Acute Lymphocitic Leukemia (ALL) is the most common cause of childhood cancer and occurs in adults in 20%. Lymphoblasts accumulation is a characteristic of the disease since the leukemic cells retain some multiplication ability without differentiation. The chemotherapy treatment for ALL has been proven effectiveness leading 95% cases to remission however, some patients may have recurrence disease. An accurate diagnosis is critical for the correct treatment and therefore longer survival. Molecular biology techniques have contributed to the early detection of recurrence, mainly by PCR method. Considering the high frequency of clonal rearrangements in leukemia (about 90 to 95%) the analysis of clonal immunoglobulin (Ig) or T-cell receptor (TCR) rearrangements by PCR has been shown to be useful for treatment monitoring the minimal residual disease. This study aimed to standardize the PCR for Ig and TCR rearrangements technique and characterize the pacients at the University Hospital of Santa Maria, through these analysis. After adjustments the technique was considered a reliable procedure and relatively easy to perform. The higher frequency of rearrangements were detected in IgH gene (82.76%) by the DH7 sequences (14 samples), Vg1 (10 samples), VH3 and V2D3 (9 cases). IgK rearrangements occurred in frequency of 31.03, TCRG and TCRD rearrangements to 41.37%, and Sil-Tal to 3.45%. / A Leucemia Linfoide Aguda (LLA) é a causa mais comum de câncer infantil e ocorre em 20% dos adultos. Tem como característica o acúmulo de linfoblastos, células leucêmicas que mantêm capacidade de multiplicação, porém, sem diferenciação. O tratamento quimioterápico para LLA tem se mostrado eficaz e levado à remissão em 95% dos casos, no entanto, alguns pacientes podem apresentar recidiva da doença. O diagnóstico preciso é fundamental para o tratamento correto do paciente e, consequentemente, elevar a sobrevida. Metodologias de biologia molecular têm contribuído para a detecção precoce de recidivas, principalmente por técnicas de reação em cadeia da polimerase (PCR). Tendo em vista que nas LLA os rearranjos clonais de imunoglobulinas (Ig) ou de receptores de células T (TCR) ocorrem em 90 a 95% dos casos, as análises destes por PCR tem-se mostrado método útil para o acompanhamento do tratamento, detecção de doença residual mínima. O presente estudo teve como objetivo padronizar a técnica de pesquisa de rearranjos de Ig e TCR, e caracterizar a sua frequência na população de pacientes com LLA do Hospital Universitário de Santa Maria. A técnica para pesquisa da prevalência de rearranjos gênicos mostrou-se, depois de ajustadas os devidos detalhes, um procedimento de reprodutibilidade confiável e relativamente fácil execução. A maior frequência de rearranjos foi detectada no gene IgH (82,76%), sendo representada por amplificações nas sequências DH7 (14 amostras), Vg1 (10 amostras), VH3 e V2D3 (9 amostras). Rearranjos de IgK ocorreram em frequência de 31,03%, rearranjos TCRG e TCRD com 41,37% e Sil-Tal em 3,45%.

O câncer é a primeira causa de mortes por doença, após 1 ano de idade, até o final da adolescência, excetuando aquelas relacionadas aos acidentes e à violência. A Leucemia Linfoide Aguda (LLA) afeta células linfoides e agrava-se rapidamente. São os tumores mais frequentes na infância e representam um terço de todas as neoplasias malignas nesta faixa etária. Em média, a taxa de cura excede 70%, todavia, apesar dos avanços das últimas décadas, os índices de crianças que apresentam recidiva da doença continua significativo. Danos endógenos ao DNA ocorrem numa frequência altíssima, além dos danos causados por terapias antitumorais. Alteração no reparo ao dano do DNA pode induzir mecanismos de resistência ao tratamento quimioterápico, resultando em aumento do reparo de lesões do DNA. Reparo por Excisão de Nucleotídeos (NER) é a via de reparo de DNA mais versátil e flexível nas células. Seus componentes estão sendo estudados como biomarcadores de prognóstico e terapias-alvo. No entanto, alguns relatórios têm abordado danos de DNA em Leucemia Linfoide Aguda (LLA) pediátrica. Neste estudo, realizamos um estudo de acompanhamento observacional em pacientes pediátricos para avaliar os danos do DNA pelo Ensaio Cometa Alcalino e expressão gênica da via de NER durante a indução da quimioterapia. Amostras de medula óssea (MO) ao diagnóstico, dia 15 (D15) e 30 (D30) do tratamento foram coletadas de 28 pacientes com LLA. Não houve aumento no índice de dano. No entanto, houve uma redução de células com baixo danos na comparação do D35 com o diagnóstico. Este resultado se confirmou em pacientes que apresentaram doença residual mínima positiva. A via de NER permaneceu constante, no entanto, em um único paciente, foi observada uma diminuição significativa da expressão dos genes, talvez devido ao silenciamento ou a regulação negativa das vias de reparo. Níveis de danos e reparação do DNA podem influenciar o resultado clínico, estar envolvidos na resistência aos fármacos e potencializar o risco de recidiva. Este é o primeiro estudo que avalia o dano ao DNA em amostras de MO de pacientes pediátricos com LLA. Apesar do pequeno número de pacientes alocados para o estudo, a partir dos achados é possível concluir que complexos de reparo merecem ser investigados a curto e a longo prazo. Acompanhamento dos resultados do paciente vai ajudar a elucidar a implicação dos nossos achados em taxas de cura e de recidiva. / Cancer is the leading cause of death by disease after 1 year old until the end of adolescence, except those related to accidents and violence. Acute Lymphoid Leukemia (ALL) affects lymphoid cells and worsens quickly. They are the most frequent tumors in childhood and account for a third of all malignancies in this age group. On average, the cure rate exceeds 70%, however, despite the progress of recent decades, rates of children with disease recurrence remains significant. Endogenous DNA damage occurs at a very high frequency, in addition to the damage caused by anti-tumor therapies. Change in the repair of DNA damage can induce resistance mechanisms to chemotherapy, resulting in increased repair of DNA lesions. Nucleotide Excision Repair (NER) pathway is the more versatile and flexible DNA repair in cells. Its components are being studied as prognostic biomarkers and targeted therapies. However, there are some reports of DNA damage in pediatric Acute Lymphoid Leukemia (ALL). In this study, we conducted an observational follow-up study in pediatric patients to assess DNA damage by alkaline comet assay and gene expression of NER pathway during induction chemotherapy. Bone marrow (BM) samples at diagnosis, 15th (D15) and 30th (D30) of treatment were collected from 28 patients with ALL. There was no increase in damage index. However, there was a reduction of cells with low damage in comparison to the D35 diagnosis. This result was confirmed in patients with positive minimal residual disease. The NER pathway remained constant, however, in one patient, a significant decrease of gene expression was observed perhaps due to the silencing or down-regulation of repair pathways. Damage levels and DNA repair can influence the clinical result and may be involved in drug resistance and enhance the risk of recurrence. This is the first study to assess DNA damage in BM samples of pediatric patients with ALL. Despite the small number of patients allocated to the study, from the findings we conclude that repair complex deserves to be investigated in the short and long term. Monitoring patient’s outcomes will help to access the implication of our findings in cure and relapse rates.

O câncer é a primeira causa de mortes por doença, após 1 ano de idade, até o final da adolescência, excetuando aquelas relacionadas aos acidentes e à violência. A Leucemia Linfoide Aguda (LLA) afeta células linfoides e agrava-se rapidamente. São os tumores mais frequentes na infância e representam um terço de todas as neoplasias malignas nesta faixa etária. Em média, a taxa de cura excede 70%, todavia, apesar dos avanços das últimas décadas, os índices de crianças que apresentam recidiva da doença continua significativo. Danos endógenos ao DNA ocorrem numa frequência altíssima, além dos danos causados por terapias antitumorais. Alteração no reparo ao dano do DNA pode induzir mecanismos de resistência ao tratamento quimioterápico, resultando em aumento do reparo de lesões do DNA. Reparo por Excisão de Nucleotídeos (NER) é a via de reparo de DNA mais versátil e flexível nas células. Seus componentes estão sendo estudados como biomarcadores de prognóstico e terapias-alvo. No entanto, alguns relatórios têm abordado danos de DNA em Leucemia Linfoide Aguda (LLA) pediátrica. Neste estudo, realizamos um estudo de acompanhamento observacional em pacientes pediátricos para avaliar os danos do DNA pelo Ensaio Cometa Alcalino e expressão gênica da via de NER durante a indução da quimioterapia. Amostras de medula óssea (MO) ao diagnóstico, dia 15 (D15) e 30 (D30) do tratamento foram coletadas de 28 pacientes com LLA. Não houve aumento no índice de dano. No entanto, houve uma redução de células com baixo danos na comparação do D35 com o diagnóstico. Este resultado se confirmou em pacientes que apresentaram doença residual mínima positiva. A via de NER permaneceu constante, no entanto, em um único paciente, foi observada uma diminuição significativa da expressão dos genes, talvez devido ao silenciamento ou a regulação negativa das vias de reparo. Níveis de danos e reparação do DNA podem influenciar o resultado clínico, estar envolvidos na resistência aos fármacos e potencializar o risco de recidiva. Este é o primeiro estudo que avalia o dano ao DNA em amostras de MO de pacientes pediátricos com LLA. Apesar do pequeno número de pacientes alocados para o estudo, a partir dos achados é possível concluir que complexos de reparo merecem ser investigados a curto e a longo prazo. Acompanhamento dos resultados do paciente vai ajudar a elucidar a implicação dos nossos achados em taxas de cura e de recidiva. / Cancer is the leading cause of death by disease after 1 year old until the end of adolescence, except those related to accidents and violence. Acute Lymphoid Leukemia (ALL) affects lymphoid cells and worsens quickly. They are the most frequent tumors in childhood and account for a third of all malignancies in this age group. On average, the cure rate exceeds 70%, however, despite the progress of recent decades, rates of children with disease recurrence remains significant. Endogenous DNA damage occurs at a very high frequency, in addition to the damage caused by anti-tumor therapies. Change in the repair of DNA damage can induce resistance mechanisms to chemotherapy, resulting in increased repair of DNA lesions. Nucleotide Excision Repair (NER) pathway is the more versatile and flexible DNA repair in cells. Its components are being studied as prognostic biomarkers and targeted therapies. However, there are some reports of DNA damage in pediatric Acute Lymphoid Leukemia (ALL). In this study, we conducted an observational follow-up study in pediatric patients to assess DNA damage by alkaline comet assay and gene expression of NER pathway during induction chemotherapy. Bone marrow (BM) samples at diagnosis, 15th (D15) and 30th (D30) of treatment were collected from 28 patients with ALL. There was no increase in damage index. However, there was a reduction of cells with low damage in comparison to the D35 diagnosis. This result was confirmed in patients with positive minimal residual disease. The NER pathway remained constant, however, in one patient, a significant decrease of gene expression was observed perhaps due to the silencing or down-regulation of repair pathways. Damage levels and DNA repair can influence the clinical result and may be involved in drug resistance and enhance the risk of recurrence. This is the first study to assess DNA damage in BM samples of pediatric patients with ALL. Despite the small number of patients allocated to the study, from the findings we conclude that repair complex deserves to be investigated in the short and long term. Monitoring patient’s outcomes will help to access the implication of our findings in cure and relapse rates.

Made available in DSpace on 2014-12-17T14:16:29Z (GMT). No. of bitstreams: 1 EricaAG_DISSERT.pdf: 1548086 bytes, checksum: c8d01670d1a770711f3300b93e502612 (MD5) Previous issue date: 2011-07-01 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Leukemia is a heterogeneous group of hematologic malignancies that result from partial or total transformation of the blast cells. The Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in childhood, especially in male, Caucasian children younger than 14 years. Several criteria are adopted to classify ALL, including the cell morphology, cytochemistry, immunophenotyping and cytogenetic analysis. Cytogenetic studies allow a more detailed analysis to detect chromosomal abnormalities of leukemic cells. These modifications will determine the diagnosis, classification, stage characterization, remission assessment and prognosis. In this study were evaluated 30 patients, aged from four months to seventeen years, of both sexes and various ethnicities. The age distribution showed that 67% of patients had between one and ten years (with mean age of XX years old), the most prevalent ethnic was Caucasian (50%) and 57% were males. According to immunophenotype, 93% of patients had B-cells progenitor ALL and 7% early lineage T. Considering the total studied population, the most frequent medical findings were lymphadenopathy (37%), hepatomegaly (77%) and splenomegaly (70%), where one patient could present more than one of these medical findings. Regarding the CBC, the majority of patients had hemoglobin below 10 g / dl (73%), leukocyte count less than 10.000/μL (60%) and platelet count below 150.000/μL (83%). Chromosomal abnormalities were observed in 64% of all patients, where hyperdiploidy was the most common numerical change (67%), followed by hypodiploid (33%). All these data are in agreement with the literature. Moreover, complexes structural and/or number changes not yet described in literature were observed, which indicated poor prognosis. Finally, we concluded that this study demonstrated the importance of cytogenetic study in the diagnosis and identification of prognostic factors in pediatric patients with ALL in Rio Grande do Norte. The results obtained in this study are extremely useful and emphasizes that surveys of this nature must be conducted more frequently in our state / As leucemias s?o grupos heterog?neos de neoplasias hematol?gicas, que resultam da transforma??o total ou parcial das c?lulas bl?sticas. A Leucemia Linf?ide Aguda (LLA) ? a neoplasia mais comum na inf?ncia, principalmente na popula??o masculina caucasiana menor de 14 anos. V?rios crit?rios podem ser adotados para classificar LLA, dentre eles a morfologia celular, a citoqu?mica, a imunofenotipagem e o estudo citogen?tico. A citogen?tica permite uma an?lise mais detalhada o que possibilita detectar as altera??es cromoss?micas das c?lulas leuc?micas. Estas altera??es ir?o auxiliar no diagn?stico, na classifica??o, na caracteriza??o de diferentes est?gios, na avalia??o da remiss?o e no progn?stico dessas neoplasias. Foram avaliados neste estudo 30 pacientes com idade variando de quatro meses a dezessete anos, de ambos os sexos e de v?rias etnias. A faixa et?ria predominante neste estudo foi de pacientes entre um e dez anos (67%) com m?dia de idade de 7 anos e meio, de etnia caucasiana (50%) e sexo masculino (57%). De acordo com a imunofenotipagem 93% dos pacientes apresentaram LLA de linhagem B precoce e 7% de linhagem T. Considerando a popula??o total estudada, os achados cl?nicos mais freq?entes foram linfoadenopatia (37%), hepatomegalia (77%) e esplenomegalia (70%), podendo, em muitos casos um paciente apresentar mais de um desses achados. Em rela??o ao hemograma, a maioria dos pacientes apresentou hemoglobina abaixo de 10 g/dl (73%), contagem de leuc?citos inferior a 10.000/μL (60%) e contagem de plaquetas abaixo de 150.000/μL (83%). As anormalidades cromoss?micas foram observadas em 64%, dessas a hiperdiploidia foi ? altera??o num?rica mais comum (67%), seguida pela hipodiploidia com 33%. Todos esses dados corroboram com os relatos da literatura. Adicionalmente, foram observadas altera??es estruturais e/ou num?ricas complexas ainda n?o descritas na literatura, as quais indicaram progn?stico desfavor?vel. Conclui-se que a partir deste trabalho foi poss?vel demonstrar a import?ncia do estudo citogen?tico no diagn?stico e na identifica??o de fatores progn?sticos nos pacientes pedi?tricos com LLA do Rio Grande do Norte. Os resultados obtidos neste estudo s?o de extrema import?ncia e ressaltam que pesquisas desta natureza devem ser realizadas com maior freq??ncia em nosso Estado

O câncer é a primeira causa de mortes por doença, após 1 ano de idade, até o final da adolescência, excetuando aquelas relacionadas aos acidentes e à violência. A Leucemia Linfoide Aguda (LLA) afeta células linfoides e agrava-se rapidamente. São os tumores mais frequentes na infância e representam um terço de todas as neoplasias malignas nesta faixa etária. Em média, a taxa de cura excede 70%, todavia, apesar dos avanços das últimas décadas, os índices de crianças que apresentam recidiva da doença continua significativo. Danos endógenos ao DNA ocorrem numa frequência altíssima, além dos danos causados por terapias antitumorais. Alteração no reparo ao dano do DNA pode induzir mecanismos de resistência ao tratamento quimioterápico, resultando em aumento do reparo de lesões do DNA. Reparo por Excisão de Nucleotídeos (NER) é a via de reparo de DNA mais versátil e flexível nas células. Seus componentes estão sendo estudados como biomarcadores de prognóstico e terapias-alvo. No entanto, alguns relatórios têm abordado danos de DNA em Leucemia Linfoide Aguda (LLA) pediátrica. Neste estudo, realizamos um estudo de acompanhamento observacional em pacientes pediátricos para avaliar os danos do DNA pelo Ensaio Cometa Alcalino e expressão gênica da via de NER durante a indução da quimioterapia. Amostras de medula óssea (MO) ao diagnóstico, dia 15 (D15) e 30 (D30) do tratamento foram coletadas de 28 pacientes com LLA. Não houve aumento no índice de dano. No entanto, houve uma redução de células com baixo danos na comparação do D35 com o diagnóstico. Este resultado se confirmou em pacientes que apresentaram doença residual mínima positiva. A via de NER permaneceu constante, no entanto, em um único paciente, foi observada uma diminuição significativa da expressão dos genes, talvez devido ao silenciamento ou a regulação negativa das vias de reparo. Níveis de danos e reparação do DNA podem influenciar o resultado clínico, estar envolvidos na resistência aos fármacos e potencializar o risco de recidiva. Este é o primeiro estudo que avalia o dano ao DNA em amostras de MO de pacientes pediátricos com LLA. Apesar do pequeno número de pacientes alocados para o estudo, a partir dos achados é possível concluir que complexos de reparo merecem ser investigados a curto e a longo prazo. Acompanhamento dos resultados do paciente vai ajudar a elucidar a implicação dos nossos achados em taxas de cura e de recidiva. / Cancer is the leading cause of death by disease after 1 year old until the end of adolescence, except those related to accidents and violence. Acute Lymphoid Leukemia (ALL) affects lymphoid cells and worsens quickly. They are the most frequent tumors in childhood and account for a third of all malignancies in this age group. On average, the cure rate exceeds 70%, however, despite the progress of recent decades, rates of children with disease recurrence remains significant. Endogenous DNA damage occurs at a very high frequency, in addition to the damage caused by anti-tumor therapies. Change in the repair of DNA damage can induce resistance mechanisms to chemotherapy, resulting in increased repair of DNA lesions. Nucleotide Excision Repair (NER) pathway is the more versatile and flexible DNA repair in cells. Its components are being studied as prognostic biomarkers and targeted therapies. However, there are some reports of DNA damage in pediatric Acute Lymphoid Leukemia (ALL). In this study, we conducted an observational follow-up study in pediatric patients to assess DNA damage by alkaline comet assay and gene expression of NER pathway during induction chemotherapy. Bone marrow (BM) samples at diagnosis, 15th (D15) and 30th (D30) of treatment were collected from 28 patients with ALL. There was no increase in damage index. However, there was a reduction of cells with low damage in comparison to the D35 diagnosis. This result was confirmed in patients with positive minimal residual disease. The NER pathway remained constant, however, in one patient, a significant decrease of gene expression was observed perhaps due to the silencing or down-regulation of repair pathways. Damage levels and DNA repair can influence the clinical result and may be involved in drug resistance and enhance the risk of recurrence. This is the first study to assess DNA damage in BM samples of pediatric patients with ALL. Despite the small number of patients allocated to the study, from the findings we conclude that repair complex deserves to be investigated in the short and long term. Monitoring patient’s outcomes will help to access the implication of our findings in cure and relapse rates.

Les neurotrophines sont des facteurs de croissance initialement découverts dans le système nerveux et ayant pour rôle de contrôler la croissance, la prolifération et la survie des cellules neuronales et astrocytaires, mais aussi dans de nombreux autres tissus. Les neurotrophines peuvent interagir avec leurs récepteurs de haute affinité Trks. Les travaux précédemment réalisés au sein de notre équipe ont mis en évidence une boucle de régulation autocrine, en réponse à un stress cellulaire, et ce de façon dépendante des neurotrophines, notamment du BDNF, dans plusieurs lignées lymphocytaires B humaines, à différents stades de différenciation. Les cellules produisent du BDNF qui agit de manière autocrine sur son récepteur spécifique, TrkB. Le transport du BDNF est assuré par la sortiline, une protéine à domaine Vps10. Les neurotrophines sont également synthétisées sous forme de progéniteurs biologiquement actifs, les pro-neurotrophines. Le pro-BDNF interagit avec le récepteur aux neurotrophines à domaine de mort p75NTR, l’interaction du pro-BDNF avec le récepteur p75NTR et de son co-récepteur, la sortiline, induit l’apoptose des lymphocytes B. La sortiline est exprimée dans les lymphocytes B humains, les lignées de lymphocytaires B. La sortiline, également appelée NTSR3, peut lier un autre neuropeptide, la neurotensine (NTS). Identifiée, dans le système nerveux, où elle joue un rôle de neurotransmetteur, impliqué dans l’analgésie et la thermorégulation. Elle est également présente dans le tube digestif, où elle est impliquée dans la régulation de la digestion et le contrôle et de la glycémie. La fonction de la neurotensine est associée à l’activation de la sortiline mais aussi de ses deux récepteurs à protéine G, le récepteur de haute affinité, NTSR1 et le récepteur de faible affinité, NTSR2. La NTS est impliquée dans l’oncogenèse de nombreux cancers solides via sa liaison au récepteur NTSR1 principalement mais également au récepteur NTSR2, notamment dans un modèle de cancer prostatique. Nous avons démontré pour la première fois l’expression de la neurotensine et de ses récepteurs NTSR1 et NTSR2 dans les lymphocytes B humains. Le stress pro-apoptotique induit par la privation sérique favorise une relocalisation des récepteurs NTSR1 et sortiline à la membrane plasmique. Au sein de ces cellules, la neurotensine induit une augmentation de la prolifération et une diminution de l’apoptose. Ces effets de la NTS sont bloqués par l’inhibiteur de NTSR1, le SR48692/Meclinertant®. Les analyses transcriptionnelles ont détecté une surexpression du récepteur NTSR2 au sein des lymphocytes B purifiés de patients ayant une LLC et au niveau des ganglions de patients atteints de lymphomes B en revanche, l’expression de la neurotensine est réduite. La surexpression de NTSR2 induit l’activation transcriptionnelle de TrkB, autre récepteur exprimé par ces lignées comme par les cellules de LLC de patients. La co-localisation de ces 2 récepteurs a été démontrée. Ce complexe protéique induit l’activation des voies de signalisation ERK, p38MAPK et JNK, après traitement par le BDNF, le ligand de TrkB. Ces données suggèrent un phénomène de transactivation entre ces 2 récepteurs, dépendant des métalloprotéases. Le blocage de l’internalisation de ce complexe protéique, induit une augmentation de l’activation des voies de signalisation. Le trafic intra-cellulaire endosomal de ce complexe apparaît perturbé dans les cellules surexprimant NTSR2, ce qui pourrait conduire à son accumulation comme cela est détecté dans les cellules de LLC. Ces cellules leucémiques se caractérisent également par une production d’exosomes contenant le complexe TrkB/NTSR2, sécrété en extra-cellulaire et retrouvé en excès dans le plasma des patients en comparaison à des témoins volontaires sains. / Neurotrophins are growth factors, initially discovered in the nervous system and whose functions are implicated in the growth, proliferation and survival of neuronal cells and astrocytes, and also in many other tissues. Neurotrophins can interact with their high-affinity receptors Trks. Previous work in our team showed a neurotrophin-dependent survival autocrine loop in response to cellular stress, including BDNF in several human B cell lines at various stages of B lymphocytes differentiation. These cells produce BDNF which acts in an autocrine manner on its specific tyrosine kinase receptor, TrkB. BDNF transport is provided by a Vps10 domain protein named, sortilin. Neurotrophins are synthesized as biologically active precursors, pro-neurotrophins. The proBDNF may interact with a death domain neurotrophins receptor p75NTR. The interaction of proBDNF with the p75NTR receptor and its co-receptor sortilin, induces B cell apoptosis. Sortilin is expressed in human lymphocytic lines B. Sortilin can bind another neuropeptide, neurotensin (NTS) and also called NTSR3 (Neurotensin Receptor 3). Identified in the nervous system, where it acts as a neurotransmitter involved in analgesia and thermoregulation, NTS is also present in the digestive tract, and involved in the digestion and glucose regulations. Neurotensin functions are associated to the sortilin activation but also its two G-protein coupled receptors, the high and the low affinity receptors, NTSR1 and NTSR2 respectively. NTS is involved in the oncogenesis of many solid cancers, especialy by its binding to the receptor NTSR1 mainly, but also NTSR2 notably in a prostate cancer model. We have demonstrated for the first time the expression of neurotensin and its receptors NTSR1 and NTSR2 in human B lymphocytes. The pro-apoptotic stress induced by serum deprivation promotes relocation NTSR1 receptor sortilin and to the plasma membrane. Within these cells, neurotensin induces increased proliferation and decreased apoptosis. These effects are blocked by the NTSR1 antagonist, SR48692/Meclinertant®. Transcriptional analyzes have detected overexpression of the receptor NTSR2 in purified B cells from patients with CLL and in lymph nodes of B-cell lymphomas patients, in contrast, the expression neurotensin is reduced. Overexpression NTSR2 induced transcriptional activation of TrkB. This receptor is expressed by B cell lines and B cells of CLL patients. The co-localization of these 2 receptors was demonstrated. This protein complex induces the activation of signaling pathways ERK, JNK and p38MAPK, after treatment with BDNF, the TrkB ligand. These data suggest a transactivation between these two receptors, depending to the metalloproteas activation. The internalization blocking of this protein complex, induces its plasma membrane sequestration and induces an increase of the signaling pathways activation. The intracellular endosomal trafficking in cells overexpressing NTSR2 cells, as detected in CLL cells, appears disrupted, which might lead to the NTSR2/TrkB complex accumulation, and releasing to the extracellular environnement. These leukemic cells are also characterized by a production of exosomes containing the TrkB/NTSR2 complex, secreted to the extracellular environement and found in excess in the plasma of patients in comparison to healthy volunteers.