Lymphomas are malignant tumours arising from cells in the lymphatic system. They are classified as B-cell lymphomas, T-cell lymphomas and Hodgkin lymphoma (HL). Of the B-cell lymphomas, one of the most common is diffuse large B-cell lymphoma (DLBCL). Many patients with lymphomas can be successfully treated however patients who relapse or are refractory have a poor prognosis, warranting further investigations to identify potential targets and develop novel drugs. Picropodophyllin (PPP), a potent and selective inhibitor of IGF-1R, inhibits malignant cell growth with low or no toxicity on normal cells in preclinical models. In paper I, we investigated the potential benefits of using PPP against DLBCL and found that the anti-tumor effects of PPP might possibly be explained by IGF-1R-unrelated mechanism(s). However, the inhibitory effects of PPP on lymphoma cells together with its low toxicity in vivo makes it a promising drug candidate for treatment. Melflufen, a derivative of melphalan, is currently being evaluated in a clinical phase I/II trial in relapsed or refractory multiple myeloma. In paper II, we confirmed previous reports of superior potency of melflufen over melphalan. Being active in cell lines and primary cultures of lymphoma cells as well as in a xenograft model in mice, melflufen considered being a candidate for further evaluation in treatment. bAP-15, a novel inhibitor of proteasome activity, inhibits ubiquitin specific peptidase 14 (USP14) and ubiquitin carboxyl-terminal hydrolase L5 (UCHL5). In paper III, we investigated the activity of b-AP15 in DLBCL and HL cell lines and compared the results to standard drugs used in treatment. Results showed inhibition of the proteasome and growth inhibition/cytotoxicity with IC50-values in the micromolar range. Treatment failure and lack of clinical benefit of proteasome inhibitors like bortezomib in DLBCL patients inspired us investigating for possible new targets, with major focus on proteasome inhibitors in DLBCL. In paper IV, we suggested that UCHL5 and/or USP14, as new targets for proteasome inhibitors in DLBCL, be further evaluated. The findings in this thesis suggest that PPP, Melflufen and b-AP15 are potential candidates for clinical drug development and UCHL5 and/or USP14 are new potential targets for proteasome inhibitors in DLBCL.

Thesis (MMedSc)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Background: Serum free light chains (FLC) are associated with imbalances in heavy and light chain production. Abnormal FLC ratios have been associated with risk of progression in certain diseases. Automated assays are available for their determination and they are used in the followup and management of patients with monoclonal gammopathies. Acceptable imprecision, specificity, accuracy and reproducibility between reagent batches is required to prevent under- or overestimation. Method validation is a standard process in every good laboratory to judge the acceptability of a new method. Reference intervals have been established in an older population, but it was considered important to verify these in our population. HIV is associated with B-cell dysfunction. As B-cell abnormalities are associated with disorders leading to monoclonal gammopathies, we postulated that the FLC levels and FLC ratio would be abnormal in HIV infected individuals. Methods and materials: Controls and pooled patient samples were used for the method validation study which included imprecision studies, linearity, recovery and interference studies, and method comparison studies, the latter compared our method to the same method used in another laboratory. For the reference interval study, blood was obtained from 120 healthy subjects. The following blood tests were performed: total protein, IgG, IgA, IgM, creatinine, protein electrophoresis, kappa FLC and lambda FLC. Using the kappa and lambda FLC results, a FLC ratio was determined. Three hundred and sixty-nine HIV positive subjects were then studied. The same tests were performed, as well as CD4+ counts and viral loads on the majority of them. Results: For the method validation study, precision, linearity and recovery was acceptable. Minimal interference was observed with haemolysis, lipaemia, bilirubin and rheumatoid factor. Our method showed comparable performance with the established method. For the reference interval study, all the creatinine values were normal, as were serum protein values. The serum protein electrophoreses were independently reviewed by 3 pathologists. Most were normal, with a few polyclonal increases seen, but no definite monoclonal bands. The 95% reference intervals for FLC’s as well as the FLC ratio were not statistically significantly different to the manufacturer’s recommendations. When examining the HIV positive study population, we found that FLC and FLC ratio were influenced by markers of HIV disease severity, such as CD4+ count, IgG, viral load, use of antiretroviral treatment and abnormal serum protein electrophoreses. Conclusion: The validation study of FLC showed excellent precision, acceptable bias, good linearity, good recovery and minimal interference, allowing routine introduction of the test. The 95% reference intervals obtained for our population were slightly higher than those recommended by the manufacturer. However, as most of the values fell within the manufacturer’s limits, we could accept the manufacturer’s recommended cut-offs. We found that FLC levels were definitely influenced by markers of HIV disease severity in our population and we postulate that they may be of use for follow-up of patients with HIV. / AFRIKAANSE OPSOMMING: Agtergrond: Serum vry ligte kettings (VLK) word geassosieer met ‘n wanbalans van ligte en swaar ketting produksie. Abnormale VLK ratios is geassosieer met ‘n risiko van verloop in sekere siektes. Geoutomatiseerde laboratorium toetse vir VLK is beskikbaar vir hul bepaling en word gebruik om pasiënte met monoklonale gammopatieë op te volg en te behandel. Aanvaarbare impresisie, spesifisiteit, akkuraatheid en herhaalbaarheid tussen reagens besendings is belangrik om onder- of oorbepaling te verhoed. Metode validasie is ’n standaard proses in elke goeie laboratorium om die aanvaarbaarheid van ’n nuwe metode te bepaal. Verwysingswaardes is al bepaal in ’n ouer populasie. Ons het besluit om die verwysingswaardes in ons populasie te bepaal. Mens-immuungebrekvirus (MIV) word geassosieer met B-sel disfunksie. Omdat B-sel abnormaliteite geassosieer word met afwykings wat tot monoklonale gammopatieë lei, het ons gepostuleer dat die VLK vlakke en VLK ratio abnormaal sal wees in MIV geïnfekteerde persone. Metodes en Materiale: Kontroles en pasiënt monsters is gebruik vir die metode validasie studie wat impresisie studies, lineariteit, herwinning, inmenging en metode korrelasie studies ingesluit het. In laasgenoemde geval is ons metode met dieselfde metode van ’n ander laboratorium vergelyk. Vir die verwysingswaardes studie is 120 gesonde persone se bloed gebruik. Die volgende toetse is bepaal: totale proteïen, IgG, IgA, IgM, kreatinien, proteïen elektroferese, kappa en lambda VLK. Die VLK ratio is bepaal deur die kappa en lambda resultate te gebruik. Driehonderd nege en sestig MIV-positiewe pasiente is gebruik vir die studie. Dieselfde toetse was gedoen, asook CD4+ tellings en virale ladings op die meerderheid van pasiente. Resultate: Vir die metode validasie studie, was presisie, lineariteit en herwinning aanvaarbaar. Minimale inmenging van hemolise, lipemie, bilirubien en rumatoïede factor is waargeneem. Ons metode het goed gekorreleer met die bepaalde metode. Die serum kreatinien en serum totale proteïen waardes was normaal tydens die verwysingswaardes studie. Die serum proteïen elektroferese was onafhanklik beoordeel deur 3 patoloë. Die meeste was normaal met enkele poliklonale verhogings, maar geen definitiewe monoklonale bande nie. Die 95% verwysings intervalle vir VLK en VLK ratio het nie statisties betekenisvol verskil van die vervaardiger se aanbevelings nie. In die studie van die MIV-positiewe studie populasie, het ons gevind dat VLK en VLK ratio beïnvloed word deur merkers van ernstige MIV siekte, soos CD4+ telling, IgG, virale lading, die gebruik van antiretrovale medikasie en abnormale serum proteïen elektroferese. Gevolgtrekking: Die validasie studie van VLK het uitstekende presisie, aanvaarbare partydigheid, goeie lineariteit, goeie herwinning en minimale inmenging gewys, wat die roetine instelling van die toets toegelaat het. Die 95% verwysingsintervalle wat vir ons populasie bepaal is, was effens hoër as die vervaardiger se aanbeveling. Die meeste van die waardes het egter binne die vervaardiger se limiete geval, dus kon ons die vervaardiger se afsnypunte aanvaar. Ons het gevind dat VLK vlakke definitief beïnvloed word deur merkers van die ernstigheidsgraad van MIV siekte in ons populasie en ons postuleer dat VLK van waarde kan wees met die opvolg van MIV pasiente. / NHLS / Harry Crossley for funding obtained

Purpose: To investigate if apparent diffusion coefficient (ADC) values within primary central nervous system lymphoma correlate with cellularity and proliferative activity in corresponding histological samples. Materials and Methods: Echo-planar diffusion-weighted magnetic resonance images obtained from 21 patients with primary central nervous system lymphoma were reviewed retrospectively. Regions of interest were drawn on ADC maps corresponding to the contrast enhancing parts of the tumors. Biopsies from all 21 patients were histologically analyzed. Nuclei count, total nuclei area and average nuclei area were measured. The proliferation index was estimated as Ki-67 positive nuclei divided by total number of nuclei. Correlations of ADC values and histopathologic parameters were determined statistically. Results: Ki-67 staining revealed a statistically significant correlation with ADCmin (r = -0.454, p = 0.038), ADCmean (r = -0.546, p = 0.010) and ADCmax (r = -0.515, p = 0.017). Furthermore, ADCmean correlated in a statistically significant manner with total nucleic area (r = -0.500, p = 0.021). Conclusion: Low ADCmin, ADCmean and ADCmax values reflect a high proliferative activity of primary cental nervous system lymphoma. Low ADCmean values—in concordance with several previously published studies—indicate an increased cellularity within the tumor.

Orientador: Maria Aparecida Custódio Domingues / Resumo: O linfoma difuso de grandes células B (LDGCB) integra o grupo das neoplasias malignas hematopoiéticas classificado como linfomas não-Hodgkin e representa o subtipo mais prevalente no Brasil e no mundo. Ao seu diagnóstico, segue-se um estadiamento clínico denominado Classificação de Ann-Arbor/Lugano, visando estimar o tratamento. Neste estadiamento, além de exames laboratoriais, parâmetros clínicos e imagens radiológicas, faz-se avaliação da medula óssea (MO) para pesquisa de infiltração neoplásica. O presente estudo comparou a análise unicamente morfológica da MO em relação à combinação da morfologia com imunoistoquímica (IHQ) na detecção de infiltração neoplásica medular em pacientes com LDGCB. Para isso, realizou-se levantamento retrospectivo de 113 pacientes diagnosticados com LDGCB submetidos a biópsia/aspirado de MO para estadiamento. Informações clínicas foram levantadas nos prontuários médicos e as lâminas histológicas de biópsias e coágulos de MO foram revisadas quanto a seus aspectos morfológicos. Procedeu-se estudo IHQ com os marcadores CD20 e CD3, sendo este o padrão ouro. A sensibilidade da análise morfológica isolada foi de 42,9%, considerada baixa se considerarmos que esta serviria como um exame de triagem. A quantidade de acúmulos linfoides (AcL) na MO e o aumento de trama reticulínica no acúmulo linfoide mostraram p-valor respectivamente de 0,02, para uma mediana de 2 acúmulos, e 0,01 para uma mediana de trama reticulínica de II, mostrando assim existir uma re... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Diffuse Large B Cell Lymphoma (DLBCL) belongs to a group of hematopoietic malignancies called Non-Hodgkin's Lymphomas, being the most prevalent in Brazil. After the diagnosis is followed a staging, called Ann-Arbor/Lugano classification, aiming to estimate the treatment. This staging, in addition to laboratory exams, clinical parameters and radiological images, includes the histological evaluation of bone marrow (BM) for the investigation of neoplastic infiltration. The present study compared BM morphological analysis only and morphology combined with immunohistochemistry (IHC) to detect BM infiltration in patients with DLBCL. For this, a retrospective survey was performed on 113 patients diagnosed with LDGCB submitted to biopsy / aspiration for BM staging. Clinical information was reviewed from medical records and histological biopsy and clots were reviewed for morphological aspects. The IHQ study was performed with CD20 and CD3 markers. The sensitivity of the isolated morphological analysis was 42.9%, considered low if we remember that this evaluation would serve as a screening test. The amount of lymphoid agreggates in BM and the increase in reticulin stain into the lymphoid agreggates showed p-value respectively of 0.02 and a median of 2 agreggates and 0.01 for a grade II reticulin, thus showing a relation of these two morphological parameters with BM infiltration. After this, we can conclude that the isolated morphological analysis is not recommended, and should always b... (Complete abstract click electronic access below) / Mestre

No description available.

Chronic Lymphocytic Leukemia (CLL) is a type of cancer that affects the B cells of the immune system causing problems in the process of producing antibodies. It can be sorted into mutated and unmutated CLL based on the percentage of somatic mutations in the Immunoglobulin Heavy chain Variable region (IgHV). The B cells of healthy individuals can be sorted into three groups; CD27dull memory B cells (MBCs), CD27bright MBCs and naïve B cells. The hypothesis for the project was that the unmutated CLL subset originates from CD27dull MBCs and the mutated CLL subset originates from CD27bright MBCs. RNA-sequencing data from healthy individuals were acquired from a collaboration partner in Rome and CLL-patients were collected from public datasets available online. Several bioinformatic tools were used to analyze the data. First, the quality of the data files was checked, then adapter sequence from the sequencing process and low-quality bases were removed (trimming). Good quality of the files was confirmed after the trimming. Secondly, these files were mapped against the human reference genome (GRCh38/hg38) for alignment, then the resulted data was used to check for genes that showed differential expression between the different groups. Results were analyzed and visualized using Venn diagrams, Principal Component Analysis (PCA) and heatmap plots and random forest. A list of 85 genes was generated based on the different comparisons and was used in one PCA plot that showed clear separation between the different groups. The SWAP70 gene was analyzed for single nucleotide polymorphisms (SNPs). The study concluded five genes that could be used as biomarkers for CLL and the diagnosis of its subtypes where some of them were discussed in previous studies. Also, the mutated CLL subset showed a similar behavior to the healthy individuals and this could validate the original hypothesis and justifies the better disease prognosis for this subtype.

Les lymphomes B non-Hodgkiniens (LNHB) représentent le type d’hémopathie maligne le plus fréquent. Ces pathologies sont traitées par l’association de chimiothérapies conventionnelles et d’immunothérapies dirigées contre le CD20. Bien qu’efficace, 40% des patients résistent ou rechutent après le traitement. Deux raisons peuvent expliquer ces échecs thérapeutiques : 1) l’absence de cibles thérapeutiques impliquées dans plusieurs processus oncogéniques et 2) l’absence de modèles pré-cliniques de LNHB pertinents pour le test de molécules thérapeutiques et la compréhension de la lymphomagenèse. Le calcium est un messager ubiquitaire qui est impliqué dans de nombreux processus cellulaires en condition physiologique et pathologique. La principale voie d’entrée de calcium dans les lymphocytes B est l’entrée capacitive de calcium médiée par Orai1 et STIM1. Ces deux protéines ont été largement décrites pour être impliquées dans les processus tumoraux de nombreux cancers, cependant leurs rôles dans la lymphomagenèse restait à élucider. Nos travaux ont révélé l'implication de la signalisation calcique dans la mort induite par le GA101, un anti CD20 de nouvelle génération actuellement en essai clinique. De plus, nous avons mis en évidence l’implication des protéines Orai1 et STIM1 dans la migration des cellules cancéreuses de LNHB. De manière intéressante, l’implication de ces deux protéines dans la migration cellulaire est calcium indépendante, suggérant donc un nouveau rôle de ces protéines. Enfin, grâce à la technologie des capsules cellulaires nous avons établi un nouveau modèle 3D de lymphome mimant la niche tumorale en incluant des cellules du microenvironnement et de la matrice extracellulaire. Ce modèle semble particulièrement pertinent pour le screening de molécules et la compréhension des mécanismes de la lymphomagenèse. Ce travail de thèse révèle ainsi le ciblage de Orai1 et STIM1 comme potentiellement intéressant dans le traitement du LNHB. / B-cell non-Hodgkin lymphomas (BNHL) are the most common hematological malignancies, usually treated with a combination of chemotherapy and anti CD20 immunothérapie. However, 40% of patients are resistant or relapse after treatment. These therapeutic failures could be due to 1) lack of therapeutic targets implicated in several oncogenic processes, 2) lack of relevant preclinical BNHL models for drug screening and lymphomagenesis studies. Calcium is an essential second messenger involved in various cell functions. In B cells, calcium entry is mainly due to Orai1 and STIM1 proteins, both of which have been associated with oncogenesis on solid tumors. However, their role in lymphomagenesis still remains to be elucidated. Our work shows that calcium signaling in BNHL cells participates in cell death induced by GA101, a novel anti-CD20 monoclonal antibody. We also demonstrate that Orai1 and STIM1 play a role in BNHL cell migration. Interestingly, both proteins controlled cell migration in a calcium-independent manner, suggesting a new role for these proteins. Finally, using cellular capsule technology, we established a new BNHL 3D model mimicking tumoral niche by including extracellular matrix and stromal cells. This new model could be used for drug screening and understanding lymphomagenesis. In summary, this work suggests that targeting of Orai1 and STIM1 is promising for BNHL treatment.

Pacientes com linfoma difuso de grande célula B (LDGCB) do mesmo grupo de risco pelos critérios do Índice de Prognóstico Internacional (IPI), tratados com quimioterapia convencional à base de antraciclina, podem ter resposta terapêutica não esperada para seu grupo de risco. Isso pode ser explicado pelo fato do prognóstico dos LDGCB, que têm origem no centro germinativo (CG), ser superior aos originados após o CG (NCG). No intuito de aprimorar a avaliação de prognóstico e a abordagem terapêutica em LDGCB de IPI ajustado para a idade (IPIa) de risco intermediário alto e alto, elaboramos projeto de pesquisa, para verificar o papel dos marcadores imuno-histoquímicos (IH) e do transplante de medula óssea autólogo (ATMO), em primeira remissão completa (RC), neste grupo de pacientes. Avaliamos o impacto da expressão dos marcadores CD10, Bcl-6, MUM-1, Bcl-2 e p63 na obtenção de RC, sobrevida livre de doença (SLD) e sobrevida global (SG), isoladamente e de acordo com a origem em CG e NCG. Avaliamos 82 pacientes abaixo dos 60 anos, dos quais 16 (19,5%) receberam ATMO em primeira RC, além de serem comparados com os pacientes tratados com quimioterapia convencional e mantidos em observação após RC. A IH foi avaliável em 73 casos, 24 (32,9%) tiveram origem no CG e 49 (67,1%) NCG, sem diferença de sobrevida entre os grupos. A proteína Bcl-2 foi positiva em 27 (37%) pacientes e foi o único fator preditivo independente para SG à análise multivariada, com tendência de significância para RC. As SG e SLD em cinco anos para os 16 pacientes que receberam ATMO foi de 75% e 85,2%, respectivamente, a taxa de recidiva de 6,5% e diferença estatisticamente significativa para SLD (p = 0,015) em comparação aos pacientes apenas observados. Concluímos que o ATMO foi seguro e capaz de melhorar a sobrevida em LDGCB de risco intermediário alto e alto, e que a expressão de Bcl-2 pode ser utilizada na programação terapêutica inicial desses pacientes. / Diffuse large B cell lymphoma (DLBCL) patients from the same risk group according to the International Prognostic Index (IPI) treated with conventional anthracycline-based chemotherapy may show an unexpected therapeutic response. This can be explained by the fact that the prognosis of DLBCL originating in germinal center (GC) cells is superior than that originating out of germinal center (NGC). In order to improve the prognostic evaluation and the therapeutic approach to DLBCL patients with high intermediate to high age-adjusted IPI (aIPI), a research project was designed for the analysis of immunohistochemical markers and the role of autologous stem cell transplantation (ASCT) in first complete remission (CR) for this group of patients. The impact of the expression of CD10, Bcl-6, MUM-1, Bcl-2 and p63 markers on complete remission (CR), disease-free survival (DFS) and overall survival (OS), either individually and according to cell origin was evaluated by means of immunohistochemistry. Eighty-two patients aged under 60 years old were assessed, of which 16 (19.5%) underwent ASCT in first CR and were compared to patients receiving conventional chemotherapy and being monitored after CR. Immunohistochemistry was assessable in 73 cases, 24 (32.9%) being classified as GC-type and 49 (67.1%) as NGC-type, with no survival difference between the two groups. Bcl-2 expression was found in 37% (27) of the patients and was the single independent predicting factor of OS prognosis according to multivariate analysis. A significant tendency of expression of this protein was also observed for achieving CR, which was essential for longer survival, as shown by multivariate analysis. OS and DFS within 5 years were of 75% and 85.2% respectively for the group of 16 patients treated with ASCT, which resulted in lower relapse rates (6.5%) with statistically significant difference for DFS (p=0.015) when compared to the group of patients who achieved CR and was kept under monitoring. In this study ASCT was found to be a safe procedure for improving survival rates of DLBCL patients with high intermediate to high aIPI risk. Also, the expression of Bcl-2 protein was found to be useful as one of the variables to be analysed in the therapeutic approach to these patients

Die Langlebigkeit reifer periphärer B Zellen ist abhängig von mindestens zwei Überlebenssignalen, einem tonischen Signal, welches vom B Zellrezeptor ausgeht und dem Zytokin B Zell aktivierender Faktor der TNF-Familie (BAFF). BAFF fördert nicht nur das Überleben von reifen B Zellen, sondern kontrolliert auch deren Funktionstüchtigkeit, indem es vielschichtige physiologische Prozesse wie Zellwachstum und –metabolismus, Energiehaushalt und Eintritt in den Zellzyklus reguliert. Zwei BAFF-induzierte molekulare Mechanismen, zum einen die Aktivierung des Akt Signaltransduktionsweges sowie die erhöhte Expression der onkogenen kinase Pim-2 zum anderen, führen zu Veränderungen in Effektorproteinen welche in der Lage sind diese physiologischen Zellveränderungen auszulösen. Die BAFF-induzierte Aktivierung von Akt hängt von der klassischen Proteinkinase C (PKC) beta ab und sowohl PKC beta-defiziente B Zellen als auch Mäuse zeigen Anzeichen von Unsensitivität gegenüber BAFF-Stimulation. Die Proteintyrosinkinase Syk spielt eine Rolle während der frühen B Zellentwicklung und wird in reifen B Zellen durch Stimulation des B Zellrezeptors aktiviert. Induzierbare Inaktivierung von Syk in Mäusen führt zum Verschwinden reifer B Zellen aus den periphären lymphoiden Organen, was auf eine unverzichtbare Funktion von Syk in der Vermittlung des tonischen B Zellrezeptorsignals schliessen läßt. / The maintenance of mature peripheral B cells depends on at least two survival cues, tonic signaling from the B cell receptor (BCR) complex and the extracellular cytokine B cell activating factor of the TNF family (BAFF). In addition to enhancing viability, BAFF controls the functional efficiency of the peripheral B cell pool by regulating complex physiological processes including cell growth, metabolism, energy homeostasis and entry into the cell cycle. BAFF-mediated induction of two molecular mechanisms, namely activation of the Akt signal transduction pathway and upregulation of the oncogenic kinase Pim-2 results in the modification of effector proteins including transcription factors and regulators of protein synthesis which are capable of executing the observed cellular physiological changes. The classic protein kinase C beta is instrumental in BAFF-induced Akt-activation and PKC beta-deficient B cells and mice show signs of partial refractiveness to BAFF. The protein tyrosine kinase Syk plays a role in early B cell development and is activated in mature B cells by immunogenic BCR-stimulation. Inducible ablation of Syk in mice results in the loss mature B cells from the peripheral lymphoid organs and reveals an indispensable function for Syk in tonic BCR survival signaling.

Le locus des chaînes lourdes d’immunoglobulines (IgH) subit trois processus de remaniements géniques durant la lymphopoïèse B. Ces événements induisent des cassures de l’ADN potentiellement oncogéniques, d’où la nécessité d’une régulation extrêmement stricte. Ceci est dû aux deux principaux éléments cis-régulateurs du locus IgH. L’enhancer 5’Eµ régule les recombinaisons VHDJH qui établissent un répertoire antigénique fonctionnel lors des phases précoces. La région régulatrice en 3’ (3’RR) est essentielle aux hypermutations somatiques (SHM) et à la recombinaison de classe (CSR) aux stades tardifs, modifiant respectivement, l’affinité et les fonctions effectrices de l’Ig. La plupart des lymphomes B matures portent les stigmates de translocations d’oncogènes au locus IgH. Le but de ma thèse a été de mieux comprendre les interactions transcriptionelles entre les enhancers Eµ et 3’RR et évaluer si le ciblage de cette dernière pourrait se révéler une approche thérapeutique potentielle. Nous avons démontré que la 3’RR est l’élément essentiel qui contrôle la transcription du locus IgH dans les lymphocytes B matures. Elle est dispensable lors des phases initiales (recombinaisons VHDJH), mais agit comme silencer sur l’expression des segments DJH. L’analyse de la lymphomagenèse dans trois modèles murins porteurs d’une insertion de Myc en trois points du locus IgH a montré des différences dans les cinétiques d’émergence des lymphomes, leurs phénotypes et index de prolifération. L’effet de la 3’RR sur l’oncogène est suffisant pour l’émergence de lymphomes B. Son absence ne semble pas être préjudiciable au développement de réactions inflammatoires/immunes. Son ciblage pourrait donc se révéler une approche thérapeutique intéressante pour diminuer son activité transcriptionelle sur l’oncogène transloqué. Un rôle potentiel des inhibiteurs des histones désacétylases est à l’étude. / The immunoglobulin heavy chain locus (IgH) undergoes several changes along B-cell differentiation. VHDJH recombinations during the early stages give the diversity of the antigenic repertoire. Somatic hypermutation (SHM) and class switch recombination (CSR) during late stages allow affinity maturation and the acquisition of new effectors functions. These rearrangements are highly regulated and are under the control of the IgH locus cis-regulatory elements. The 5’ Eµ enhancer is important for VHDJH recombination. The 3’ regulatory region (3’ RR) is essential for both CSR and SHM. These events induce breaks into the IgH locus, making it a hotspot for oncogenic translocations. The aim of my thesis was to understand the transcriptional interactions between Eμ and 3'RR enhancers and to evaluate whether the targeting of the latter could be of a potential therapeutic approach. We have demonstrated that 3'RR is essential to control IgH transcription in mature B cells. It is dispensable during the initial stages of developement (VHDJH recombinations). At the pro-B cell stage, it has a silencer effect rather than a transcriptional one on the DJH segments expression. The analysis of lymphomagenesis in three mice models carrying an insertion of Myc in different locations at the IgH locus showed significant differences in lymphoma kinetics, phenotypes and proliferation index. 3'RR alone, as a major transcriptional activator of the IgH locus, is capable of leading to B-cell lymphomas. Its absence is not detrimental for the development of classical inflammatory/immune reactions. Its targeting may be of a potentially interesting therapeutic approach to decrease its transcriptional activity on the translocated oncogene. A potential role for histone deacetylase inhibitors is under study.