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1.
Leukemia ; 34(7): 1760-1774, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32015491

RESUMEN

Despite advances in chronic lymphocytic leukaemia (CLL) treatment, globally chemotherapy remains a central treatment modality, with chemotherapy trials representing an invaluable resource to explore disease-related/genetic features contributing to long-term outcomes. In 499 LRF CLL4 cases, a trial with >12 years follow-up, we employed targeted resequencing of 22 genes, identifying 623 mutations. After background mutation rate correction, 11/22 genes were recurrently mutated at frequencies between 3.6% (NFKBIE) and 24% (SF3B1). Mutations beyond Sanger resolution (<12% VAF) were observed in all genes, with KRAS mutations principally composed of these low VAF variants. Firstly, employing orthogonal approaches to confirm <12% VAF TP53 mutations, we assessed the clinical impact of TP53 clonal architecture. Whilst ≥ 12% VAF TP53mut cases were associated with reduced PFS and OS, we could not demonstrate a difference between <12% VAF TP53 mutations and either wild type or ≥12% VAF TP53mut cases. Secondly, we identified biallelic BIRC3 lesions (mutation and deletion) as an independent marker of inferior PFS and OS. Finally, we observed that mutated MAPK-ERK genes were independent markers of poor OS in multivariate survival analysis. In conclusion, our study supports using targeted resequencing of expanded gene panels to elucidate the prognostic impact of gene mutations.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/genética , Biomarcadores de Tumor/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Sistema de Señalización de MAP Quinasas/genética , Mutación , Proteína p53 Supresora de Tumor/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de Cohortes , Ciclofosfamida/administración & dosificación , Quinasas MAP Reguladas por Señal Extracelular/genética , Estudios de Seguimiento , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Pronóstico , Tasa de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados
2.
Blood Adv ; 3(16): 2474-2481, 2019 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-31434681

RESUMEN

Chronic lymphocytic leukemia patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemoimmunotherapy (CIT). DNA methylation profiling can subdivide early-stage patients into naive B-cell-like CLL (n-CLL), memory B-cell-like CLL (m-CLL), and intermediate CLL (i-CLL), with differing times to first treatment and overall survival. However, whether DNA methylation can identify patients destined to respond favorably to CIT has not been ascertained. We classified treatment-naive patients (n = 605) from 3 UK chemo and CIT clinical trials into the 3 epigenetic subgroups, using pyrosequencing and microarray analysis, and performed expansive survival analysis. The n-CLL, i-CLL, and m-CLL signatures were found in 80% (n = 245/305), 17% (53/305), and 2% (7/305) of IGHV-unmutated (IGHV-U) cases, respectively, and in 9%, (19/216), 50% (108/216), and 41% (89/216) of IGHV-M cases, respectively. Multivariate Cox proportional analysis identified m-CLL as an independent prognostic factor for overall survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.87; P = .018) in CLL4, and for progression-free survival (HR, 0.25; 95% CI, 0.10-0.57; P = .002) in ARCTIC and ADMIRE patients. The analysis of epigenetic subgroups in patients entered into 3 first-line UK CLL trials identifies m-CLL as an independent marker of prolonged survival and may aid in the identification of patients destined to demonstrate prolonged survival after CIT.


Asunto(s)
Metilación de ADN , Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Adulto , Anciano , Anciano de 80 o más Años , Aberraciones Cromosómicas , Biología Computacional/métodos , Epigénesis Genética , Epigenómica/métodos , Femenino , Perfilación de la Expresión Génica , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/terapia , Masculino , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales
3.
Blood ; 133(12): 1269-1270, 2019 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-30898773
5.
Nat Commun ; 7: 11889, 2016 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-27297662

RESUMEN

NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas. NKX2-3 induces B-cell receptor signalling by phosphorylating Lyn/Syk kinases, which in turn activate multiple integrins (LFA-1, VLA-4), adhesion molecules (ICAM-1, MadCAM-1) and the chemokine receptor CXCR4. These molecules enhance migration, polarization and homing of B cells to splenic and extranodal tissues, eventually driving malignant transformation through triggering NF-κB and PI3K-AKT pathways. This study implicates oncogenic NKX2-3 in lymphomagenesis, and provides a valid experimental mouse model for studying the biology and therapy of human marginal-zone B-cell lymphomas.


Asunto(s)
Proteínas de Homeodominio/genética , Linfocitos/metabolismo , Linfoma de Células B de la Zona Marginal/genética , Receptores de Antígenos de Linfocitos B/genética , Transducción de Señal/genética , Factores de Transcripción/genética , Animales , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Perfilación de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Humanos , Estimación de Kaplan-Meier , Tejido Linfoide/metabolismo , Linfoma de Células B de la Zona Marginal/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Receptores de Antígenos de Linfocitos B/metabolismo , Quinasa Syk/genética , Quinasa Syk/metabolismo , Factores de Transcripción/metabolismo
7.
Haematologica ; 99(4): 736-42, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24584352

RESUMEN

ATM mutation and BIRC3 deletion and/or mutation have independently been shown to have prognostic significance in chronic lymphocytic leukemia. However, the relative clinical importance of these abnormalities in patients with a deletion of 11q encompassing the ATM gene has not been established. We screened a cohort of 166 patients enriched for 11q-deletions for ATM mutations and BIRC3 deletion and mutation and determined the overall and progression-free survival among the 133 of these cases treated within the UK LRF CLL4 trial. SNP6.0 profiling demonstrated that BIRC3 deletion occurred in 83% of 11q-deleted cases and always co-existed with ATM deletion. For the first time we have demonstrated that 40% of BIRC3-deleted cases have concomitant deletion and mutation of ATM. While BIRC3 mutations were rare, they exclusively occurred with BIRC3 deletion and a wild-type residual ATM allele. In 11q-deleted cases, we confirmed that ATM mutation was associated with a reduced overall and progression-free survival comparable to that seen with TP53 abnormalities, whereas BIRC3 deletion and/or mutation had no impact on overall and progression-free survival. In conclusion, in 11q-deleted patients treated with first-line chemotherapy, ATM mutation rather than BIRC3 deletion and/or mutation identifies a subgroup with a poorer outcome.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Cromosomas Humanos Par 11 , Proteínas Inhibidoras de la Apoptosis/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Mutación , Eliminación de Secuencia , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína 3 que Contiene Repeticiones IAP de Baculovirus , Aberraciones Cromosómicas , Femenino , Eliminación de Gen , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Evaluación del Resultado de la Atención al Paciente , Polimorfismo de Nucleótido Simple , Pronóstico , Ubiquitina-Proteína Ligasas
8.
J Clin Oncol ; 32(12): 1236-41, 2014 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-24638012

RESUMEN

PURPOSE: Most patients with chronic lymphocytic leukemia (CLL) are elderly and/or have comorbidities that may make them ineligible for fludarabine-based treatment. For this population, chlorambucil monotherapy is an appropriate therapeutic option; however, response rates with chlorambucil are low, and more effective treatments are needed. This trial was designed to assess how the addition of rituximab to chlorambucil (R-chlorambucil) would affect safety and efficacy in patients with CLL. PATIENTS AND METHODS: Patients with first-line CLL were treated with rituximab (375 mg/m(2) on day 1, cycle one, and 500 mg/m(2) thereafter) plus chlorambucil (10 mg/m(2)/d all cycles; day 1 through 7) for six 28-day cycles. For patients not achieving complete response (CR), six additional cycles of chlorambucil alone could be administered. The primary end point of the study was safety. RESULTS: A total of 100 patients were treated with R-chlorambucil, with a median follow-up of 30 months. Median age of patients was 70 years (range, 43 to 86 years), with patients having a median of seven comorbidities. Hematologic toxicities accounted for most grade 3/4 adverse events reported, with neutropenia and lymphopenia both occurring in 41% of patients and leukopenia in 23%. Overall response rates were 84%, with CR achieved in 10% of patients. Median progression-free survival was 23.5 months; median overall survival was not reached. CONCLUSION: These results compare favorably with previously published results for chlorambucil monotherapy, suggesting that the addition of rituximab to chlorambucil may improve efficacy with no unexpected adverse events. R-chlorambucil may improve outcome for patients who are ineligible for fludarabine-based treatments.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorambucilo/administración & dosificación , Clorambucilo/efectos adversos , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rituximab , Resultado del Tratamiento
9.
PLoS One ; 8(12): e83244, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-24349473

RESUMEN

The pathogenesis of splenic marginal zone lymphoma (SMZL) remains largely unknown. Recent high-throughput sequencing studies have identified recurrent mutations in key pathways, most notably NOTCH2 mutations in >25% of patients. These studies are based on small, heterogeneous discovery cohorts, and therefore only captured a fraction of the lesions present in the SMZL genome. To identify further novel pathogenic mutations within related biochemical pathways, we applied whole exome sequencing (WES) and copy number (CN) analysis to a biologically and clinically homogeneous cohort of seven SMZL patients with 7q abnormalities and IGHV1-2*04 gene usage. We identified 173 somatic non-silent variants, affecting 160 distinct genes. In additional to providing independent validation of the presence of mutation in several previously reported genes (NOTCH2, TNFAIP3, MAP3K14, MLL2 and SPEN), our study defined eight additional recurrently mutated genes in SMZL; these genes are CREBBP, CBFA2T3, AMOTL1, FAT4, FBXO11, PLA2G4D, TRRAP and USH2A. By integrating our WES and CN data we identified three mutated putative candidate genes targeted by 7q deletions (CUL1, EZH2 and FLNC), with FLNC positioned within the well-characterized 7q minimally deleted region. Taken together, this work expands the reported directory of recurrently mutated cancer genes in this disease, thereby expanding our understanding of SMZL pathogenesis. Ultimately, this work will help to establish a stratified approach to care including the possibility of targeted therapy.


Asunto(s)
Cromosomas Humanos Par 7/genética , Exoma/genética , Linfoma de Células B de la Zona Marginal/genética , Mutación , Proteínas de Neoplasias/genética , Neoplasias del Bazo/genética , Cromosomas Humanos Par 7/metabolismo , Análisis Mutacional de ADN , Femenino , Humanos , Linfoma de Células B de la Zona Marginal/metabolismo , Linfoma de Células B de la Zona Marginal/patología , Linfoma de Células B de la Zona Marginal/terapia , Masculino , Proteínas de Neoplasias/metabolismo , Neoplasias del Bazo/metabolismo , Neoplasias del Bazo/patología , Neoplasias del Bazo/terapia
10.
Blood ; 122(26): 4253-8, 2013 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-24128861

RESUMEN

Fludarabine plus cyclophosphamide (FC) is the chemotherapy backbone of modern chronic lymphocytic leukemia (CLL) treatment. CYP2B6 is a polymorphic cytochrome P450 isoform that converts cyclophosphamide to its active form. This study investigated the possible impact of genetic variation in CYP2B6 on response to FC chemotherapy in CLL. Available DNA samples from the LRF CLL4 trial, which compared chlorambucil, fludarabine, and FC, were screened by TaqMan real-time polymerase chain reaction assays for CYP2B6 SNPs c.516G>T and c.785A>G, which define the most common variant allele (*6). Among the 455 samples successfully genotyped, 265 (58.2%), 134 (29.5%), and 29 (6.4%) were classified as *1/*1, *1/*6, and *6/*6, respectively. Patients expressing at least one *6 allele were significantly less likely to achieve a complete response (CR) after FC (odds ratio 0.27; P = .004) but not chlorambucil or fludarabine. Analysis of individual response indicators confirmed that this inferior response resulted from impaired cytoreduction rather than delayed hemopoietic recovery. Multivariate analysis controlling for age, gender, stage, IGHV mutational status, 11q deletion, and TP53 deletion/mutation identified CYP2B6*6 and TP53 mutation/deletion as the only independent determinants of CR attainment after FC. Our study provides the first demonstration that host pharmacogenetics can influence therapeutic response in CLL. This trial is registered as an International Standard Randomised Control Trial, number NCT 58585610 at www.clinicaltrials.gov.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Ciclofosfamida/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Vidarabina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/efectos adversos , Citocromo P-450 CYP2B6 , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Farmacogenética , Pronóstico , Inducción de Remisión , Vidarabina/administración & dosificación , Vidarabina/efectos adversos
11.
Blood ; 121(3): 468-75, 2013 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-23086750

RESUMEN

NOTCH1 and SF3B1 mutations have been previously reported to have prognostic significance in chronic lymphocytic leukemia but to date they have not been validated in a prospective, controlled clinical trial. We have assessed the impact of these mutations in a cohort of 494 patients treated within the randomized phase 3 United Kingdom Leukaemia Research Fund Chronic Lymphocytic Leukemia 4 (UK LRF CCL4) trial that compared chlorambucil and fludarabine with and without cyclophosphamide in previously untreated patients. We investigated the relationship of mutations in NOTCH1 (exon 34) and SF3B1 (exon 14-16) to treatment response, survival and a panel of established biologic variables. NOTCH1 and SF3B1 mutations were found in 10% and17% of patients, respectively. NOTCH1 mutations correlated with unmutated IGHV genes, trisomy 12, high CD38/ ZAP-70 expression and were associated with reduced overall (median 54.8 vs 74.6 months, P = .02) and progression-free (median 22.0 vs 26.4 months, P = .02) survival. SF3B1 mutations were significantly associated with high CD38 expression and with shorter overall survival (median 54.3 vs 79.0 months, P < .001). Furthermore, multivariate analysis, including baseline clinical variables, treatment, and adverse prognostic factors demonstrated that although TP53 alterations remained the most informative marker of dismal survival in this cohort, NOTCH1 (HR 1.58, P = .03) and SF3B1 (HR 1.52, P = .01) mutations have added independent prognostic value.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Fosfoproteínas/genética , Receptor Notch1/genética , Ribonucleoproteína Nuclear Pequeña U2/genética , ADP-Ribosil Ciclasa 1/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Alquilantes/uso terapéutico , Biomarcadores de Tumor/genética , Clorambucilo/uso terapéutico , Cromosomas Humanos Par 12/genética , Ciclofosfamida/uso terapéutico , Educación Médica Continua , Femenino , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Incidencia , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Glicoproteínas de Membrana/genética , Persona de Mediana Edad , Pronóstico , Factores de Empalme de ARN , Factores de Riesgo , Trisomía/genética , Proteína p53 Supresora de Tumor/genética , Vidarabina/análogos & derivados , Vidarabina/uso terapéutico
12.
Clin Cancer Res ; 18(15): 4191-200, 2012 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-22675167

RESUMEN

PURPOSE: This study sought to establish whether functional analysis of the ATM-p53-p21 pathway adds to the information provided by currently available prognostic factors in patients with chronic lymphocytic leukemia (CLL) requiring frontline chemotherapy. EXPERIMENTAL DESIGN: Cryopreserved blood mononuclear cells from 278 patients entering the LRF CLL4 trial comparing chlorambucil, fludarabine, and fludarabine plus cyclophosphamide were analyzed for ATM-p53-p21 pathway defects using an ex vivo functional assay that uses ionizing radiation to activate ATM and flow cytometry to measure upregulation of p53 and p21 proteins. Clinical endpoints were compared between groups of patients defined by their pathway status. RESULTS: ATM-p53-p21 pathway defects of four different types (A, B, C, and D) were identified in 194 of 278 (70%) samples. The type A defect (high constitutive p53 expression combined with impaired p21 upregulation) and the type C defect (impaired p21 upregulation despite an intact p53 response) were each associated with short progression-free survival. The type A defect was associated with chemoresistance, whereas the type C defect was associated with early relapse. As expected, the type A defect was strongly associated with TP53 deletion/mutation. In contrast, the type C defect was not associated with any of the other prognostic factors examined, including TP53/ATM deletion, TP53 mutation, and IGHV mutational status. Detection of the type C defect added to the prognostic information provided by TP53/ATM deletion, TP53 mutation, and IGHV status. CONCLUSION: Our findings implicate blockade of the ATM-p53-p21 pathway at the level of p21 as a hitherto unrecognized determinant of early disease recurrence following successful cytoreduction.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal/fisiología , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular/genética , Clorambucilo/administración & dosificación , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Ciclofosfamida/administración & dosificación , Proteínas de Unión al ADN/genética , Femenino , Citometría de Flujo , Humanos , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Proteínas Serina-Treonina Quinasas/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genética , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados
13.
Haematologica ; 97(1): 142-6, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21933854

RESUMEN

Ataxia telangiectasia patients, with constitutional bi-allelic ATM mutations, have a marked risk of lymphoid tumors and ATM mutation carriers have a smaller risk of cancer. Sporadic ATM mutations occur in 10-20% of chronic lymphocytic leukemia and are often associated with chromosome 11q deletions which cause loss of an ATM allele. The role of constitutional ATM mutations in the pathogenesis of chronic lymphocytic leukemia is unknown. Here we investigated the frequency of constitutional ATM mutations in either of two chronic lymphocytic leukemia cohorts, those with and without a chromosome 11q deletion. We found that in comparison to controls, constitutional pathogenic ATM mutations were increased in patients with chromosome 11q deletions (6 of 140 vs. 0 of 281, P = 0.001) but not in those without 11q deletions (2 of 178 vs. 0 of 281, P = 0.15). These results suggest that ATM germline heterozygosity does not play a role in chronic lymphocytic leukemia initiation but rather influences rapid disease progression through ATM loss.


Asunto(s)
Alelos , Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Progresión de la Enfermedad , Mutación de Línea Germinal , Heterocigoto , Leucemia Linfocítica Crónica de Células B/genética , Pérdida de Heterocigocidad , Proteínas Serina-Treonina Quinasas/genética , Proteínas Supresoras de Tumor/genética , Anciano , Proteínas de la Ataxia Telangiectasia Mutada , Deleción Cromosómica , Cromosomas Humanos Par 11 , Humanos , Persona de Mediana Edad , Modelos Biológicos
14.
Blood ; 118(9): 2530-40, 2011 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-21768293

RESUMEN

The anti-CD20 mAb rituximab is central to the treatment of B-cell malignancies, but resistance remains a significant problem. We recently reported that resistance could be explained, in part, by internalization of rituximab (type I anti-CD20) from the surface of certain B-cell malignancies, thus limiting engagement of natural effectors and increasing mAb consumption. Internalization of rituximab was most evident in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but the extent of internalization was heterogeneous within each disease. Here, we show that the inhibitory FcγRIIb on target B cells promotes this process and is largely responsible for the observed heterogeneity across a range of B-cell malignancies. Internalization correlated strongly with FcγRIIb expression on normal and malignant B cells, and resulted in reduced macrophage phagocytosis of mAb-coated targets. Furthermore, transfection of FcγRIIb into FcγRIIb negative Ramos cells increased internalization of rituximab in a dose-dependent manner. Target-cell FcγRIIb promoted rituximab internalization in a cis fashion and was independent of FcγRIIb on neighboring cells. It became phosphorylated and internalized along with CD20:anti-CD20 complexes before lysosomal degradation. In MCL patients, high FcγRIIb expression predicted less durable responses after rituximab-containing regimens. Therefore, target-cell FcγRIIb provides a potential biomarker of response to type I anti-CD20 mAb.


Asunto(s)
Anticuerpos Monoclonales de Origen Murino/metabolismo , Anticuerpos Antineoplásicos/metabolismo , Complejo Antígeno-Anticuerpo/metabolismo , Antígenos CD20/metabolismo , Antígenos de Neoplasias/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos B/inmunología , Resistencia a Antineoplásicos/fisiología , Endocitosis/fisiología , Linfoma de Células del Manto/tratamiento farmacológico , Receptores de IgG/metabolismo , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/inmunología , Anticuerpos Antineoplásicos/administración & dosificación , Anticuerpos Antineoplásicos/inmunología , Antígenos CD20/inmunología , Antígenos de Neoplasias/inmunología , Linfocitos B/metabolismo , Biomarcadores , Línea Celular Tumoral/inmunología , Línea Celular Tumoral/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Linfoma de Células B/inmunología , Linfoma de Células B/patología , Linfoma de Células del Manto/patología , Lisosomas/metabolismo , Macrófagos/fisiología , Fagocitosis , Fosforilación , Procesamiento Proteico-Postraduccional , Receptores de IgG/genética , Proteínas Recombinantes de Fusión/metabolismo , Rituximab , Transfección , Resultado del Tratamiento
15.
Haematologica ; 96(10): 1496-503, 2011 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-21659360

RESUMEN

BACKGROUND: There is variability in the outcome of patients with chronic lymphocytic leukemia with apparently the same stage of disease. Identifying genetic variants that influence patients' outcome and response to treatment may provide important insights into the biology of the disease. DESIGN AND METHODS: We investigated the possibility that genetic variation influences outcome by conducting a genome-wide analysis of 346,831 single nucleotide polymorphisms in 356 patients entered into a phase III trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Genotypes were linked to individual patients' outcome data and response to chemotherapy. The association between genotype and progression-free survival was assessed by Cox regression analysis adjusting for treatment and clinicopathology. RESULTS: The strongest associations were shown for rs1949733 (ACOX3; P=8.22x10-7), rs1342899 (P=7.72×10(-7)) and rs11158493 (PPP2R5E; P=8.50×10(-7)). In addition, the 52 single nucleotide polymorphisms associated at P<10(-4) included rs438034 (CENPF; P=4.86×10(-6)), previously correlated with cancer progression, and rs2255235 (B2M; P=3.10×10(-5)) and rs2064501 (IL22RA2; P=4.81×10(-5)) which map to B-cell genes. CONCLUSIONS: Our findings provide evidence that genetic variation is a determinant of progression-free survival of patients with chronic lymphocytic leukemia. Specific associations warrant further analyses.


Asunto(s)
Genotipo , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Polimorfismo de Nucleótido Simple , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Regulación Leucémica de la Expresión Génica , Técnicas de Genotipaje , Humanos , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Proteína Fosfatasa 2/genética , Control de Calidad , ARN Mensajero , Reproducibilidad de los Resultados
16.
Leuk Res ; 35(6): 750-6, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21093051

RESUMEN

The world of chronic lymphocytic leukemia (CLL) research is awash with prognostic markers. However, very few of the current group play a clearly defined role in the pathology of this disease and even fewer represent a tractable therapeutic target. One such marker that fulfils both of these criteria is the integrin CD49d. This molecule been implicated in the capacity of CLL cells to migrate into lymphoid tissues and there is a CD49d blocking antibody, Natalizumab, currently in clinical trials. Here we carried out the largest multi-centre evaluation of CD49d as a prognostic marker in 652 primary CLL samples. We confirm that CD49d is predictive for time to first treatment (P<0.0001) and overall survival (P<0.0001) and increases the prognostic power of CD38, ZAP-70 and IGHV gene mutation status in concordant cases. Furthermore, CD49d retained independent prognostic significance in multivariate analysis. In contrast to previous studies, we showed no correlation between CD49d expression and in vitro resistance to fludarabine in liquid cultures (P=0.28) but CD49d(hi) cells were significantly more resistant than CD49d(lo) cells when assays were carried out on fibronectin-coated plates (P=0.03). Furthermore, we showed for the first time that the expression of CD49d is strongly associated with expression of the chemokine receptor CXCR4 suggesting a co-ordinated role for these molecules in the trafficking of CLL cells to the lymphoid tissues. Taken together, our data support the introduction of CD49d into routine immunophenotyping panels for CLL and indicate that the therapeutic targeting of this molecule may prove useful in this disease.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Integrina alfa4/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Receptores CXCR4/metabolismo , ADP-Ribosil Ciclasa 1/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Citometría de Flujo , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Persona de Mediana Edad , Análisis Multivariante , Mutación , Pronóstico , Análisis de Supervivencia , Células Tumorales Cultivadas , Vidarabina/análogos & derivados , Vidarabina/farmacología , Proteína Tirosina Quinasa ZAP-70/metabolismo
17.
Epigenetics ; 6(3): 300-6, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21051931

RESUMEN

Chronic lymphocytic leukemia (CLL) exhibits a very variable clinical course. Altered DNA methylation of genes has shown promise as a source of novel prognostic makers in a number of cancers. Here we have studied the potential utility of a panel of methylation markers (CD38, HOXA4 and BTG4) in 118 CLL patients. Each of the three loci assessed exhibited frequent methylation, as determined by COBRA analysis, and individually correlated with either good (CD38, BTG4 methylation) or poor (HOXA4 methylation) prognosis. Using a combined approach to produce an overall methylation score, we found that methylation score was significantly associated with time to first treatment in CLL patients. Multivariate Cox regression analysis revealed that methylation score was the strongest predictor of time to first treatment, and was independent of IGHV gene mutational status and CD38 expression. This study provides proof of principle that a panel of methylation markers can be used for additional risk stratification of CLL patients.


Asunto(s)
Biomarcadores de Tumor/genética , Metilación de ADN , Leucemia Linfocítica Crónica de Células B/diagnóstico , ADP-Ribosil Ciclasa 1/genética , ADP-Ribosil Ciclasa 1/metabolismo , Biomarcadores de Tumor/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Estudios de Cohortes , Femenino , Genes de las Cadenas Pesadas de las Inmunoglobulinas , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Mutación , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores de Transcripción
18.
Blood ; 116(22): 4578-87, 2010 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-20739657

RESUMEN

The Ataxia Telangiectasia Mutated (ATM) gene is frequently inactivated in lymphoid malignancies such as chronic lymphocytic leukemia (CLL), T-prolymphocytic leukemia (T-PLL), and mantle cell lymphoma (MCL) and is associated with defective apoptosis in response to alkylating agents and purine analogues. ATM mutant cells exhibit impaired DNA double strand break repair. Poly (ADP-ribose) polymerase (PARP) inhibition that imposes the requirement for DNA double strand break repair should selectively sensitize ATM-deficient tumor cells to killing. We investigated in vitro sensitivity to the poly (ADP-ribose) polymerase inhibitor olaparib (AZD2281) of 5 ATM mutant lymphoblastoid cell lines (LCL), an ATM mutant MCL cell line, an ATM knockdown PGA CLL cell line, and 9 ATM-deficient primary CLLs induced to cycle and observed differential killing compared with ATM wildtype counterparts. Pharmacologic inhibition of ATM and ATM knockdown confirmed the effect was ATM-dependent and mediated through mitotic catastrophe independently of apoptosis. A nonobese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft model of an ATM mutant MCL cell line demonstrated significantly reduced tumor load and an increased survival of animals after olaparib treatment in vivo. Addition of olaparib sensitized ATM null tumor cells to DNA-damaging agents. We suggest that olaparib would be an appropriate agent for treating refractory ATM mutant lymphoid tumors.


Asunto(s)
Antineoplásicos/uso terapéutico , Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Linfoma de Células del Manto/tratamiento farmacológico , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Proteínas Serina-Treonina Quinasas/genética , Proteínas Supresoras de Tumor/genética , Animales , Antineoplásicos/farmacología , Proteínas de la Ataxia Telangiectasia Mutada , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Daño del ADN/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Linfoma de Células del Manto/genética , Ratones , Ratones SCID , Mutación , Ftalazinas/farmacología , Piperazinas/farmacología
19.
Mol Med ; 14(11-12): 665-74, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-19009014

RESUMEN

Chronic lymphocytic leukemia (CLL) represents the outgrowth of a CD5(+) B cell. Its etiology is unknown. The structure of membrane Ig on CLL cells of unrelated patients can be remarkably similar. Therefore, antigen binding and stimulation could contribute to clonal selection and expansion as well as disease promotion. Initial studies suggest that CLL mAbs bind autoantigens. Since apoptosis can make autoantigens accessible for recognition by antibodies, and also create neo-epitopes by chemical modifications occurring naturally during this process, we sought to determine if CLL mAbs recognize autoantigens associated with apoptosis. In general, ~60% of CLL mAbs bound the surfaces of apoptotic cells, were polyreactive, and expressed unmutated IGHV. mAbs recognized two types of antigens: native molecules located within healthy cells, which relocated to the external cell surface during apoptosis; and/or neoantigens, generated by oxidation during the apoptotic process. Some of the latter epitopes are similar to those on bacteria and other microbes. Although most of the reactive mAbs were not mutated, the use of unmutated IGHV did not bestow autoreactivity automatically, since several such mAbs were not reactive. Particular IGHV and IGHV/D/J rearrangements contributed to autoantigen binding, although the presence and degree of reactivity varied based on specific structural elements. Thus, clonal expansion in CLL may be stimulated by autoantigens occurring naturally during apoptosis. These data suggest that CLL may derive from normal B cells whose function is to remove cellular debris, and also to provide a first line of defense against pathogens.


Asunto(s)
Apoptosis/inmunología , Epítopos/inmunología , Leucemia Linfocítica Crónica de Células B/inmunología , Secuencia de Aminoácidos , Anticuerpos Monoclonales/inmunología , Autoantígenos/inmunología , Autoinmunidad/inmunología , Línea Celular Tumoral , Humanos , Técnicas para Inmunoenzimas , Leucemia Linfocítica Crónica de Células B/patología , Linfocitos/inmunología , Microscopía Confocal , Datos de Secuencia Molecular , Oxidación-Reducción
20.
Blood ; 111(3): 1625-33, 2008 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-18006695

RESUMEN

To identify genetic variants associated with outcome from chronic lymphocytic leukemia (CLL), we genotyped 977 nonsynonymous single nucleotide polymorphisms (nsSNPs) in 755 genes with relevance to cancer biology in 425 patients participating in a phase 3 trial comparing the efficacy of fludarabine, chlorambucil, and fludarabine with cyclophosphamide as first-line treatment. Selection of nsSNPs was biased toward those likely to be functionally deleterious. SNP genotypes were linked to individual patient outcome data and response to chemotherapy. The effect of genotype on progression-free survival (PFS) and overall survival (OS) was assessed by Cox regression analysis adjusting for treatment and clinico-pathologic variables. A total of 78 SNPs (51 dominantly acting and a further 27 recessively acting) were associated with PFS (9 also affecting OS) at the 5% level. These included SNPs mapping to the immune-regulation genes IL16 P434S (P = .03), IL19 S213F (P = .001), LILRA4 P27L (P = .004), KLRC4 S29I (P = .007), and CD5 V471A (P = .002); and DNA response genes POLB P242R (P = .04) and TOPBP1 S730L (P = .02), which were all independently prognostic of immunoglobulin heavy-chain variable region (IgV(H)) mutational status. The variants identified warrant further evaluation as promising prognostic markers of patient outcome. To facilitate the identification of prognostic markers through pooled analyses, we have made all data from our analysis publicly available.


Asunto(s)
Ensayos Clínicos Fase III como Asunto , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Daño del ADN/genética , Femenino , Genotipo , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/inmunología , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/inmunología , Masculino , Persona de Mediana Edad , Mutación/genética , Pronóstico , Tasa de Supervivencia
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