normal B subpopulations. I screened a bank of 1040 synthetic and natural compounds (essential chemical library) reflecting the chemical diversity of the French national chemical library. This screening, combined with dose-response counter-screening, enabled me to identify 5 molecules of interest. Overall, my work demonstrates the feasibility of small-molecule screening on a population enriched in leukemia-initiating cells, taking into account the intrinsic complexity of primary B-cells. Finally, I edited and published a review in the journal Cancers outlining the concepts of tumor heterogeneity in patients' leukemic cells, the utility of transgenic mouse models to explore the leukemia initiating cell compartment, and current efforts to discover new targeted therapies (Fregona V*, Bayet M* et al, Cancers (Basel), 2021), wich I co-authored
Bergeron, Christophe. "Les polyamines : agents diagnostiques et cibles thérapeutiques en oncologie pédiatrique". Rennes 1, 1993. http://www.theses.fr/1993REN1B006.
Testo completoMalti, Talby Leïla [Faiza]. "Etude de leucémies aigue͏̈s lymphoblastiques de type B de l'enfant par la technique de puces ADN : identification de gènes prédictifs de la chimiosensibilité des cellules leucémiques au diagnostic". Aix-Marseille 2, 2005. http://www.theses.fr/2005AIX22007.
Testo completoQuelen, Cathy. "La translocation chromosomique t(X;6) (p11;q23) dans la leucémie aigüe à basophiles". Toulouse 3, 2011. http://thesesups.ups-tlse.fr/1650/.
Testo completoChildhood acute myeloblastic leukemias are haematological malignancies frequently associated with chromosomal translocations. The molecular characterization of these chromosomal rearrangements highlights genes important in haematopoietic differentiation. Furthermore, the discovery of recurrent chromosomal translocation is essential for the detection of residual disease, establishment of prognostic value and therapeutic choices. Acute basophilic leukemia is a rare sub-type of acute myeloblastic leukaemia. Despite rare cases of t(X;6)(p11;q23) translocation reported for this pathology, no molecular characterization was available until recently. The aim of our work was to characterize genes rearrangement in four cases of male infants carrying t(X;6). Because of its location on chromosome 6q23, MYB was a good candidate gene. Our molecular investigations, based on fluorescence in situ hybridization and rapid amplification of cDNA ends, revealed a complex chromosomal rearrangement leading to the creation of a MYB-GATA1 fusion gene. Moreover, this translocation is associated with an invalidation of the GATA1 gene located on chromosome X. These two proteins are master regulators of haematopoiesis. GATA1 is essential for normal erythropoiesis and MYB is involved in hematopoietic stem cell renewal and myeloid differentiation. Expression of MYB-GATA1 in mouse lineage-negative cells committed them to the granulocyte lineage and blocked them at an early stage of differentiation. Moreover, this protein increased clonogenic potential. Taken together, these results establish, for the first time, a link between a recurrent chromosomal translocation and the development of this particular subtype of infant leukemia
Grandemenge-Arnould, Cécile. "Caractérisation d'une fusion génique originale au cours d'une leucémie aiguë promyélocytaire atypique : STAT5b, nouveau partenaire du gène codant le récepteur [alpha] de l'acide rétinoïque". Nancy 1, 1999. http://www.theses.fr/1999NAN19911.
Testo completoAcute promyelocytic leukaemia (APL) exhibits a characteristic t(15;17) translocation that fuses the PML gene on 15q22 to the retinoic acid receptor [alpha] (RARA) gene on 17q12-q21. 1. In a small subset of acute promyelocytic-like leukaemias (APL-L), RARA is fused to a different partner: PLZF, NPM or NuMA. We report on the molecular characterization of a RARA gene rearrangement in a patient with an APL-L associated with a der(17). Thanks to the 5' RACE PCR approach, we demonstrate that the Signal Transducer and Activator of Transcription STAT5b gene is fused to RARA; STAT5b belongs to a family of latent cytosolic transcription factors activated by JAK tyrosine kinases
Baghdassarian, Nathalie. "Inhibition de la prolifération des cellules lymphoïdes par les glucocorticoïdes". Lyon 1, 1999. http://www.theses.fr/1999LYO1T117.
Testo completoLavau, Catherine. "Étude des propriétés transformantes de la protéine PML-RARα associée aux leucémies aiguës promyélocytaires". Lyon 1, 1995. http://www.theses.fr/1995LYO1T096.
Testo completoGonzalez, Ricardo. "Transfert de gènes dans les leucémies aiguës". Lille 1, 1998. https://pepite-depot.univ-lille.fr/LIBRE/Th_Num/1998/50376-1998-321.pdf.
Testo completoBare, Hadjara. "Activité antitumorale de mycéliums de septomycètes en culture". Lyon 1, 1985. http://www.theses.fr/1985LYO1W229.
Testo completoGeimer-Le, Lay Anne-Solen. "Rôle du facteur de transcription Ikaros dans la répression de la voie Notch lors de la différenciation des cellules T murines". Strasbourg, 2010. http://www.theses.fr/2010STRA6271.
Testo completoThe Notch signalling pathway plays a major role in controlling fundamental aspects of multicellular life including proliferation, stem cell maintenance, differentiation and death. It has a central role in the haematopoietic system and the requirement for Notch activation in thymocyte differentiation is well established. Moreover, when deregulated, the Notch pathway is oncogenic as more than 50% of the T Lymphoblastic Acute Leukemia (T-ALL) display activating mutations in the Notch gene. However, the mechanisms that could regulate the Notch pathway during T cell differentiation are still poorly understood. Ikaros is a zinc finger transcription factor, predominantly expressed in haematopoietic cells; it functions as a transcriptional repressor and a tumor suppressor. Our data show that Ikaros-deficient mice develop T cell lymphomas, which are associated with an early activation of the Notch pathway. Using the Notch target gene Hes1 as a model, we recently reported that Ikaros and RBPJ, the transcriptional mediator of Notch signalling, compete for binding to two elements in the Hes1 promoter in immature thymocytes. These results indicate that Ikaros functions as a transcriptional checkpoint to repress the Notch target gene Hes1 expression in T cells. The molecular basis of this repression could be due to the similarity between the sequences recognized by Ikaros and RBPJ. To determine if Ikaros repression plays a central role in silencing Notch target genes during T ymphopoiesis, I have studied its capacity to regulate the transcription of Notch target genes on a global scale in gain- and loss-of-function systems. My results indicate that Ikaros represses most of Notch induced genes. Furthermore, both Ikaros and RBPJ bind to the promoters of half the common target genes, exactly at the same place. I have also demonstrated on several genes that Ikaros directly competes with RBPJ in order to bind to same consensus sequence in the promoter of these common target genes. Finally, loss of Ikaros causes the deregulation of a significant number of Notch target genes during T cell differentiation, before the cells get transformed. These data suggest a new molecular pathway by which the Notch pathway is regulated during T cell development. Ikaros competes with RBPJ to repress a set of common target genes, and this mechanism plays a central role in silencing Notch target genes during T lymphopoiesis. Furthermore, the loss of Ikaros would cause a deregulation of the Notch target genes and this could lead to leukemogenesis
Poyer, Florent. "Rôle d'une boucle autocrine dépendante des VEGFs dans la physiopathologie des leucémies aiguës lymphoblastiques de l'enfant". Rouen, 2008. http://www.theses.fr/2008ROUEN005.
Testo completoGandemer, Virginie. "Utilisation des puces à adn pour l’étude fonctionnelle du génome dans les leucémies aiguës lymphoblastiques de la lignée B de l’enfant". Rennes 1, 2007. http://www.theses.fr/2007REN1S040.
Testo completoB-ALL is a common pediatric malignancy but leucemogenesis and prognostic biological mechanisms still remain uncertain. We explored critical pathways of TEL/AML1 B-ALL with gene expression profile approach. We highlighted 5 enriched Gene Ontology categories characterized by 14 genes, able to discriminate the TEL/AML1 sub-group. Over-expression of RUNX1 was proposed to become a additional surrogate marker of this subgroup. Cell motility was for the first time identified as a representative process of this subgroup and epigenetic regulation of the 2 underexpressed genes is underanalysis. We could not show patterns of expression in pediatric B-ALL lacking common cytogenetic abnormatities that correlated with the NCI risk factors (age and blood cell count). Our results suggest the refinement of existing classification and risk algorithms
Eveillard, Marion. "Identification de marqueurs prédictifs de la rechute ou de mauvaise réponse au traitement dans les leucémies aiguës lymphoblastiques". Nantes, 2015. http://www.theses.fr/2015NANT09VS.
Testo completoAcute lymphoblastic leukemias (ALL) are of good prognosis in children and their prognosis improves in adults, yet almost one of five children and half the adults relapse. Several prognostic factors allow to identify these patients at risk. Pre-therapeutic factors depending on the patient (age, comorbidities) or on the disease (leukocytosis, immunophenotype, karyotypic or molecular anomalies) are good prognostic indicators. In the first part of this work, the immunophenotype of paired diagnosis and relapse samples has been compared by targeting new antigenic markers. Then the genome of 17 childhood ALL was analyzed by Single Nucleotide Polymorphism (SNP) array to identify poor prognosis markers such as IKZF1 deletion, identified in 2 patients, one of whom then relapsed. Finally, early response to chemotherapy was studied in a multicenter (Nantes, Marseille) exploration of minimal residual disease at Day 21 of induction (MRD0) by flow cytometry in 123 de novo childhood ALL treated in the FRALLE. Three risk groups were identified with significantly different event-free survival (p=0,00017) and overall survival (p=0,048): low risk (MRD<10-4), intermediate risk (10-210-2). MRD0 discriminates the 14 corticoresistant patients and the 109 chemosensitive patients by identifying those of poorer prognosis. MRD0 is also more discriminant than day 35 MRD1 and isolates MRD0+/MRD1- poor prognosis patients. All these techniques will be implemented in a research protocol supported by Nantes University Hospital
Calvo, Julien. "Etude de l'impact des adipocytes de la moelle osseuse sur le développement et la chimiorésistance des leucémies aigues lymphoblastiques T (LAL-T)". Thesis, Université de Paris (2019-....), 2019. http://www.theses.fr/2019UNIP7114.
Testo completoT-cell acute lymphoblastic leukemia (T-ALLs) is a T cell progenitor proliferation malignancy that mostly occurs in children and young adults. Over the years, intrinsic and extrinsic factors have been demonstrated to play a role in initiation and onset of the leukemic proliferation. Among other organs, T-ALL expands in most cases in various Bone Marrow (BM) sites. These niches have a complex cellular composition with hematopoietic, stromal, endothelial, nervous cells and also adipocytes that form the Medullar Adipose Tissue (MAT). Two types of MAT exist in the BM niches. The constitutive MAT takes place in long bones extremities whereas the regulated MAT arises and grows as a results of external stimuli like aging and BM ablation. Mice harbor both constitutive MAT enriched and deprived BM niches respectively in tail and thoracic vertebrae. Hence, using in vivo models we observed that mouse and human T-ALL develop slowly in tail compared to thoracic vertebrae. Tail-derived T-ALL cells display lowered cell surface marker expression, decreased metabolism and cell cycle progression demonstrating a dormancy phenotype. Functionally tail-derived T-ALL cells exhibit a deficient short-term ex vivo growth and a delayed in vivo propagation. These features are non-cell autonomous as T-ALL from tail and thorax share identical genomic abnormalities, and also functional disparities disappear in vivo and in prolonged in vitro assays. Importantly, tail-derived T-ALL display higher intrinsic resistance to cell cycle-related drugs, i.e. Vincristine sulfate and Cytarabine. Moreover, T-ALL recovered from gonadal adipose tissues or from co-cultures with adipocytes share metabolic, cell cycle and phenotypic or chemoresistance features with tail-derived T-ALL. These results demonstrate that BM niches differentially orchestrate T-ALL propagation and that adipocyte enriched BM protects T-ALL during drug treatments. To support these findings, single cell RNA sequencing analysis suggests that a few thoracic derived T-ALL cells exhibit a similar mRNA expression pattern to those from the tail. Altogether, these results emphasize the hypothesis of chemoresistance inducing niche among the thoracic hematopoietic-enriched adipocytes-deprived BM
Touzart, Aurore. "Leucémies aigüs lymphoblastiques T (LAL-T) et dérégulation épigénétique Site- and allele-specific polycomb dysregulation in T-cell leukaemia Epigenetic silencing affects L-asparaginase sensitivity and predicts outcome in T-ALL Low level CpG island promoter methylation predicts a poor outcome in adult T-ALL". Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB221.
Testo completoT-ALLs are rare lymphoid neoplasms characterized by the proliferation of immature T precursors arrested at specific stages of maturation. While the genetic abnormalities involved in T-ALL leukemogenesis are becoming better known, alterations in epigenetic regulation, a very important component of the cellular homeostasis, are much less studied. My work was to tsudy the epigenetic deregulation in T-ALL through 3 main projects. In the first project, we identified an original mechanism of TAL1 oncogene deregulation. TAL1 is one of the most frequently deregulated oncogenes in T-ALL. This deregulation results mainly from translocations with the TCRδ locus or micro-deletions SIL-TAL1, two chromosomal abnormalities altering cis-regulatory elements leading to monoallelic TAL1 expression. But in a significant proportion of cases (about 50%) of TAL1+ T-ALL, an aberrant expression of TAL1 is observed without recognized mechanism suggesting unknown genetic or epigenetic mechanisms. We discovered a new somatic alteration consisting of a focal and recurrent microinsertion 7 kbp upstream of TAL1, in a non-coding intergenic region, responsible for the creation of an oncogenic "neo-enhancer" accompanied by a modification of epigenetic histone marks i.e. a “switch” from H3H27me3 repressive marks to H3K27ac activating marks. These microinsertions are a recurrent event in T-ALL and have been found in 20% of “unresolved” TAL1+ T-ALL. Through the second project, I tried to better understand the biological bases for discrepancies in patients related response to treatment. Indeed, considering two close oncogenic groups, the prognosis of TLX1+ patients, already rather favourable in the LALA-94 protocol, has not been significantly improved in the paediatric-inspired GRAALL2003-2005 trial , whereas TLX3+ patients seem to have benefited particularly from the latter; the two protocols differing mainly by L-asparaginase doses. We showed that TLX1+ patients expressed less ASNS (Asparagine synthetase) than TLX3+ and TLX- patients and that this lower expression resulted from ASNS epigenetic silencing, both by methylation of the promoter and reduction of active histone marks. A low level of ASNS methylation is also associated with lower in vitro sensitivity to L-asparaginase. Finally, ASNS methylation is an independent prognostic factor for patients included in the 2003-2005 GRAALL trial suggesting that the ASNS methylation status may be relevant for the adaptation of L-asparaginase doses. In the third project, I was interested in the global DNA methylation. MeDIP-array methylation data of a series of 24 T-ALLs allowed us to identify differential methylation signatures. We then studied the methylation status in a large series of adult T-ALL by MS-MLPA using a predictor containing 9 gene promoters. We observed that main driver oncogenes dictated methylation status. TLX1+ and TLX3+ T-ALLs displayed a hypermethylated profile and conversely, SIL-TAL1+ cases were associated with a hypomethylated profile. This methylation status is also an independent prognostic factor and hypomethylated patients have a significantly unfavorable prognosis compared to hypomethylated patients. Together, these results illustrate how disruptions in epigenetic regulation can be involved both in the T-ALL oncogenesis and in the response to treatment
Sancerni, Tiphaine. "Rôle du transporteur mitochondrial UCP2 dans la leucémie". Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCC088.
Testo completoUCP2 protein is a C4 metabolites transporter in the inner mitochondrial membrane. It has been shown to decrease proliferation by rewiring metabolism from glycolysis to oxidative phosphorylation when it is overexpressed in melanoma cells. It also controls both activated LT proliferation and macrophages ROS production. Then during my thesis, we chose to investigate UCP2 role in an immune cancer: T-cell acute lymphoblastic leukemia (T-ALL). We studied in vitro 4 T-ALL cell lines and in vivo, a T-ALL mouse model overexpressing Notch1ICD. We showed that UCP2 is able to control glutamine use in T-ALL cells, a primordial nutrient for these cancer cells. When UCP2 is knockdown cells rewired their metabolism toward glycolysis. UCP2 inhibition could be design as a therapy to weaken T-ALL and avoid relapses, main problem after treatment
Familiades, Julien. "Anomalies moléculaires du gène PAX5 dans les leucémies aiguës lymphoblastiques de la lignée B". Toulouse 3, 2010. http://thesesups.ups-tlse.fr/1269/.
Testo completoB cell lymphocytes are essential for humoral adaptive immunity. The expression of transcription factors drives the commitment of cells in B lineage. Among those factors, PAX5 fulfils a dual role by repressing B lineage ‘inappropriate’ genes and simultaneously activating B lineage–specific genes. PAX5 is expressed at similar levels throughout B cell development from the pro-B to the mature B cell stage and is subsequently repressed during terminal plasma cell differentiation. When Pax5–/– pro-B cells are stimulated with other lineageappropriate cytokines, they are able to differentiate into functional macrophages, granulocytes, dendritic cells, osteoclasts and natural killer cells. Transcription factors mutations are frequently detected in hematopoietic cancers. The PAX5 gene was the prevalent target of somatic mutation, being altered in 38. 9% of cases. We screened PAX5 mutations in a unique cohort of adult BCP-ALL treated according to the protocols of the GRAALL03 (Group of Research on Adult Acute Lymphoblastic Leukemia) and we reported that PAX5 is mutated in 34% of cases. Moreover, PAX5 complete loss and PAX5 point mutations differ. Indeed, PAX5 complete loss is significantly associated with BCR-ABL1 fusion gene and seems to be a secondary event consequence of genetic instability, whereas PAX5 point mutation might be the initial event in leukemogenesis. Using classic cytogenetic techniques and a newly developed molecular strategy, we investigated 9p abnormalities, focusing especially on the PAX5 locus, on 153 childhood and adult B-ALL include in the Groupe Francophone de Cytogénétique Hématologique (GFCH). Finally we undertook the functional characterization of PAX5 mutants using the ex vivo differentiation system described by Rolink and showed that the various kind of muations not have the same impact on the B cell pathogenesis
Linassier, Claude. "Signalisation cellulaire par les enzymes de la famille des phosphatidylinositol 3-kinases : caractérisation d'un enzyme de classe III et recherche d'une application en cancérogenèse". Paris 11, 1998. http://www.theses.fr/1998PA11T062.
Testo completoGuillaume, Nicolas. "Implications des facteurs de transcription et des voies de signalisation cellulaire dans les leucémies aigües lymphoblastiques B : mise en évidence de l'expression et de l'activation de ZAP-70". Amiens, 2007. http://www.theses.fr/2007AMIED009.
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