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2.
Int J Mol Sci ; 24(24)2023 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-38139452

RESUMO

In the microenvironment, cell interactions are established between different cell types to regulate their migration, survival and activation. ß-Catenin is a multifunctional protein that stabilizes cell-cell interactions and regulates cell survival through its transcriptional activity. We used chronic lymphocytic leukemia (CLL) cells as a cellular model to study the role of ß-catenin in regulating the adhesion of tumor cells to their microenvironment, which is necessary for tumor cell survival and accumulation. When co-cultured with a stromal cell line (HS-5), a fraction of the CLL cells adhere to stromal cells in a dynamic fashion regulated by the different levels of ß-catenin expression. In non-adherent cells, ß-catenin is stabilized in the cytosol and translocates into the nucleus, increasing the expression of cyclin D1. In adherent cells, the level of cytosolic ß-catenin is low but membrane ß-catenin helps to stabilize the adhesion of CLL to stromal cells. Indeed, the overexpression of ß-catenin enhances the interaction of CLL with HS-5 cells, suggesting that this protein behaves as a regulator of cell adhesion to the stromal component and of the transcriptional regulation of cell survival. Inhibitors that block the stabilization of ß-catenin alter this equilibrium and effectively disrupt the support that CLL cells receive from the cross-talk with the stroma.


Assuntos
Tirosina Quinase da Agamaglobulinemia , Leucemia Linfocítica Crônica de Células B , beta Catenina , Humanos , beta Catenina/genética , beta Catenina/metabolismo , Comunicação Celular , Linhagem Celular Tumoral , Leucemia Linfocítica Crônica de Células B/patologia , Células Estromais/metabolismo , Microambiente Tumoral , Tirosina Quinase da Agamaglobulinemia/metabolismo
3.
Blood ; 142(17): 1478-1493, 2023 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-37339584

RESUMO

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma having a poor overall survival that is in need for the development of new therapeutics. In this study, we report the identification and expression of a new isoform splice variant of the tyrosine kinase receptor AXL in MCL cells. This new AXL isoform, called AXL3, lacks the ligand-binding domain of the commonly described AXL splice variants and is constitutively activated in MCL cells. Interestingly, functional characterization of AXL3, using CRISPR inhibition, revealed that only the knock down of this isoform leads to apoptosis of MCL cells. Importantly, pharmacological inhibition of AXL activity resulted in a significant decrease in the activation of well-known proproliferative and survival pathways activated in MCL cells (ie, ß-catenin, Ak strain transforming, and NF-κB). Therapeutically, preclinical studies using a xenograft mouse model of MCL indicated that bemcentinib is more effective than ibrutinib in reducing the tumor burden and to increase the overall survival. Our study highlights the importance of a previously unidentified AXL splice variant in cancer and the potential of bemcentinib as a targeted therapy for MCL.


Assuntos
Linfoma de Célula do Manto , Proteínas Tirosina Quinases , Humanos , Adulto , Animais , Camundongos , Tirosina Quinase da Agamaglobulinemia , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Apoptose
4.
Cancer Gene Ther ; 30(7): 1018-1028, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36973425

RESUMO

Chronic Lymphocytic Leukemia (CLL) is a heterogeneous B cell neoplasm ranging from indolent to rapidly progressive disease. Leukemic cell subsets with regulatory properties evade immune clearance; however, the contribution of such subsets during CLL progression is not completely elucidated. Here, we report that CLL B cells crosstalk with their immune counterparts, notably by promoting the regulatory T (Treg) cell compartment and shaping several helper T (Th) subsets. Among various constitutively- and BCR/CD40-mediated factors secreted, tumour subsets co-express two important immunoregulatory cytokines, IL10 and TGFß1, both associated with a memory B cell phenotype. Neutralizing secreted IL10 or inhibiting the TGFß signalling pathway demonstrated that these cytokines are mainly involved in Th- and Treg differentiation/maintenance. In line with the regulatory subsets, we also demonstrated that a CLL B cell population expresses FOXP3, a marker of regulatory T cells. Analysis of IL10, TGFß1 and FOXP3 positive subpopulations frequencies in CLL samples discriminated 2 clusters of untreated CLL patients that were significantly different in Tregs frequency and time-to-treatment. Since this distinction was pertinent to disease progression, the regulatory profiling provides a new rationale for patient stratification and sheds light on immune dysfunction in CLL.


Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Interleucina-10/genética , Interleucina-10/metabolismo , Linfócitos T Reguladores , Citocinas/metabolismo , Fatores de Transcrição Forkhead
6.
Leukemia ; 37(2): 339-347, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36566271

RESUMO

Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.


Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Prognóstico , Fator 88 de Diferenciação Mieloide/genética , Mutação , Fenótipo
7.
EJHaem ; 3(3): 913-918, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36051066

RESUMO

Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma that remains incurable with the treatment options available today. In the present study, we have identified the dihydroorotate dehydrogenase (DHODH), an essential enzyme for the de novo biosynthesis of pyrimidine-based nucleotides, to be overexpressed in MCL in comparison to healthy peripheral blood mononuclear cells (PBMC). In vitro inhibition of the DHODH activity using a newly developed DHODH inhibitor, namely (R)-HZ05, can induce MCL cell death in the nanomolar range independently than the P53 status of the investigated cell lines. Moreover, the combination of (R)-HZ05 with tyrosine kinase inhibitor shows the synergistic activity on cell death. Pre-clinical investigation on the efficacy of (R)-HZ05 shows that it can be prolonged animal lifespan similar to ibrutinib. (R)-HZ05 use in combination with tyrosine kinase inhibitor demonstrated a superior efficacy on tumor burden reduction and survival than either drug alone. We have demonstrated that the depletion of the pyrimidine nucleotide pool, using DHODH inhibitor, represents a new therapeutic strategy that may benefit MCL patients.

8.
Front Oncol ; 12: 841630, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35211418

RESUMO

In chronic lymphocytic leukemia (CLL), TP53 abnormalities are associated with reduced survival and resistance to chemoimmunotherapy (CIT). The recommended threshold to clinically report TP53 mutations is a matter of debate given that next-generation sequencing technologies can detect mutations with a limit of detection of approximately 1% with high confidence. However, the clinical impact of low-burden TP53 mutations with a variant allele frequency (VAF) of less than 10% remains unclear. Longitudinal analysis before and after fludarabine based on NGS sequencing demonstrated that low-burden TP53 mutations were present before the onset of treatment and expanded at relapse to become the predominant clone. Most studies evaluating the prognostic or predictive impact of low-burden TP53 mutations in untreated patients show that low-burden TP53 mutations have the same unfavorable prognostic impact as clonal defects. Moreover, studies designed to assess the predictive impact of low-burden TP53 mutations showed that TP53 mutations, irrespective of mutation burden, have an inferior impact on overall survival for CIT-treated patients. As low-burden and high-burden TP53 mutations have comparable clinical impacts, redefining the VAF threshold may have important implications for the clinical management of CLL.

9.
Ann Biol Clin (Paris) ; 80(1): 69-73, 2022 Feb 01.
Artigo em Francês | MEDLINE | ID: mdl-35135750

RESUMO

We report a case of acquired von Willebrand syndrome relapse in association with Crohn's disease, in a context of non-compliance in a 85-year-old woman suffering from epistaxis and melena. The acquired von Willebrand syndrome is a rare bleeding disorder. This case underlines the importance of maintaining the corticosteroid therapy in order to prevent the reappearance of autoantibodies and the recurrence of this syndrome.


Assuntos
Doença de Crohn , Doenças de von Willebrand , Idoso de 80 Anos ou mais , Autoanticorpos , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Feminino , Hemorragia/complicações , Humanos , Recidiva , Doenças de von Willebrand/complicações , Doenças de von Willebrand/diagnóstico , Fator de von Willebrand
11.
Hemasphere ; 5(12): e658, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34805765

RESUMO

Molecular tests have become an indispensable tool for the diagnosis and prognosis of hematological malignancies and are subject to accreditation according to the International Standard ISO 15189. National standardization of these techniques is essential to ensure that patients throughout France benefit from the same care. We report here on the experience of the GBMHM (Groupe des Biologistes Moléculaires des Hémopathies Malignes). By organizing External Evaluation of Quality (EEQ) programs and training meetings, the GBMHM has contributed to improvement and standardization of molecular tests in 64 French laboratories. A retrospective analysis of the quality-control results of 11 national campaigns spanning 10 years was performed for the 3 most frequently prescribed tests: BCR-ABL1, JAK2 V617F, and lymphoid clonality. For each test, particular attention was placed on comparing methodologies and their evolution throughout the period. The establishment of the BCR-ABL1, JAK2 V617F, and lymphoid clonality EEQ programs and the associated training meetings have initiated a process of collective standardization concerning the methods of implementation (JAK2 V617F) and the interpretation and formulation of results (lymphoid clonality). In addition, it resulted in objective improvement in technical performance (BCR-ABL1). Our evaluation of the impact of these EEQ programs demonstrates that it is possible to obtain reproducible values across different laboratories in France by applying national recommendations. To our knowledge, this is the first publication that evaluates the impact of a national quality assurance program on improving molecular results in hematology.

13.
Cancer Cell ; 39(3): 380-393.e8, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33689703

RESUMO

Hotspot mutation of IKZF3 (IKZF3-L162R) has been identified as a putative driver of chronic lymphocytic leukemia (CLL), but its function remains unknown. Here, we demonstrate its driving role in CLL through a B cell-restricted conditional knockin mouse model. Mutant Ikzf3 alters DNA binding specificity and target selection, leading to hyperactivation of B cell receptor (BCR) signaling, overexpression of nuclear factor κB (NF-κB) target genes, and development of CLL-like disease in elderly mice with a penetrance of ~40%. Human CLL carrying either IKZF3 mutation or high IKZF3 expression was associated with overexpression of BCR/NF-κB pathway members and reduced sensitivity to BCR signaling inhibition by ibrutinib. Our results thus highlight IKZF3 oncogenic function in CLL via transcriptional dysregulation and demonstrate that this pro-survival function can be achieved by either somatic mutation or overexpression of this CLL driver. This emphasizes the need for combinatorial approaches to overcome IKZF3-mediated BCR inhibitor resistance.


Assuntos
Linfócitos B/patologia , Fator de Transcrição Ikaros/genética , Leucemia Linfocítica Crônica de Células B/genética , Mutação/genética , Transcrição Gênica/genética , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , NF-kappa B/genética , Receptores de Antígenos de Linfócitos B/genética , Transdução de Sinais/genética
15.
Oncogene ; 39(14): 2934-2947, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32034308

RESUMO

B-cell receptor (BCR) signaling pathways and interactions with the tumor microenvironment account for mantle cell lymphoma (MCL) cells survival in lymphoid organs. In several MCL cases, the WNT/ß-catenin canonical pathway is activated and ß-catenin accumulates into the nucleus. As both BCR and ß-catenin are important mediators of cell survival and interaction with the microenvironment, we investigated the crosstalk between BCR and WNT/ß-catenin signaling and analyzed their impact on cellular homeostasis as well as their targeting by specific inhibitors. ß-catenin was detected in all leukemic MCL samples and its level of expression rapidly increased upon BCR stimulation. This stabilization was hampered by the BCR-pathway inhibitor Ibrutinib, supporting ß-catenin as an effector of the BCR signaling. In parallel, MCL cells as compared with normal B cells expressed elevated levels of WNT16, a NF-κB target gene. Its expression increased further upon BCR stimulation to participate to the stabilization of ß-catenin. Upon BCR stimulation, ß-catenin translocated into the nucleus but did not induce a Wnt-like transcriptional response, i.e., TCF/LEF dependent. ß-catenin rather participated to the regulation of NF-κB transcriptional targets, such as IL6, IL8, and IL1. Oligo pull down and chromatin immunoprecipitation experiments demonstrated that ß-catenin is part of a protein complex that binds the NF-κB DNA consensus sequence, strengthening the idea of an association between the two proteins. An inhibitor targeting ß-catenin transcriptional interactions hindered both NF-κB DNA recruitment and induced primary MCL cells apoptosis. Thus, ß-catenin likely represents another player through which BCR signaling impacts on MCL cell survival.


Assuntos
Linfoma de Célula do Manto/genética , NF-kappa B/genética , Receptores de Antígenos de Linfócitos B/genética , Transcrição Gênica/genética , Via de Sinalização Wnt/genética , beta Catenina/genética , Animais , Apoptose/genética , Linfócitos B/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/genética , Sobrevivência Celular/genética , Feminino , Células HEK293 , Homeostase/genética , Humanos , Camundongos , Fatores de Transcrição TCF/genética , Microambiente Tumoral/genética
16.
Ann Biol Clin (Paris) ; 77(5): 557-561, 2019 10 01.
Artigo em Francês | MEDLINE | ID: mdl-31512579

RESUMO

We report here a case of primitive plasma cell leukemia with immunoglobulin (Ig) E. IgE myeloma is an exceptional variant of multiple myeloma, with a very poor prognosis. Its biological diagnosis requires specific analyzes in order to detect IgE gammopathy. Plasma cell leukemia (PCL) is also a very rare and very severe form of multiple myeloma. There are two variants: primitive PCL (pPCL) occurring de novo and secondary PCL (sPCL), evolution of a preexisting myeloma. Its diagnosis is essentially biological since it is defined by a blood plasmocytosis greater than 2 G/L or 20% of the leucocytes.


Assuntos
Imunoglobulina E/sangue , Leucemia Plasmocitária/sangue , Leucemia Plasmocitária/diagnóstico , Idoso , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Humanos , Leucemia Plasmocitária/imunologia , Masculino , Prognóstico
17.
Blood ; 134(7): 641-644, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31243043

RESUMO

Mutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in Bruton tyrosine kinase (BTK) and/or phospholipase Cγ2 (PLCG2) genes. Mutational information for patients still on ibrutinib is limited. We report a study aimed to provide a "snapshot" of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least 3 years of treatment. Of 204 patients who initiated ibrutinib via an early-access program at 29 French Innovative Leukemia Organization (FILO) centers, 63 (31%) were still on ibrutinib after 3 years and 57 provided a fresh blood sample. Thirty patients had a CLL clone ≥0.5 × 109/L, enabling next-generation sequencing (NGS); BTK and PLCG2 mutations were detected in 57% and 13% of the NGS samples, respectively. After median follow-up of 8.5 months from sample collection, the presence of a BTK mutation was significantly associated with subsequent CLL progression (P = .0005 vs no BTK mutation). Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Fosfolipase C gama/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Piperidinas
19.
Blood ; 133(11): 1205-1216, 2019 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-30602617

RESUMO

Recent evidence suggests that complex karyotype (CK) defined by the presence of ≥3 chromosomal aberrations (structural and/or numerical) identified by using chromosome-banding analysis (CBA) may be relevant for treatment decision-making in chronic lymphocytic leukemia (CLL). However, many challenges toward the routine clinical application of CBA remain. In a retrospective study of 5290 patients with available CBA data, we explored both clinicobiological associations and the clinical impact of CK in CLL. We found that patients with ≥5 abnormalities, defined as high-CK, exhibit uniformly dismal clinical outcomes, independently of clinical stage, TP53 aberrations (deletion of chromosome 17p and/or TP53 mutations [TP53abs]), and the expression of somatically hypermutated (M-CLL) or unmutated immunoglobulin heavy variable genes. Thus, they contrasted with CK cases with 3 or 4 aberrations (low-CK and intermediate-CK, respectively) who followed aggressive disease courses only in the presence of TP53abs. At the other end of the spectrum, patients with CK and +12,+19 displayed an exceptionally indolent profile. Building upon CK, TP53abs, and immunoglobulin heavy variable gene somatic hypermutation status, we propose a novel hierarchical model in which patients with high-CK exhibit the worst prognosis, whereas those with mutated CLL lacking CK or TP53abs, as well as CK with +12,+19, show the longest overall survival. Thus, CK should not be axiomatically considered unfavorable in CLL, representing a heterogeneous group with variable clinical behavior. High-CK with ≥5 chromosomal aberrations emerges as prognostically adverse, independent of other biomarkers. Prospective clinical validation is warranted before ultimately incorporating high-CK in risk stratification of CLL.


Assuntos
Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Citogenética/métodos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Mutação , Idoso , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Hipermutação Somática de Imunoglobulina/genética , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética
20.
Eur Respir J ; 49(6)2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28596432

RESUMO

The objectives of this prospective study were: 1) to determine the prevalence and determinants of obstructive sleep apnoea (OSA) in patients with newly diagnosed idiopathic pulmonary fibrosis (IPF); 2) to determine whether OSA was associated with cardiovascular disease (CVD) as well as increased oxidative stress and levels of IPF biomarkers in the blood.A group of 45 patients with newly diagnosed IPF attended polysomnography. The prevalence of CVD and the severity of coronary artery calcification were investigated by high-resolution computed tomography. The levels of 8-hydroxydeoxyguanosine (8-OH-DG) and various IPF biomarkers in the blood were compared between patients with no or mild OSA (apnoea-hypopnoea index (AHI) <15 events·h-1), with moderate OSA (15 ≤AHI <30 events·h-1) and with severe OSA (AHI ≥30 events·h-1).The prevalence of moderate-to-severe OSA and severe OSA was 62% and 40%, respectively. AHI did not correlate with demographic or physiological data. All patients with severe OSA had a medical history of CVD, versus 41.2% and 40% of those with no or mild OSA, or with moderate OSA, respectively (p<0.0001). Ischaemic heart disease (IHD) and moderate-to-severe coronary artery calcifications were strongly associated with severe OSA. The 8-OH-DG and matrix metalloproteinase-7 serum levels were significantly increased in the severe OSA group.Moderate-to-severe OSA is highly prevalent in incident IPF and severe OSA is strongly associated with the presence of CVD, particularly IHD.


Assuntos
Fibrose Pulmonar Idiopática/complicações , Apneia Obstrutiva do Sono/complicações , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Idoso , Biomarcadores/metabolismo , Calcinose/fisiopatologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/fisiopatologia , Comorbidade , Vasos Coronários/patologia , Desoxiguanosina/análogos & derivados , Desoxiguanosina/química , Feminino , França , Humanos , Fibrose Pulmonar Idiopática/epidemiologia , Fibrose Pulmonar Idiopática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Polissonografia , Prevalência , Estudos Prospectivos , Risco , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/fisiopatologia , Tomografia Computadorizada por Raios X
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