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1.
Haematologica ; 105(2): 448-456, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31371416

RESUMO

BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in BIRC3-mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3-mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P<0.001) similar to cases harboring TP53 mutations (median progression-free survival: 2.6 years, P<0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, P=0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.


Assuntos
Leucemia Linfocítica Crônica de Células B , Protocolos de Quimioterapia Combinada Antineoplásica , Proteína 3 com Repetições IAP de Baculovírus , Ciclofosfamida/uso terapêutico , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Prognóstico , Estudos Retrospectivos , Rituximab/uso terapêutico
3.
Curr Cancer Drug Targets ; 16(8): 659-668, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27514846

RESUMO

Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation/expansion of a clonal population of neoplastic cells with the morphological appearance of small mature B lymphocytes in blood, bone marrow, and lymphoid organs. CD49d, the α chain of the α4ß1 integrin heterodimer, is one of the main interactors between CLL cells and accessory cells in the microenvironmental sites and one of the main predictors of overall survival. In particular, CD49d is known to play a pivotal role in mediating both cell-cell and cell-matrix interactions in CLL-involved tissues eventually delivering prosurvival signals and protecting CLL cells from drug-induced damages. Treatment strategies targeting the α4ß1 integrin could represent an interesting option in CLL. In this context, the recombinant anti-CD49d antibody natalizumab demonstrated the potential to overcome stromal cell-induced resistance of B cell lymphoma cells against cytotoxic drugs and rituximab in vitro. Moreover, a specific interest for the CD49d molecule raises from the clinical activity of the recently proposed inhibitors of kinases downstream the BCR that has been recently related with the inside-out activation of the α4ß1 integrin. In the review, we addressed in detail the role of CD49d in CLL cells, including clinical impact, relationship with specific cytogenetic features, and CD49d-dependent interactions in lymph node and bone marrow microenvironment responsible for growth- and survival- supporting signals, eventually influencing CLL prognosis and therapeutic options.


Assuntos
Cadeias alfa de Integrinas/metabolismo , Integrina alfa4/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Humanos , Integrina alfa4beta1/metabolismo , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico
4.
Br J Haematol ; 126(1): 29-42, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15198729

RESUMO

Cases of B-cell chronic lymphocytic leukaemia (B-CLL) with mutated (M) IgV(H) genes have a better prognosis than unmutated (UM) cases. We analysed the IgV(H) mutational status of B-CLL according to the features of a canonical somatic hypermutation (SHM) process, correlating this data with survival. In a series of 141 B-CLLs, 124 cases were examined for IgV(H) gene per cent mutations and skewing of replacement/silent mutations in the framework/complementarity-determining regions as evidence of antigen-driven selection; this identified three B-CLL subsets: significantly mutated (sM), with evidence of antigen-driven selection, not significantly mutated (nsM) and UM, without such evidence and IgV(H) gene per cent mutations above or below the 2% cut-off. sM B-CLL patients had longer survival within the good prognosis subgroup that had more than 2% mutations of IgV(H) genes. sM, nsM and UM B-CLL were also characterized for the biased usage of IgV(H) families, intraclonal IgV(H) gene diversification, preference of mutations to target-specific nucleotides or hotspots, and for the expression of enzymes involved in SHM (translesion DNA polymerase zeta and eta and activation-induced cytidine deaminase). These findings indicate the activation of a canonical SHM process in nsM and sM B-CLLs and underscore the role of the antigen in defining the specific clinical and biological features of B-CLL.


Assuntos
Região Variável de Imunoglobulina/genética , Leucemia Linfocítica Crônica de Células B/genética , Hipermutação Somática de Imunoglobulina , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Análise Mutacional de DNA , DNA Polimerase Dirigida por DNA/genética , Feminino , Seguimentos , Expressão Gênica , Humanos , Imunofenotipagem , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Taxa de Sobrevida
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