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1.
J Leukoc Biol ; 111(2): 313-325, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34288092

RESUMO

Chronic lymphocytic leukemia (CLL) is characterized by significant biologic and clinical heterogeneity. This study was designed to explore CLL B-cells' proteomic profile in order to identify biologic processes affected at an early stage and during disease evolution as stable or progressive. Purified B cells from 11 untreated CLL patients were tested at two time points by liquid chromatography-tandem mass spectrometry. Patients included in the study evolved to either progressive (n = 6) or stable disease (n = 5). First, at an early stage of the disease (Binet stage A), based on the relative abundance levels of 389 differentially expressed proteins (DEPs), samples were separated into stable and progressive clusters with the main differentiating factor being the RNA splicing pathway. Next, in order to test how the DEPs affect RNA splicing, a RNA-Seq study was conducted showing 4217 differentially spliced genes between the two clusters. Distinct longitudinal evolutions were observed with predominantly proteomic modifications in the stable CLL group and spliced genes in the progressive CLL group. Splicing events were shown to be six times more frequent in the progressive CLL group. The main aberrant biologic processes controlled by DEPs and spliced genes in the progressive group were cytoskeletal organization, Wnt/ß-catenin signaling, and mitochondrial and inositol phosphate metabolism with a downstream impact on CLL B-cell survival and migration. This study suggests that proteomic profiles at the early stage of CLL can discriminate progressive from stable disease and that RNA splicing dysregulation underlies CLL evolution, which opens new perspectives in terms of biomarkers and therapy.


Assuntos
Linfócitos B/patologia , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/patologia , Proteoma/metabolismo , Splicing de RNA/genética , Via de Sinalização Wnt , Idoso , Linfócitos B/metabolismo , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteoma/análise , RNA-Seq , Estudos Retrospectivos
2.
Front Nucl Med ; 2: 829138, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-39354989

RESUMO

Currently, prognostic models in diffuse large B-cell lymphoma (DLBCL) fail to closely reflect patients' biological, clinical, and survival heterogeneity. We, therefore, assessed the impact of clinical, biological, immunohistochemical (IHC), baseline (0), and interim (after 2 and 4 treatment cycles) PET (PET0, PET2, and PET4) data not yet included in any scoring system on DLBCL outcome. The analysis was conducted on 89 previously untreated adult patients of the Finistere Observatory Cohort (O.Ly.Fin) with documented DLBCL, recruited between January 2010 and December 2017, with progression-free survival (PFS) and overall survival (OS) as primary and secondary endpoints, respectively. Seventy-eight patients were treated with rituximab, cyclophosphamide, hydroxyadriamycin, vincristine, and prednisone (R-CHOP), while 11 received R-dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and hydroxyadriamycin (EPOCH). Patients were followed up until June 20, 2020. On multivariate analysis, Ki67 ≥ 70% on IHC (K), bulky presentation ≥7.5 cm (B), meningeal lymphomatosis (M), and PET0-PET4 ΔSUVmax <71% (P4) were identified as strong independent predictors of PFS, and all variables but bulky disease also strongly and independently predicted OS. Using these 4 parameters, we designed a scoring model named KBMP4 stratifying patients into low- (0 parameter), intermediate- (1 or 2), and high-risk (≥3) subgroups by the Kaplan-Meier analysis. At a median follow-up of 43 months, PFS and OS were both 100% in the low-risk subgroup, 71.4 and 90.5%, respectively, in the intermediate-risk subgroup, and 0 and 55.5%, respectively, in the high-risk subgroup. Use of the KBMP4 model in clinical practice may improve accuracy in prognostic prediction and treatment decisions in de novo DLBCL patients.

3.
Onco Targets Ther ; 12: 1181-1184, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863085

RESUMO

Richter syndrome (RS) is an aggressive lymphoma arising on the back of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and is the most common B-cell malignancy in the Western world. In the majority of cases, RS presents an activated B cell (ABC) phenotype of diffuse large B-cell lymphoma (DLBCL). From the therapeutic point of view, selective inhibition of PI3Kδ with idelalisib represents a valuable addition to available treatment options for patients with CLL/SLL, many of whom do not respond to or cannot tolerate chemoimmunotherapy. However, to our knowledge, there have been no prospective studies evaluating idelalisib efficacy in a DLBCL-ABC form of RS. Here, we present a case of a DLBCL-ABC form of RS achieving a complete response at 3 weeks after initiating idelalisib and rituximab therapy for six cycles. This response was maintained during the idelalisib monotherapy, but the patient relapsed rapidly after treatment was withdrawn, because of a grade three immune colitis that developed at 10 months of treatment. This report demonstrates that idelalisib is highly effective in RS and provides an attractive option in this aggressive disease. This agent could meet an unmet need by providing a treatment option with a tolerable safety profile for elderly patients with RS.

4.
Oncoimmunology ; 8(3): 1554968, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30723588

RESUMO

Chronic lymphocytic leukemia (CLL) is associated with abnormal T-cell responses responsible for defective anti-tumor activities. Intriguingly, CLL B cells share phenotypical characteristics with regulatory B (Breg) cells suggesting that they might negatively control the T-cell activation and immune responses. We elaborated an in vitro co-culture system with T cells to evaluate the Breg capacities of CLL B cells following innate Toll-like receptor 9 (TLR9) engagement. We demonstrated that B cells from half of the patients exhibited regulatory capacities, whilst B cells from the remaining patients were unable to develop a Breg function. The T cell sensitivities of all patients were normal suggesting that defective Breg activities were due to intrinsic CLL B cell deficiencies. Thus, TLR-dedicated gene assays highlighted differential signature of the TLR9 negative regulation pathway between the two groups of patients. Furthermore, correlations of the doubling time of lymphocytosis, the time to first treatment, the mutational status of IgVH and the Breg functions indicate that patients with efficient Breg activities have more aggressive CLL than patients with defective Breg cells. Our in vitro observations may open new approaches for adjusting therapeutic strategies targeting the Breg along with the evolution of the disease.

5.
J Immunother Cancer ; 7(1): 22, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696487

RESUMO

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia and the anti-CD20 monoclonal antibody, rituximab, represents the therapeutic gold standard for more than 2 decades in this pathology, when used in combination with chemotherapy. However, some patients experience treatment resistance or rapid relapses, and in particular, those harboring a 17p/TP53 deletion (del(17p)). This resistance could be explained by a chemo-resistance, but it could also result from the direct impact of del(17p) on the pharmacokinetics of rituximab, which represents the aim of the present study. Accordingly, 44 CLL patients were included in the study, and among them 9 presented a del(17p). Next, a total of 233 rituximab sera were selected for a pharmacokinetic study and analyzed in a two-compartment model showing important differences when del(17p) CLL patients were compared with non-del(17p) patients treated with rituximab and chemotherapy: (1) clearance of rituximab was faster; (2) central volume of rituximab distribution V1 (peripheral blood) was reduced while peripheral volume V2 (lymphoid organs and tissues) was increased; and (3) the rate of rituximab elimination (Kout) was faster. In contrast, the group with a better prognosis harboring isolated del(13q) presented a slower rate of elimination (Kout). Pharmacokinetic parameters were independent from the other factors tested such as age, sex, chemotherapy regimen (fludarabine/cyclophosphamide versus bendamustine), IGHV mutational status, and FCGR3A 158VF status. In conclusion, this study provides an additional argument to consider that del(17p) is effective not only to control chemoresistance but also monoclonal antibody activity, based on higher rituximab turnover.


Assuntos
Antineoplásicos Imunológicos/farmacocinética , Deleção Cromossômica , Cromossomos Humanos Par 17 , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Rituximab/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Feminino , Variação Genética , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Estadiamento de Neoplasias , Prognóstico , Rituximab/uso terapêutico , Proteína Supressora de Tumor p53/genética
6.
Oncotarget ; 9(60): 31590-31605, 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30167081

RESUMO

The anti-CD20-specific monoclonal antibody rituximab (RTX), in combination with chemotherapy, is commonly used for primary treatment in chronic lymphocytic leukemia (CLL). However, relapses remain important and activation of the complement pathway is one of the mechanisms by which RTX generates the destruction of B cells directly by complement-dependent cytotoxicity (CDC), or indirectly by antibody-dependent cellular phagocytosis. In this study, the RTX capacity to induce CDC was established in 69 untreated CLL patients, this cohort including 34 patients tested before the initiation of RTX-chemotherapy. In vitro CDC-resistance to RTX predicts lower response rates to RTX-chemotherapy and shorter treatment free survival. Furthermore, the predictive value of CDC-resistance was independent from the clinical, cytogenetic and FcγR3A V158F polymorphism status. In contrast, CLL cell resistance to CDC predominates in IGHV unmutated patients and was related to an important α2-6 sialyl transferase activity, which in turn increases cell surface α2-6 hypersialylation. Suspected factors associated with resistance to CDC (CD20, CD55, CD59, factor H, GM1, and sphingomyelin) were not differentially expressed or recruited between the two CLL groups. Altogether, results provide evidence that testing RTX capacity to induce CDC in vitro represents an independent predictive factor of therapeutic effects of RTX, and that α2-6 hypersialylation in CLL cells controls RTX response through the control of the complement pathway. At a time when CLL therapy is moving towards chemo-free treatments, further experiments are required to determine whether performing an initial in vitro assay to appreciate CLL CDC resistance might be useful to select patients.

7.
Clin Epigenetics ; 9: 122, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29209431

RESUMO

Background: Both defective DNA methylation and active DNA demethylation processes are emerging as important risk factors in chronic lymphocytic leukemia (CLL). However, associations between 5-cytosine epigenetic markers and the most frequent chromosomal abnormalities detected in CLL remain to be established. Methods: CLL patients were retrospectively classified into a cytogenetic low-risk group (isolated 13q deletion), an intermediate-risk group (normal karyotype or trisomy 12), and a high-risk group (11q deletion, 17p deletion, or complex karyotype [≥ 3 breakpoints]). The two 5-cytosine derivatives, 5-methylcytosine (5-mCyt) and 5-hydroxymethylcytosine (5-hmCyt), were tested by ELISA (n = 60), while real-time quantitative PCR was used for determining transcriptional expression levels of DNMT and TET (n = 24). Results: By using global DNA methylation/demethylation levels, in the low-risk disease group, two subgroups with significantly different clinical outcomes have been identified (median treatment-free survival [TFS] 45 versus > 120 months for 5-mCyt, p = 0.0008, and 63 versus > 120 months for 5-hmCyt, p = 0.04). A defective 5-mCyt status was further associated with a higher percentage of 13q deleted nuclei (> 80%), thus suggesting an acquired process. When considering the cytogenetic intermediate/high-risk disease groups, an association of 5-mCyt status with lymphocytosis (p = 0.0008) and the lymphocyte doubling time (p = 0.04) but not with TFS was observed, as well as a reduction of DNMT3A, TET1, and TET2 transcripts. Conclusions: Combining cytogenetic studies with 5-mCyt assessment adds accuracy to CLL patients' prognoses and particularly for those with 13q deletion as a sole cytogenetic abnormality.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 13/genética , Análise Citogenética/métodos , Epigenômica/métodos , Hibridização in Situ Fluorescente/métodos , Leucemia Linfocítica Crônica de Células B/genética , 5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Idoso , Idoso de 80 Anos ou mais , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Proteínas de Ligação a DNA/genética , Dioxigenases , Progressão da Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Oxigenases de Função Mista/genética , Prognóstico , Proteínas Proto-Oncogênicas/genética , Estudos Retrospectivos
8.
Oncotarget ; 8(39): 65699-65716, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-29029465

RESUMO

Cytosine derivative dysregulations represent important epigenetic modifications whose impact on the clinical outcome in chronic lymphocytic leukemia (CLL) is incompletely understood. Hence, global levels of 5-methylcytosine (5-mCyt), 5-hydroxymethylcytosine (5-hmCyt), 5-carboxylcytosine (5-CaCyt) and 5-hydroxymethyluracil were tested in purified B cells from CLL patients (n = 55) and controls (n = 17). The DNA methylation 'writers' (DNA methyltransferases [DNMT1/3A/3B]), 'readers' (methyl-CpG-binding domain [MBD2/4]), 'editors' (ten-eleven translocation [TET1/2/3]) and 'modulators' (SAT1) were also evaluated. Accordingly, patients were stratified into three subgroups. First, a subgroup with a global deficit in cytosine derivatives characterized by hyperlymphocytosis, reduced median progression free survival (PFS = 52 months) and shorter treatment free survival (TFS = 112 months) was identified. In this subgroup, major epigenetic modifications were highlighted including a reduction of 5-mCyt, 5-hmCyt, 5-CaCyt associated with DNMT3A, MBD2/4 and TET1/2 downregulation. Second, the cytosine derivative analysis revealed a subgroup with a partial deficit (PFS = 84, TFS = 120 months), mainly affecting DNA demethylation (5-hmCyt reduction, SAT1 induction). Third, a subgroup epigenetically similar to controls was identified (PFS and TFS > 120 months). The prognostic impact of stratifying CLL patients within three epigenetic subgroups was confirmed in a validation cohort. In conclusion, our results suggest that dysregulations of cytosine derivative regulators represent major events acquired during CLL progression and are independent from IGHV mutational status.

9.
J Soc Biol ; 201(3): 307-15, 2007.
Artigo em Francês | MEDLINE | ID: mdl-18157083

RESUMO

mRNA translation is now recognized as a important regulatory step for gene expression in different physiological and pathophysiological processes including cell proliferation and apoptosis. B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of resting lymphocytes and defective apoptosis. The mRNA cap-binding protein eIF4E (eukaryotic Initiation Factor 4E) and its repressor 4E-BP (eIF4E Binding protein) are crucial translational regulators that have been involved in survival and apoptosis processes of cells. We have shown that the release of eIF4E from its translational repressor 4E-BP is an important event for the first mitotic division triggered by fertilization and that the degradation of 4E-BP is a new means to regulate 4E-BP function that has to be analyzed in other physiological and physiopathological processes. In this chapter, we describe recent advances illustrating the importance of eIF4E and 4E-BP in cancer processes, suggesting that these actors can be targeted for potential therapy against cancer in general and LLC in particular.


Assuntos
Regulação Neoplásica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Fatores de Iniciação de Peptídeos/genética , Biossíntese de Proteínas , RNA Mensageiro/genética , Apoptose , Fator de Iniciação 4E em Eucariotos/genética , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Modelos Genéticos , Oócitos/fisiologia , Elongação Traducional da Cadeia Peptídica , Iniciação Traducional da Cadeia Peptídica , Terminação Traducional da Cadeia Peptídica
10.
Cancer ; 104(1): 110-7, 2005 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-15912518

RESUMO

BACKGROUND: Acute leukemia (AL) requiring cytotoxic treatment occurring during pregnancy poses a very difficult therapeutic dilemma. METHODS: By means of a mail questionnaire, information on a series of 37 patients with a diagnosis of AL during pregnancy was collected from 13 French centers between December, 1988 and November, 2003. RESULTS: Thirty-one patients had acute myeloid leukemia (AML), and 6 patients had acute lymphoblastic leukemia (ALL). Nine patients were diagnosed during the first trimester, 10 patients were diagnosed during the second trimester, and 18 patients were diagnosed during the third trimester. Fifteen pregnancies ended with therapeutic or spontaneous abortion. There were 13 normal deliveries, including 1 gemellary pregnancy, and 9 Cesarean sections. Twenty-three healthy babies survived from the 37 pregnancies, of whom 15 babies had been exposed to chemotherapeutic agents. A complete remission was achieved in 34 patients. Eleven women had severe extrahematologic complications during the induction remission course. The median disease-free survival (DFS) was not reached, with a 5-year DFS of 54%. Ten patients developed recurrent disease. Overall, 12 of 37 pregnant women died from leukemia. CONCLUSIONS: Pregnancy does not affect the course of AL. In the first trimester, termination of pregnancy should be discussed because of the potential fetal consequences of chemotherapy. Chemotherapy treatment during the second or third trimester may not require termination of pregnancy, because as remission of AL and delivery of a normal infant are likely to be obtained.


Assuntos
Leucemia/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Complicações Neoplásicas na Gravidez , Doença Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Leucemia Mieloide/tratamento farmacológico , Gravidez , Resultado da Gravidez , Trimestres da Gravidez , Indução de Remissão
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