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1.
Leukemia ; 35(1): 169-176, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32203141

RESUMO

Richter transformation (RT) is defined as development of aggressive lymphoma in patients (pts) with CLL. The incidence rates of RT among pts with CLL range from 2 to 10%. The aim of this analysis is to report the frequency, characteristics and outcomes of pts with RT enrolled in trials of the GCLLSG. A total of 2975 pts with advanced CLL were reviewed for incidence of RT. Clinical, laboratory, and genetic data were pooled. Time-to-event data, starting from time of CLL diagnosis, of first-line therapy or of RT diagnosis, were analyzed by Kaplan-Meier methodology. One hundred and three pts developed RT (3%): 95 pts diffuse large B-cell lymphoma (92%) and eight pts Hodgkin lymphoma (8%). Median observation time was 53 months (interquartile range 38.1-69.5). Median OS from initial CLL diagnosis for pts without RT was 167 months vs 71 months for pts with RT (HR 2.64, CI 2.09-3.33). Median OS after diagnosis of RT was 9 months. Forty-seven pts (46%) received CHOP-like regimens for RT treatment. Three pts subsequently underwent allogeneic and two pts autologous stem cell transplantation. Our findings show that within a large cohort of GCLLSG trial participants, 3% of the pts developed RT after receiving first-line chemo- or chemoimmunotherapy. This dataset confirms the ongoing poor prognosis and high mortality associated with RT.


Assuntos
Transformação Celular Neoplásica , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Transformação Celular Neoplásica/genética , Progressão da Doença , Feminino , Variação Genética , Alemanha , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/terapia , Linfoma/etiologia , Linfoma/mortalidade , Linfoma/terapia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Fatores de Tempo , Adulto Jovem
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(11): 1021-1025, 2020 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-33210597

RESUMO

Objective To investigate the regulation and clinical significance of T cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3)/galectin-9 signaling pathway in regulatory T cells (Tregs) and Th17 cells in patients with chronic lymphocytic leukemia (CLL). Methods The study enrolled 36 healthy individuals and 40 newly diagnosed CLL patients. The Tregs, Th17 cells, TIM-3+ Tregs and TIM-3+ Th17 cells were detected by the flow cytometry in their peripheral blood. Concentrations of IL-10, IL-17 and galectin-9 in serum were measured by the ELISA. Results Compared with the healthy controls, the CLL group had the higher levels of TIM-3+ Tregs, Tregs/Th17 cell ratio, TIM-3+ Tregs/TIM-3+ Th17 cell ratio, IL-10, galectin-9, and IL-10/IL-17 ratio. The level of TIM-3 expression on T cells, galectin-9 and the IL-10/IL-17 ratio in the CLL patients increased with the advance of Binet stage. Conclusion The TIM-3/galectin-9 signaling pathway is involved in the negative regulation of T cells in patients with CLL.


Assuntos
Galectinas , Receptor Celular 2 do Vírus da Hepatite A , Leucemia Linfocítica Crônica de Células B , Transdução de Sinais , Doença Crônica , Galectinas/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
3.
Nucleic Acids Res ; 48(22): 12727-12745, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33245769

RESUMO

Bcl-2 phosphorylation at serine-70 (S70pBcl2) confers resistance against drug-induced apoptosis. Nevertheless, its specific mechanism in driving drug-resistance remains unclear. We present evidence that S70pBcl2 promotes cancer cell survival by acting as a redox sensor and modulator to prevent oxidative stress-induced DNA damage and execution. Increased S70pBcl2 levels are inversely correlated with DNA damage in chronic lymphocytic leukemia (CLL) and lymphoma patient-derived primary cells as well as in reactive oxygen species (ROS)- or chemotherapeutic drug-treated cell lines. Bioinformatic analyses suggest that S70pBcl2 is associated with lower median overall survival in lymphoma patients. Empirically, sustained expression of the redox-sensitive S70pBcl2 prevents oxidative stress-induced DNA damage and cell death by suppressing mitochondrial ROS production. Using cell lines and lymphoma primary cells, we further demonstrate that S70pBcl2 reduces the interaction of Bcl-2 with the mitochondrial complex-IV subunit-5A, thereby reducing mitochondrial complex-IV activity, respiration and ROS production. Notably, targeting S70pBcl2 with the phosphatase activator, FTY720, is accompanied by an enhanced drug-induced DNA damage and cell death in CLL primary cells. Collectively, we provide a novel facet of the anti-apoptotic Bcl-2 by demonstrating that its phosphorylation at serine-70 functions as a redox sensor to prevent drug-induced oxidative stress-mediated DNA damage and execution with potential therapeutic implications.


Assuntos
Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma/tratamento farmacológico , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Apoptose/genética , Proliferação de Células/genética , Cisplatino/farmacologia , Dano ao DNA/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Etoposídeo/farmacologia , Fluoruracila/farmacologia , Humanos , Células Jurkat , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma/genética , Linfoma/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Oxirredução/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo , Serina/genética
4.
J Ayub Med Coll Abbottabad ; 32(4): 523-526, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33225656

RESUMO

BACKGROUND: Chronic lymphocytic leukaemia (CLL), an indolent but malignant lymphoproliferative disorder, is characterized by unregulated and uninhibited growth of mature monoclonal lymphocytes, with deletion of 17p containing TP53 gene being the most important prognostic factor. TP53 mutations, reported in 10% of CLL cases, seem to have a direct correlation to a more advanced stage and aggressive transformation of CLL. METHODS: This was a retrospective cross-sectional descriptive study limited to a period from 1st June 2013 to 30th June 2016, conducted at Section of haematology, Department of Pathology and Laboratory Medicine, Aga Khan University Hospital, Karachi. One thirty-nine cases of CLL received for TP53 mutation analysis at the Aga Khan University hospital clinical Laboratory were included in the study. Five ml of whole blood or one ml of bone marrow aspirate sample in EDTA tube was collected for the detection of TP53 mutation by the FISH technique. Statistical package for social sciences 21 was used for data entry and analysis. RESULTS: Of the 139 chronic lymphocytic leukaemia patients, 43 (31%) were females and 96 (69%) were males. The mean age of all patients was 56.3±10.84 years. Tp53 gene mutation in patients with chronic lymphocytic leukaemia was found only in 19(13.7%) patients. Among these patients 15 (10.9%) were male and 04(2.9%) were females. Age and gender were not statistically significant with Tp53 mutation with a p-value > 0.05 at a 95% confidence interval. CONCLUSIONS: In a cohort of Pakistani patients with Chronic lymphocytic leukaemia, TP53 gene mutation was found in 19 (13.7%).


Assuntos
Leucemia Linfocítica Crônica de Células B/epidemiologia , Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Proteína Supressora de Tumor p53/genética , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paquistão , Estudos Retrospectivos
5.
Rinsho Ketsueki ; 61(9): 1275-1280, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33162526

RESUMO

Molecular targeted therapies with small molecule inhibitors and antibodies have rapidly replaced chemoimmunotherapy, which has been the gold standard of care for patients with chronic lymphocytic leukemia (CLL). We discuss the current treatment strategies for CLL with special emphasis on genomic and molecular risk factors including IGHV unmutated status, 11q deletion, and 17p deletion. Ibrutinib and venetoclax are two molecular targeted agents currently available in Japan. They are highly effective, well tolerated, and have improved overall survival. Therefore, molecular targeted therapies are preferred to chemoimmunotherapy for most patients. Ongoing studies will clarify the optimal option between combination and sequence of treatment regimens with an appropriate timing of therapeutic intervention for longer survival. We are nearing an era of chemotherapy-free CLL management.


Assuntos
Leucemia Linfocítica Crônica de Células B , Terapia de Alvo Molecular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Imunoterapia , Japão , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética
6.
Zhonghua Xue Ye Xue Za Zhi ; 41(9): 737-742, 2020 Sep 14.
Artigo em Chinês | MEDLINE | ID: mdl-33113605

RESUMO

Objective: This study aims to investigate the expression of E3 ubiquitin-ligase (WWP1) in chronic lymphocytic leukemia (CLL) patients and analyze its correlation with clinical prognostic indicators (TP53, CD38, IGHV mutation) and its prognostic value. Methods: A total of 48 CLL patients and 9 age-matched normal subjects were enrolled in the study. The WWP1 expression was detected by SYBR Green-based real-time PCR, and the clinical relationship was analyzed by GraphPad Prism software. Results: The WWP1 median expression was 0.007 (95% CI 0.005-0.010) in the normal control group and 0.031 (95% CI 0.019-0.044) in the CLL group (P<0.001) . A sub-groups analysis implicated a statistically significant result (P=0.022) , showing that the median time from a relatively high and low transcription level of WWP1 to the first treatment was 24 months and 35 months, respectively. Positive CD38 and ZAP-70 expressions were associated with a higher WWP1 expression (P=0.012 and 0.029, respectively) . Conclusion: An abnormal WWP1 mRNA expression was found in CLL patients with significant correlation with ZAP-70 and CD38 expressions, and WWP1 may become a new supplement of CLL prognostic markers.


Assuntos
Leucemia Linfocítica Crônica de Células B , Ubiquitina-Proteína Ligases/genética , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Ubiquitina-Proteína Ligases/metabolismo
7.
J Steroid Biochem Mol Biol ; 204: 105767, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33011313

RESUMO

Sex hormone synthesis occurs in various organs and tissues besides the gonads, such as adrenal glands, brain, intestines, skin, fat, bone, and cells of the immune system. Regarding the latter, it is still not clear which pathways are active, and if they are modified in case of illness of the immune system. Our goal in this study was to determine mRNA expression of different steroidogenic enzymes in peripheral blood mononuclear cells (PBMCs) from healthy individuals of both sexes and of different ages, and then to compare their expression between healthy individuals and patients with Chronic Lymphocytic Leukemia (CLL). Furthermore, to elucidate possible mechanisms that regulate enzyme expression, we analyzed epigenetic events like promoter methylation. We determined that normal cells of the immune system, regardless of sex and age, expressed P450 side chain cleavage (P450scc), cytochrome P450 17α-hydroxylase/c17,20-lyase (P45017α), 3ß-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase (3ß-HSD), steroid 5 α reductase (5α-R) types 1, 2 and 3, 3α-hydroxysteroid dehydrogenase (3α-HSD) type 3, and 17ß-hydroxysteroid dehydrogenase (17ß-HSD) types 1, 3 and 5. We also established that 5α-R 1, 5α-R 3, 3α-HSD 3, 17ß-HSD 1 and 17ß-HSD 5 expression was altered in CLL patients, and that promoter regions of 5α-R 1, 17ß-HSD 1 and 17ß-HSD 5 were diferentially methylated. These results suggest that steroidogenic pathways may be affected in CLL cells, and this could be related to disease pathogenesis.


Assuntos
Sistema Enzimático do Citocromo P-450/genética , Hidroxiesteroide Desidrogenases/genética , Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/genética , Leucócitos Mononucleares/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Epigênese Genética , Estradiol/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Progesterona/sangue , RNA Mensageiro/metabolismo , Testosterona/sangue , Adulto Jovem
8.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1474-1479, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067940

RESUMO

OBJECTIVE: To investigate the value of fluorescence in situ hybridization (FISH) in the diagnosis and prognosis evaluation of patients with chronic lymphocytic leukemia (CLL). METHODS: Ninty-three patients with newly diagnosed CLL were tested by five probes including RB1 (13q14.1), D13S25 (13q14.3), p53(17p13.1), ATM( 11q22.3) and CSP12, while conventional cytogenetics (CC) was used for karyotype analysis. Then the correlation of the molecular cytogenetic abnormalities with the clinical Binet stages, Rai stages and the other related laboratory examinations was analyzed. RESULTS: The detection rate of chromosome abnormality in 93 patients was 79.6%, out of which detection rate of 13q (13q- was the highest and accounted for 45.2%), followed by trisomy 12 (+12) 26.9%, p53 deletion (17p-) 19.4% and ATM deletion (11p-) 17.2%. There were 27 cases (29.0%) with 2 or more abnormalities, including 13 cases with 13q-/17q-, 5 with 13q-/11q-, and 4 with 13q-/+12. Compared with CC test results, the positive rate of FISH detection was significantly higher (χ2=32.127, P<0.01). There was no significant correlation between FISH results and Rai stages (P>0.05), meanwhile 17p- highly correlated with later stage of the Binet stages (P=0.012). The molecular cytogenetic abnormalities significantly correlated with age, absolute value of peripheral lymphocyte count and CD38 expression level (P>0.05). The incidence of 13q- in female (65.4%) was statistically significantly higher than that in male (37.3%) (P=0.015). The unmutated IGHV rate of CLL patients with a 17p- was significantly higher than that in patients without this genetic abnormality (P=0.013). The expression of CD38 was detected among 29.0% of the patients, which significantly correlated with Binet stages (P=0.027) and unmutated IGHV (P=0.006). CONCLUSION: FISH can greatly increase the detection rate of molecular cytogenetic abnormalities in CLL patients, which, as a powerful supplement to the conventional cytogenetics, can be applied for the clinical staging and prognosis evaluation of CLL patients.


Assuntos
Leucemia Linfocítica Crônica de Células B , Aberrações Cromossômicas , Citogenética , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Masculino
9.
Exp Mol Pathol ; 116: 104524, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32882207

RESUMO

BACKGROUND: Prospective data on the value of oxidative stress in the pathogenesis of B-CLL are limited, and data on the relationship between oxidative stress and the presence of cytogenetic abnormalities (CA) in this pathology are almost absent. In the present study, we evaluated the serum levels of oxidative stress biomarkers [conjugated dienes (CD), malondialdehyde (MDA), and nitrite levels] and antioxidant biomarkers [ceruloplasmin (CP) level and glutathione peroxidase (GPx) activity] in B-CLL and investigated the relationship between these biomarkers and the presence of CA. MATERIAL AND METHODS: A total of 64 B-CLL patients were grouped with respect to the Rai stages of the disease, then to the mutated/unmutated status of IGHV genes as well as to the presence/absence of CA. The type and frequency of CA in the B-CLL cells were determined by fluorescence in situ hybridization. Control group included 30 healthy volunteers. The CD, MDA, and nitrite levels as well as the GPx activity were evaluated spectrophotometrically; the CP level was evaluated turbidimetrically. RESULTS: Compared to control, the B-CLL patients had increased CD, MDA, and nitrite levels as well as increased CP level and decreased GPx activity, which was observed at all Rai stages of the disease. CA were identified in 47 patients: del(13q14.3) as a single CA occurred in 18 patients, del(11q22.3) in 5 patients, del(17p13.1) in 4 patients, tri 12 in 5 patients, and multiple CA occurred in 15 patients. Compared to patients without CA, isolated del(17p13.1) was associated with higher CD and MDA levels while multiple CA with elevated CD levels only. The nitrite and CP levels and the activity of GPx in patients with CA were close to those in patients with normal FISH. The odds of harboring CA increased by a factor of 1.88 (p = 0.004) for every one unit increase in serum CD level (µmol/L), as assessed by binomial logistic regression. CONCLUSION: The results indicate that B-CLL patients experience increased oxidative stress and the relative deficiency of the antioxidant defense system. Increased CD level was independently associated with greater likelihood of harboring CA.


Assuntos
Aberrações Cromossômicas , Leucemia Linfocítica Crônica de Células B/genética , Trissomia/genética , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Análise Citogenética , Feminino , Humanos , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/genética , Trissomia/patologia
10.
Hematol Oncol ; 38(5): 689-697, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32738175

RESUMO

Non-chronic lymphocytic leukemia (non-CLL) clonal B-cell lymphocytosis (CBL) encompasses a heterogeneous group of hematologic disorders that are still poorly understood. To shed light on their biological aspects, we retrospectively analyzed a highly selected series of 28 patients, who had a clonal B-cell population in the peripheral blood and in the bone marrow, without evidence of lymphoma. Extended targeted next-generation sequencing revealed wide molecular heterogeneity with MYD88 (14%), PDE4DIP (14%), BIRC3 (11%), CCND3 (11%), NOTCH1 (11%), and TNFAIP3 (11%) as the most mutated genes. Mutations of MYD88 were "nonclassic" in most cases. Although some genetic lesions were overlapping with indolent lymphomas, mainly splenic B-cell lymphomas of marginal zone origin and splenic diffuse red pulp small B-cell lymphoma, the genetic profile of our non-CLL CBL series seemed to suggest that various pathways could be involved in the pathogenesis of these disorders, not mirroring any specific lymphoma entity. These data better enlighten the molecular characteristics of non-CLL CBL; however, more efforts are needed in order to improve the diagnostic process, prognostication, and clinical management.


Assuntos
Biomarcadores Tumorais , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Idoso , Alelos , Suscetibilidade a Doenças , Feminino , Expressão Gênica , Predisposição Genética para Doença , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imuno-Histoquímica , Imunofenotipagem , Leucemia Linfocítica Crônica de Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação
11.
Am J Hematol ; 95(11): 1361-1367, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32777106

RESUMO

Chromosomal abnormalities are frequently observed in patients with chronic lymphocytic leukemia (CLL) and have prognostic value. Deletions of the short arm of chromosome 17 (and/or mutations TP53) predict resistance to chemoimmunotherapy and shorter progression-free survival after targeted therapies. Although the complex karyotype (CK) is strongly predictive of a poor prognosis in hematologic malignancies such acute myeloid leukemia or myelodysplastic syndrome, its value in CLL is subject to debate. Here, we review the literature on the CK in CLL and examine its prognostic value with different treatments. We also propose a standardized method for defining a CK in all types of hematopoietic neoplasm.


Assuntos
Cariótipo Anormal , Cromossomos Humanos Par 17/genética , Neoplasias Hematológicas , Leucemia Linfocítica Crônica de Células B , Proteína Supressora de Tumor p53/genética , Intervalo Livre de Doença , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/terapia , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/terapia , Taxa de Sobrevida
12.
Sci Rep ; 10(1): 13156, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32753714

RESUMO

Protein kinase Cß (PKCß) expressed in mammalian cells as two splice variants, PKCßI and PKCßII, functions in the B cell receptor (BCR) signaling pathway and contributes to B cell development. We investigated the relative role of PKCßII in B cells by generating transgenic mice where expression of the transgene is directed to these cells using the Eµ promoter (Eµ-PKCßIItg). Our findings demonstrate that homozygous Eµ-PKCßIItg mice displayed a shift from IgD+IgMdim toward IgDdimIgM+ B cell populations in spleen, peritoneum and peripheral blood. Closer examination of these tissues revealed respective expansion of marginal zone (MZ)-like B cells (IgD+IgM+CD43negCD21+CD24+), increased populations of B-1 cells (B220+IgDdimIgM+CD43+CD24+CD5+), and higher numbers of immature B cells (IgDdimIgMdimCD21neg) at the expense of mature B cells (IgD+IgM+CD21+). Therefore, the overexpression of PKCßII, which is a phenotypic feature of chronic lymphocytic leukaemia cells, can skew B cell development in mice, most likely as a result of a regulatory influence on BCR signaling.


Assuntos
Linfócitos B/enzimologia , Regulação Enzimológica da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/enzimologia , Proteínas de Neoplasias/biossíntese , Proteína Quinase C beta/biossíntese , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Linfócitos B/patologia , Imunoglobulina D/genética , Imunoglobulina D/metabolismo , Imunoglobulina M/genética , Imunoglobulina M/metabolismo , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Proteína Quinase C beta/genética , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais
13.
Exp Hematol ; 89: 55-60.e6, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32781097

RESUMO

Despite recent identification of several prognostic markers, there is still a need for new prognostic parameters able to predict clinical outcome in chronic lymphocytic leukemia (CLL) patients. Here, we aimed to validate the prognostic ability of known (proteomic) markers measured pretreatment and to search for new proteomic markers that might be related to treatment response in CLL. To this end, baseline serum samples of 51 CLL patients treated with chemo-immunotherapy were analyzed for 360 proteomic markers, using Olink technology. Median event-free survival (EFS) was 23 months (range: 1.25-60.9). Patients with high levels of sCD23 (>11.27, p = 0.026), sCD27 (>11.03, p = 0.04), SPINT1 (>1.6, p = 0.001), and LY9 (>8.22, p = 0.0003) had a shorter EFS than those with marker levels below the median. The effect of sCD23 on EFS differed between immunoglobulin heavy chain variable gene-mutated and unmutated patients, with the shortest EFS for unmutated CLL patients with sCD23 levels above the median. Taken together, our results validate the prognostic impact of sCD23 and highlight SPINT1 and LY9 as possible promising markers for treatment response in CLL patients.


Assuntos
Biomarcadores Tumorais/genética , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/terapia , Proteínas Secretadas Inibidoras de Proteinases/genética , Receptores de IgE/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/sangue , Clorambucila , Intervalo Livre de Doença , Feminino , Expressão Gênica , Humanos , Cadeias Pesadas de Imunoglobulinas/sangue , Cadeias Pesadas de Imunoglobulinas/genética , Imunoterapia/métodos , Lenalidomida , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Proteínas Secretadas Inibidoras de Proteinases/sangue , Proteômica/métodos , Receptores de IgE/sangue , Rituximab , Família de Moléculas de Sinalização da Ativação Linfocitária/sangue , Resultado do Tratamento , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/sangue , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética
14.
Ann Hematol ; 99(10): 2343-2349, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32833105

RESUMO

Ibrutinib-based therapy represents a recent success in managing high-risk CLL patients with 17p/TP53 deletion. However, a subset of CLL patients are resistant to therapy. Deletion of lipoprotein lipase (LPL) has been postulated as a potential evasion mechanism to ibrutinib-based therapy. In this study, we assessed for LPL deletion by fluorescence in situ hybridization in 176 consecutive CLL patients with 17p/TP53 deletion. LPL deletion was detected in 35 (20%) of CLL patients. Patients with LPL deletion (del) showed a higher frequency of CD38 expression but have comparable frequencies of somatic hypermutation and ZAP-70 expression compared with patients with normal (nml) LPL. Gene mutation analysis showed that TP53 was mutated in 68% of LPL-del versus 91% of LPL-nml patients. The overall response to ibrutinib-based therapy was 57%, including 37% complete remission (CR) and 20% partial remission (PR) in patients with LPL-del versus 90% (56% CR and 34% PR) in patients with LPL-nml (p < 0.001). LPL-del patients also showed a poorer overall survival (OS) compared with patients with LPL-nml (median OS, 236 months versus undefined, p < 0.001). In summary, the data presented establish an association between LPL deletion, resistance to ibrutinib-based therapy, and poorer overall survival in TP53-deleted CLL patients. We suggest that LPL deletion might be utilized as a biomarker for risk stratification and to predict therapeutic response in this high-risk group of CLL patients.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Deleção de Genes , Leucemia Linfocítica Crônica de Células B/genética , Lipase Lipoproteica/deficiência , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Feminino , Genes p53 , Humanos , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Lipase Lipoproteica/genética , Lipase Lipoproteica/fisiologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Modelos de Riscos Proporcionais , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Medição de Risco , Rituximab/administração & dosagem , Sulfonamidas/administração & dosagem , Resultado do Tratamento , Proteína Supressora de Tumor p53/deficiência , Proteína-Tirosina Quinase ZAP-70/biossíntese , Proteína-Tirosina Quinase ZAP-70/genética
15.
Clin Adv Hematol Oncol ; 18(6): 348-357, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32649656

RESUMO

The increased use of several effective novel targeted therapy agents has revolutionized therapy for patients with chronic lymphocytic leukemia (CLL). Disease progression in patients with CLL continues to occur, however. In particular, 3% to 25% of patients treated with a novel agent develop Richter transformation (RT); that is, histologic transformation of CLL to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). RT that develops in the novel agent era is frequently associated with adverse molecular alterations, such as TP53 disruption and complex karyotype. As a result, patients with RT in the era of novel agents typically have poor responses to the traditional chemotherapy used to treat de novo DLBCL. These patients also tend to have poor survival outcomes, with a median overall survival of less than 1 year. In this article, we review the contemporary literature of RT, particularly in the context of novel agents used for CLL, and discuss the management approach of RT in the novel agent era.


Assuntos
Cariótipo Anormal , Antineoplásicos/uso terapêutico , Transformação Celular Neoplásica , Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Proteína Supressora de Tumor p53 , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Intervalo Livre de Doença , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/mortalidade , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/mortalidade , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
18.
Sci Rep ; 10(1): 12572, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724091

RESUMO

Evading apoptosis and sustained survival signaling pathways are two central hallmarks of B-cell chronic lymphocytic leukemia (B-CLL) cells. In this regard, nurse-like cells (NLC), the monocyte-derived type 2 macrophages, deliver stimulatory signals via B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), and the C-X-C Motif Chemokine Ligand 12 (CXCL12). Previously, we demonstrated that brain-derived neurotrophic factor (BDNF) protects B-CLL cells from spontaneous apoptosis by activating the oncogenic complex NTSR2-TrkB (neurotensin receptor 2-tropomyosin-related kinase receptor B), only overexpressed in B-CLL cells, inducing anti-apoptotic protein Bcl-2 (B-cell lymphoma 2) expression and Src kinase survival signaling pathways. Herein, we demonstrate that BDNF belongs to the NLC secretome and promotes B-CLL survival. This was demonstrated in primary B-CLL co-cultured with their autologous NLC, compared to B-CLL cells cultured alone. Inhibition of BDNF in co-cultures, enhances B-CLL apoptosis, whereas its exogenous recombinant activates pro-survival pathways in B-CLL cultured alone (i.e. Src activation and Bcl-2 expression), at a higher level than those obtained by the exogenous recombinant cytokines BAFF, APRIL and CXCL12, the known pro-survival cytokines secreted by NLC. Together, these results showed that BDNF release from NLC trigger B-CLL survival. Blocking BDNF would support research strategies against pro-survival cytokines to limit sustained B-CLL cell survival.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Macrófagos/metabolismo , Apoptose , Fator Ativador de Células B/genética , Fator Ativador de Células B/metabolismo , Linfócitos B/citologia , Linfócitos B/metabolismo , Transporte Biológico , Fator Neurotrófico Derivado do Encéfalo/genética , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Monócitos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor trkB/genética , Receptor trkB/metabolismo , Receptores de Neurotensina/genética , Receptores de Neurotensina/metabolismo , Transdução de Sinais
19.
Exp Hematol ; 88: 68-82.e5, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32682001

RESUMO

The myeloid nuclear differentiation antigen (MNDA) is a stress-induced protein that promotes degradation of the anti-apoptotic factor MCL-1 and apoptosis in myeloid cells. MNDA is also expressed in normal lymphoid cells and in B-cell clones isolated from individuals with chronic lymphocytic leukemia (CLL), a disease characterized by abnormal apoptosis control. We found that MNDA expression levels inversely correlate with the amount of the anti-apoptotic proteins MCL-1 and BCL-2 in human CLL samples. We report that in response to chemotherapeutic agents that induce genotoxic stress, MNDA exits its typical nucleolar localization and accumulates in the nucleoplasm of CLL and lymphoid cells. Then, MNDA binds chromatin at Mcl1 and Bcl2 genes and affects the transcriptional competence of RNA polymerase II. Our data also reveal that MNDA specifically associates with Mcl1 and Bcl2 (pre-) mRNAs and favors their rapid turnover as a prompt response to genotoxic stress. We propose that this rapid dynamic tuning of RNA levels, which leads to the destabilization of Mcl1 and Bcl2 transcripts, represents a post-transcriptional mechanism of apoptosis control in CLL cells. These results provide an explanation of previous clinical data and corroborate the finding that higher MNDA expression levels in CLL are associated with a better clinical course.


Assuntos
Antígenos de Diferenciação Mielomonocítica/metabolismo , Regulação Leucêmica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/biossíntese , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Fatores de Transcrição/metabolismo , Idoso , Idoso de 80 Anos ou mais , Antígenos de Diferenciação Mielomonocítica/genética , Apoptose/genética , Cromatina/genética , Cromatina/metabolismo , Feminino , Células HL-60 , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Fatores de Transcrição/genética
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