RESUMEN
Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability. By analysing tumour DNA from patients with sporadic T-cell prolymphocytic leukaemia (T-PLL), a rare clonal malignancy with similarities to a mature T-cell leukaemia seen in A-T, we demonstrate a high frequency of ATM mutations in T-PLL. In marked contrast to the ATM mutation pattern in A-T, the most frequent nucleotide changes in this leukaemia were missense mutations. These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast and Drosophila. The resulting amino-acid substitutions are predicted to interfere with ATP binding or substrate recognition. Two of seventeen mutated T-PLL samples had a previously reported A-T allele. In contrast, no mutations were detected in the p53 gene, suggesting that this tumour suppressor is not frequently altered in this leukaemia. Occasional missense mutations in ATM were also found in tumour DNA from patients with B-cell non-Hodgkin's lymphomas (B-NHL) and a B-NHL cell line. The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor. As constitutional DNA was not available, a putative hereditary predisposition to T-PLL will require further investigation.
Asunto(s)
Ataxia Telangiectasia/genética , Leucemia de Células T/genética , Mutación , Proteínas Serina-Treonina Quinasas , Proteínas/genética , Secuencia de Aminoácidos , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Secuencia de Bases , Proteínas de Ciclo Celular , Cartilla de ADN , Proteínas de Unión al ADN , Mutación del Sistema de Lectura , Genes p53 , Granulocitos , Humanos , Leucina Zippers , Leucemia de Células T/epidemiología , Ratones , Datos de Secuencia Molecular , Mutación Puntual , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Biosíntesis de Proteínas , Proteínas/química , Factores de Riesgo , Alineación de Secuencia , Eliminación de Secuencia , Homología de Secuencia de Aminoácido , Proteínas Supresoras de TumorRESUMEN
BACKGROUND: Prolyl hydroxylation is a post-translational modification that affects the structure, stability and function of proteins including collagen by catalysing hydroxylation of proline to hydroxyproline through action of collagen prolyl hydroxylases3 (C-P3H) and 4 (C-P4H). Three C-P3Hs (nomenclature was amended according to approval by the HGNC symbols and names at http://www.genenames.org/ and Entrez database at http://www.ncbi.nlm.nih.gov/gene) leucineproline-enriched proteoglycan (leprecan) 1 (Lepre1), leprecan-like 1 (Leprel1), leprecan-like 2 (Leprel2) and two paralogs Cartilage-Related Protein (CRTAP) and leprecan-like 4 (Leprel4) are found in humans. The C-P4Hs are tetrameric proteins comprising a variable α subunit, encoded by the P4HA1, P4HA2 and P4HA3 genes and a constant ß subunit encoded by P4HB. METHODS: We used RT-PCR, qPCR, pyrosequencing, methylation-specific PCR, western blotting and immunohistochemistry to investigate expression and regulation of the C-P3H and C-P4H genes in B lymphomas and normal bone marrow. RESULTS: C-P3H and C-P4H are downregulated in lymphoma. Down-regulation is associated with methylation in the CpG islands and is detected in almost all common types of B-cell lymphoma, but the CpG islands are unmethylated or methylated at lower levels in DNA isolated from normal bone marrow and lymphoblastoid cell lines. Methylation of multiple C-P3H and C-P4H genes is present in some lymphomas, particularly Burkitt's lymphoma. CONCLUSIONS: Methylation of C-P3H and C-P4H is common in B lymphomas and may have utility in differentiating disease subtypes.
Asunto(s)
Colágeno/genética , Linfoma de Células B/genética , Procolágeno-Prolina Dioxigenasa/genética , Línea Celular Tumoral , Colágeno/metabolismo , Islas de CpG/genética , Regulación de la Expresión Génica , Silenciador del Gen , Humanos , Linfoma de Células B/metabolismo , Metilación , Procolágeno-Prolina Dioxigenasa/metabolismoRESUMEN
The existence of stem cells committed to the T lymphoid lineage was deduced from studying how rat T and B stem cells differ in their expression of membrane W3/13 antigen and in their susceptibility in vivo to gamma irradiation. Stem cell activity of rat bone marrow and fetal liver was measured in long-term radiation chimeras using B and T cell alloantigenic surface markers to identify the progeny of donor cells. Monoclonal mouse anti-rat thymocyte antibody W3/13 labeled approximately 40% of fetal liver cells and 60-70% of young rat bone marrow cells (40% brightly, 25% dimly). Bright, dim, and negative cells were separated on a fluorescence-activated cell sorter. All B and T lymphoid stem cells in fetal liver were W3/13 bright, as were B lymphoid stem cells in bone marrow. W3/13 dim bone marrow had over half the T cell repopulating activity of unseparated marrow but gave virtually no B cell repopulation. In further experiments, the radiosensitivity of endogenous B and T lymphoid stem cells was determined by exposing host rats to between 4.5 and 10 Gy of gamma irradiation before repopulation with genetically marked marrow. The results depended on whether chimerism was assayed before day 50 or after day 100. At early times, a radioresistant T stem cell was indicated, whose activity waned later. Thus committed T stem cells of rats carry moderate amounts of W3/13 antigen and are more radioresistant but less permanently chimeragenic than the stem cells that regenerate B lymphocytes.
Asunto(s)
Antígenos de Superficie , Linfocitos B/efectos de la radiación , Células de la Médula Ósea , Linfocitos T/citología , Animales , Médula Ósea/metabolismo , Médula Ósea/efectos de la radiación , Diferenciación Celular , Separación Celular , Femenino , Feto/citología , Citometría de Flujo , Hígado/inmunología , Masculino , Embarazo , Quimera por Radiación , Ratas , Ratas Endogámicas , Linfocitos T/efectos de la radiaciónRESUMEN
BACKGROUND: To evaluate the activity and safety of nonpegylated liposomal doxorubicin (Myocet) when substituted for doxorubicin in the R-CHOP regimen (R-COMP). PATIENTS AND METHODS: Seventy-five elderly patients with diffuse large B-cell lymphoma (DLBCL) were studied. Only patients with left ventricular ejection fraction (LVEF) > or =50% were allowed. R-COMP regimen was administered every 3 weeks for three cycles, followed by additional five cycles in case of complete response (CR) or partial response. RESULTS: From November 2002 to April 2005, 75 patients were registered, of which 72 were evaluated. Median age was 72 years (range 61-83); 56% of patients had high or high-intermediate International Prognostic Index score. Median LVEF at baseline was 61%. Thirty-eight patients had history of abnormal cardiovascular conditions. The overall response rate was 71%, with a CR rate of 57%. After a median follow-up of 33 months, the 3-year overall survival, failure-free survival, and progression-free survival rates were 72%, 39%, and 69%, respectively. Neutropenia (54%) was the most frequent grade 3-4 adverse event (AE); 21% of patients experienced cardiac AEs, graded as 3-4 in 4% of the cases. CONCLUSION: R-COMP is an effective regimen for the treatment of DLBCL in elderly patients, with an acceptable tolerability profile.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Estudios Prospectivos , Rituximab , Tasa de Supervivencia , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
Thalidomide and lenalidomide are immunomodulatory drugs that show promise in mantle cell lymphoma (MCL). In this study, their potential mechanisms of action against MCL cells were investigated, both alone and in combination with rituximab. Thalidomide, lenalidomide and rituximab have no direct effect on MCL cell viability. However, both immunomodulatory drugs indirectly affect viability by enhancing peripheral blood mononuclear cell-mediated cytotoxicity, with lenalidomide inducing significantly higher levels of toxicity than thalidomide. Rituximab induces both complement-dependent and antibody-dependent cellular cytotoxicity (ADCC) against MCL cells. Rituximab-induced ADCC is enhanced by lenalidomide and, to a lesser extent, thalidomide. Preliminary in vivo findings in MCL patients treated with thalidomide support a role for natural killer cells in the efficacy of these drugs. In conclusion, our data support a role for immunomodulatory drugs in the treatment of MCL.
Asunto(s)
Factores Inmunológicos/farmacología , Linfoma de Células del Manto/tratamiento farmacológico , Talidomida/análogos & derivados , Talidomida/farmacología , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Proteínas del Sistema Complemento/metabolismo , Citotoxicidad Inmunológica/efectos de los fármacos , Sinergismo Farmacológico , Humanos , Factores Inmunológicos/administración & dosificación , Técnicas In Vitro , Lenalidomida , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Linfoma de Células del Manto/inmunología , Linfoma de Células del Manto/patología , Linfoma de Células del Manto/terapia , Rituximab , Talidomida/administración & dosificaciónRESUMEN
Primary chronic lymphocytic leukemia (CLL) cells are exquisitely sensitive to ABT-737, a small molecule BCL2-antagonist, which induces many of the classical biochemical and ultrastructural features of apoptosis, including BAX/BAK oligomerization, cytochrome c release, caspase activation and chromatin condensation. Surprisingly, ABT-737 also induces mitochondrial inner membrane permeabilization (MIMP) resulting in mitochondrial matrix swelling and rupture of the outer mitochondrial membrane (OMM), so permitting the rapid efflux of cytochrome c from mitochondrial cristae and facilitating rapid caspase activation and apoptosis. BAX and BAK appear to be involved in the OMM discontinuities as they localize to the OMM break points. Notably, ABT-737 induced mitochondrial matrix swelling and OMM discontinuities in other primary B-cell malignancies, including mantle cell, follicular and marginal zone lymphoma cells but not in several cell lines studied. Thus, we describe a new paradigm of apoptosis in primary B-cell malignancies, whereby targeting of BCL2 results in all the classical features of apoptosis together with OMM rupture independent of caspase activation. This mechanism may be far more prevalent than hitherto recognized due to the failure of most methods, used to measure apoptosis, to recognize such a mechanism.
Asunto(s)
Apoptosis/efectos de los fármacos , Compuestos de Bifenilo/farmacología , Leucemia Linfocítica Crónica de Células B/metabolismo , Membranas Mitocondriales/efectos de los fármacos , Nitrofenoles/farmacología , Sulfonamidas/farmacología , Adulto , Clorometilcetonas de Aminoácidos/metabolismo , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Linfocitos B/patología , Línea Celular Tumoral , Inhibidores de Cisteína Proteinasa/metabolismo , Relación Dosis-Respuesta a Droga , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Membranas Mitocondriales/ultraestructura , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Proteína X Asociada a bcl-2/metabolismoRESUMEN
BACKGROUND: The purpose of this study was to determine whether there was a relationship between disease activity and health functioning, as measured by a range of patient-reported outcome (PRO) measures in patients with follicular lymphoma (FL). PATIENTS AND METHODS: A total of 222 patients with FL were recruited from eight sites across the UK and they completed a number of PRO measures. The participants were analyzed across five disease states: 'active disease-newly diagnosed', 'active disease-relapsed', 'partial response', 'complete response' and 'disease free'. The relationship between these disease states and their level of health functioning was assessed as well as the relationship between being 'on' or 'off' chemotherapy and disease state. RESULTS: In terms of health-related quality of life (HRQoL), participants in the relapsed category had the lowest mean physical well-being, emotional well-being, functional well-being and social well-being score. In a regression analysis, the 'active disease-relapsed' group acted as a significant predictor for each PRO variable. In addition, the remission group acted as a significant predictor of high anxiety scores as measured by the Hospital Anxiety and Depression Scale. CONCLUSION: The results of this study demonstrate that various aspects of patient-reported health outcomes differ according to disease state in patients with FL. For those patients who have relapsed, they are more likely to experience worse HRQoL and other patient-reported health outcomes than patients newly diagnosed, in partial or complete remission or when completely disease free.
Asunto(s)
Ansiedad/epidemiología , Depresión/epidemiología , Linfoma Folicular/clasificación , Linfoma Folicular/epidemiología , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Comorbilidad , Empleo/estadística & datos numéricos , Femenino , Humanos , Linfoma Folicular/terapia , Masculino , Persona de Mediana Edad , Análisis de Regresión , Resultado del Tratamiento , Reino Unido/epidemiologíaRESUMEN
Several histone deacetylase inhibitors (HDACi), which have recently entered early clinical trials, exert their anticancer activity in part through the induction of apoptosis although the precise mechanism of this induction is not known. Induction of apoptosis by structurally diverse HDACi in primary cells from patients with chronic lymphocytic leukemia (CLL) and different leukemic cell lines was mediated by the Bcl-2 regulated intrinsic pathway and demonstrated a requirement for de novo protein synthesis. A marked time-dependent induction of the pro-apoptotic BH3-only proteins, Bim, Noxa and Bmf was observed, which preceded the induction of apoptosis. A key role for both Bim and Noxa was proposed in HDACi-mediated apoptosis based on our findings that siRNA for Bim and Noxa but not Bmf largely prevented the HDACi-induced loss in mitochondrial membrane potential, caspase processing and phosphatidylserine externalization. Noxa, induced by HDACi, in CLL cells and tumor cell lines, bound extensively to Mcl-1, a major anti-apoptotic Bcl-2 family member present in CLL cells. Our data strongly suggests that HDACi induce apoptosis primarily through inactivation of anti-apoptotic Bcl-2 family members by increases in Bim and Noxa and highlights these increases as a potential clinical target for CLL/lymphoma therapy.
Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Apoptosis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Proteínas de la Membrana/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Reguladoras de la Apoptosis/antagonistas & inhibidores , Proteínas Reguladoras de la Apoptosis/genética , Proteína 11 Similar a Bcl2 , Western Blotting , Línea Celular , Núcleo Celular/metabolismo , Humanos , Inmunoprecipitación , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-bcl-2/genética , Interferencia de ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Activación Transcripcional , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/metabolismo , Proteína Destructora del Antagonista Homólogo bcl-2/antagonistas & inhibidores , Proteína Destructora del Antagonista Homólogo bcl-2/genética , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismoRESUMEN
The biologic and pathologic features of B-cell malignancies bearing a translocation t(14;19)(q32;q13) leading to a fusion of IGH and BCL3 are still poorly described. Herein we report the results of a comprehensive cytogenetic, fluorescence in situ hybridization (FISH), molecular and histopathological survey of a large series of B-cell malignancies with t(14;19) or variant translocations. A total of 56 B-cell malignancies with a FISH-proven BCL3 involvement were identified with the translocation partners being IGH (n=51), IGL (n=2), IGK (n=2) and a non-IG locus (n=1). Hierarchical clustering of chromosomal changes associated with the t(14;19) indicated the presence of two different groups of IG/BCL3-positive lymphatic neoplasias. The first group included 26 B-cell malignancies of various histologic subtypes containing a relatively high number of chromosomal changes and mostly mutated IgVH genes. This cluster displayed three cytogenetic branches, one with rearrangements in 7q, another with deletions in 17p and a third one with rearrangements in 1q and deletions in 6q and 13q. The second group included 19 cases, mostly diagnosed as B-cell chronic lymphocytic leukemia (B-CLL), and characterized by few additional chromosomal changes (e.g. trisomy 12) and unmutated IgVH genes. In conclusion, our study indicates that BCL3 translocations are not restricted to B-CLL but present in a heterogeneous group of B-cell malignancies.
Asunto(s)
Leucemia de Células B/genética , Linfoma de Células B/genética , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción/genética , Translocación Genética , Adulto , Anciano , Proteínas del Linfoma 3 de Células B , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 19 , Análisis Citogenético , Femenino , Reordenamiento Génico , Genes de Inmunoglobulinas , Histocitoquímica , Humanos , Hibridación Fluorescente in Situ , Leucemia de Células B/clasificación , Leucemia de Células B/patología , Linfoma de Células B/clasificación , Linfoma de Células B/patología , Masculino , Persona de Mediana EdadRESUMEN
Clinical trials have been initiated with Apo2L/TRAIL (Genentech) and agonistic mAbs to TRAIL receptors, -R1 and -R2 (Human Genome Sciences). The apoptosis-inducing ability of these mAbs and different TRAIL preparations, in the presence or absence of histone deacetylase inhibitors (HDACi), varied markedly against primary chronic lymphocytic leukaemia (CLL) cells and various tumor cell lines, demonstrating an unanticipated preferential apoptotic signaling via either TRAIL-R1 or -R2. Contrary to literature reports that TRAIL-induced apoptosis occurs primarily via signaling through TRAIL-R2, CLL cells, in the presence of HDACi, undergo predominantly TRAIL-R1-mediated apoptosis. Consequently, Apo2L/TRAIL, which signals primarily through TRAIL-R2, is virtually devoid of activity against CLL cells. To maximize therapeutic benefit, it is essential to ascertain whether a primary tumor signals via TRAIL-R1/-R2, prior to initiating therapy. Thus combination of an agonistic TRAIL-R1 Ab and an HDACi, such as the anticonvulsant sodium valproate, could be of value in treating CLL.
Asunto(s)
Apoptosis , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Glicoproteínas de Membrana/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/metabolismo , Adulto , Anciano , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis , Depsipéptidos/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Histona Desacetilasas/metabolismo , Humanos , Células K562 , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Persona de Mediana Edad , Receptores de Superficie Celular/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF , Receptores del Factor de Necrosis Tumoral/metabolismo , Transducción de Señal/efectos de los fármacos , Ligando Inductor de Apoptosis Relacionado con TNF , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/metabolismo , Células U937RESUMEN
B-cell leukaemia or lymphoma with a combination of t(8;14)(q24;q32) of Burkitt leukaemia/lymphoma and t(14;18)(q32;q21) of follicular lymphoma may present clinically as de novo acute lymphoblastic leukaemia or transformation of follicular lymphoma to aggressive histology diffuse lymphoma. A number of cell lines have been reported with a complex t(8;14;18) with fusion of MYC, IGH and BCL2 on the same derivative 8 chromosome. The objective of this study was to determine the frequency and chromosomal features of this der(8)t(8;14;18) in a series of acute leukaemias and malignant lymphomas. A database of 1350 leukaemia and lymphoma karyotypes was searched for cases with structural alterations affecting both 8q24 and 18q21. A total of 55 cases were identified, of which eight revealed a complex der(8)t(8;14;18) with an MYC-IGH-BCL2 rearrangement resulting from translocation of BCL2 and MYC with a single disrupted IGH allele. Molecular cytogenetic investigation is essential to identify cases of high-grade leukaemia/lymphoma with concurrent translocations affecting the BCL2 and MYC loci.
Asunto(s)
Genes bcl-2/genética , Genes myc/genética , Cadenas Pesadas de Inmunoglobulina/genética , Linfoma de Células B/genética , Translocación Genética , Adulto , Anciano , Cromosomas Humanos Par 14 , Cromosomas Humanos Par 18 , Cromosomas Humanos Par 8 , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Linfoma Folicular/genética , Masculino , Persona de Mediana Edad , Leucemia-Linfoma Linfoblástico de Células Precursoras/genéticaRESUMEN
New insights into prognostic markers and the pathophysiology of chronic lymphocytic leukemia (CLL) are beginning to change the concept of CLL treatment. Alemtuzumab has evolved as a potent and effective therapeutic option for patients with CLL. Specifically, alemtuzumab has demonstrated substantial efficacy in fludarabine-refractory patients and has shown impressive responses when administered subcutaneously in first-line therapy. A group of experts gathered to discuss new data related to the use of alemtuzumab in CLL and to assess its place in the rapidly changing approach to treating patients with this disease. The main goals of this program were to update the management guidelines that were previously developed for alemtuzumab-treated patients and to provide community oncologists with guidance on the most effective way to integrate alemtuzumab into a CLL treatment plan.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Alemtuzumab , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/administración & dosificación , Manejo de la Enfermedad , Humanos , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/mortalidad , Guías de Práctica Clínica como Asunto , Resultado del TratamientoRESUMEN
We have used polysome profiling coupled to microarray analysis to examine the translatome of a panel of peripheral blood (PB) B cells isolated from 34 chronic lymphocytic leukaemia (CLL) patients. We have identified a 'ribosome-related' signature in CLL patients with mRNAs encoding for ribosomal proteins and factors that modify ribosomal RNA, e.g. DKC1 (which encodes dyskerin, a pseudouridine synthase), showing reduced polysomal association and decreased expression of the corresponding proteins. Our data suggest a general impact of dyskerin dysregulation on the translational apparatus in CLL and importantly patients with low dyskerin levels have a significantly shorter period of overall survival following treatment. Thus, translational dysregulation of dyskerin could constitute a mechanism by which the CLL PB B cells acquire an aggressive phenotype and thus have a major role in oncogenesis.
Asunto(s)
Perfilación de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/genética , Ribosomas/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Nucléolo Celular/metabolismo , Regulación hacia Abajo/genética , Factores Eucarióticos de Iniciación/genética , Factores Eucarióticos de Iniciación/metabolismo , Regulación Leucémica de la Expresión Génica , Humanos , Immunoblotting , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Polirribosomas/metabolismo , Biosíntesis de Proteínas , ARN Ribosómico/metabolismo , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Chromosomal translocation t(X;14)(q28;q11) has been observed in patients with pro-lymphocytic T-cell leukaemia (T-PLL). In two cases of T-PLL, one of which was associated with Ataxia telangiectasia (AT), the chromosomal break occurred in two different introns of a gene c6.1A, located at the Xq28 locus. Fusion transcripts, consisting of 5' sequences of c6.1A and the TCR alpha constant (C) region, were expressed at high levels in the leukaemic cells from both patients, but in only one case did this fusion generate an in-frame c6.1A-C alpha mRNA. However, the breaks within c6.1A seem to affect another gene, c6.1B, which is transcribed from the same CpG rich island as c6.1A but in the opposite transcriptional orientation. The c6.1B gene is not damaged by the translocation but is transcribed in both T-PLL cases. Furthermore, c6.1B may lack protein coding capacity and thus this translocation might result in a novel mechanism in tumorigenesis. In any event, this is the first cloned gene which is implicated in pathogenesis of chronic/pro-lymphocytic leukaemia of the T-cell lineage.
Asunto(s)
Cromosomas Humanos Par 14 , Regulación Neoplásica de la Expresión Génica/genética , Leucemia Prolinfocítica/genética , Leucemia de Células T/genética , Translocación Genética/genética , Cromosoma X , Anciano , Secuencia de Aminoácidos , Animales , Ataxia Telangiectasia/complicaciones , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/patología , Secuencia de Bases , Northern Blotting , Clonación Molecular , Humanos , Leucemia Prolinfocítica/complicaciones , Leucemia Prolinfocítica/patología , Leucemia de Células T/complicaciones , Leucemia de Células T/patología , Masculino , Ratones , Datos de Secuencia Molecular , ARN Mensajero/análisis , ARN Mensajero/genética , Linfocitos T/patología , Transcripción Genética , Células Tumorales CultivadasRESUMEN
In an effort to elucidate the biological role played by cyclin D1, a candidate BCL-1 oncogene, in human B-cell tumours carrying the t(11;14) translocation, we have studied the properties of this cyclin protein in a series of human lymphoid lines with rearrangements in the BCL-1 locus. The BCL-1/cyclin D1 protein was easily detectable in both immunocytochemistry and immunoblotting, its abundance grossly correlating with the mRNA levels. The cyclin D1 protein was localised predominantly to nuclei and there was a striking variation of staining intensity among the exponentially growing cells, reflecting the maximum level reached in mid/late G1 and the lowest level in S-phase. This characteristic mode of cell cycle-dependent oscillation was confirmed by three independent approaches, demonstrating that even upon rearrangement, the expression of cyclin D1 is regulated in a cyclical manner. Antibody-mediated and anti-sense oligonucleotide 'knockout' experiments revealed that the aberrantly expressed BCL-1/cyclin D1 protein is required for G1 phase progression of all four B-cell tumours with the BCL-1 rearrangement. Consistent with the proposed oncogenic role of this cyclin, our data demonstrate that the BCL-1 deregulation caused by chromosomal rearrangement leads to expression of a functionally active cyclin D1 protein which subverts the G1 phase control in the human B-cell tumours carrying the t(11;14) translocation.
Asunto(s)
Cromosomas Humanos Par 11 , Cromosomas Humanos Par 14 , Ciclinas/fisiología , Leucemia de Células B/genética , Linfoma de Células B/genética , Proteínas Oncogénicas/fisiología , Proteínas Proto-Oncogénicas/fisiología , Translocación Genética , Secuencia de Bases , Ciclina D1 , Fase G1 , Humanos , Leucemia de Células B/patología , Linfoma de Células B/patología , Datos de Secuencia Molecular , Células Tumorales CultivadasRESUMEN
Patients with the recessively inherited disorder ataxia telangiectasia (A-T) have a high level of specific chromosome translocations which can be easily observed in peripheral T cells and show a greatly increased predisposition to leukaemia/lymphoma, mainly of T cell origin. Some translocation cells proliferate into a large clone and may develop into T cell prolymphocytic leukaemia (T-PLL). By the time of diagnosis of T-PLL, the clone contains many more genetic changes in the form of additional translocations. T-PLL is also seen in non-A-T individuals where expression of either TCL1 (at 14q32) or the c6.1B/MTCP1 A1 transcript (at-Xq28) has been demonstrated in just a few instances. We show here, that expression of TCL1 occurs in leukaemic T cells from A-T patients with chromosome 14 rearrangements. Expression of TCL1 also occurs in the preleukaemic clone cells of A-T patients containing the primary translocation alone. Some expression of TCL1 could also be detected in randomly selected A-T patients without large cytogenetic clones and without any evidence of leukaemic change. We also show that expression of the B1 transcript from a second gene, MTCP1, occurred at a relatively high level only in two T-PLL tumours from A-T patients with t(X;14) translocations whereas the MTCP1/A1 transcript is much more widely expressed in both tumour and non tumour cells of A-T and non-A-T individuals.
Asunto(s)
Ataxia Telangiectasia/genética , Proteínas de Unión al ADN/genética , Leucemia Prolinfocítica/genética , Oncogenes , Proteínas Proto-Oncogénicas , ARN Mensajero/análisis , Linfocitos T/metabolismo , Factores de Transcripción/genética , Secuencia de Bases , Humanos , Datos de Secuencia Molecular , Translocación GenéticaRESUMEN
T-prolymphocytic leukaemia (T-PLL) is a rare, sporadic leukaemia similar to a mature T-cell leukaemia seen in some patients with Ataxia Telangiectasia (A-T), a recessive multisystem disorder caused by mutations of the ATM gene at chromosome 11q23. ATM sequence mutations have been reported in 46% of T-PLL cases, but some cases also have karyotypic abnormalities at 11q, including 11q23. This led us to investigate the structure of the ATM locus in a panel of eight cases, two of which had 11q23 abnormalities. As expected, nucleotide changes were detected in some samples. Two remission samples were wild type. To test for structural lesions, DNA fibres were hybridized with a contig of four labelled cosmids spanning the ATM locus. In all samples there were structural lesions and in four samples both alleles were affected. This provides strong evidence for our suggestion that ATM acts as a tumour suppressor during T-PLL tumorigenesis. Some additional role for ATM during T-PLL tumorigenesis is possible since nucleotide changes were present in addition to structural lesions disrupting both alleles. The mechanism of inactivation appeared to be unusual because multiple structural lesions on one allele were often observed.
Asunto(s)
ADN de Neoplasias/análisis , Leucemia Prolinfocítica/genética , Proteínas Serina-Treonina Quinasas , Proteínas/genética , Proteínas de la Ataxia Telangiectasia Mutada , Proteínas de Ciclo Celular , Proteínas de Unión al ADN , Humanos , Linfocitos T , Proteínas Supresoras de TumorRESUMEN
New therapies are required for chronic lymphocytic leukemia (CLL), an incurable disease characterized by failure of mature lymphocytes to undergo apoptosis. Activation of cell surface death receptors, such as via TRAIL receptor ligation, may provide a novel therapeutic target for various malignancies. However, CLL and other lymphoid malignancies are resistant to TRAIL. We report that low concentrations of histone deacetylase (HDAC) inhibitors, such as depsipeptide, which alone failed to induce apoptosis, markedly sensitize CLL cells and other primary lymphoid malignancies to TRAIL-induced apoptosis. These combinations caused little or no toxicity to normal lymphocytes. HDAC inhibitors sensitized resistant cells to TRAIL-induced apoptosis by facilitating formation of an active death-inducing signalling complex (DISC), leading to the rapid activation of caspase-8. The facilitated DISC formation also occurred in the absence of TRAIL-R2 upregulation. Thus, the combination of HDAC inhibitors and TRAIL may be valuable in the treatment of various hemopoietic malignancies.
Asunto(s)
Apoptosis/efectos de los fármacos , Depsipéptidos/farmacología , Inhibidores Enzimáticos/farmacología , Inhibidores de Histona Desacetilasas , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/patología , Glicoproteínas de Membrana/farmacología , Factor de Necrosis Tumoral alfa/farmacología , Proteínas Reguladoras de la Apoptosis , Caspasa 8 , Caspasas/efectos de los fármacos , Caspasas/metabolismo , Línea Celular Tumoral , Cicloheximida/farmacología , Proteínas Adaptadoras de Señalización del Receptor del Dominio de Muerte , Humanos , Células Jurkat/efectos de los fármacos , Leucemia Linfocítica Crónica de Células B/metabolismo , Linfocitos/efectos de los fármacos , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF , Receptores del Factor de Necrosis Tumoral/análisis , Receptores del Factor de Necrosis Tumoral/efectos de los fármacos , Receptores del Factor de Necrosis Tumoral/metabolismo , Transducción de Señal/efectos de los fármacos , Ligando Inductor de Apoptosis Relacionado con TNF , Células U937/efectos de los fármacosRESUMEN
PURPOSE: CAMPATH-1H is a human immunoglobulin G1 (IgG1) anti-CD52 monoclonal antibody (MAb) that binds to nearly all B- and T-cell lymphomas and leukemias. We report the results of a multicenter phase II trial that used CAMPATH-1H in previously chemotherapy-treated patients with chronic lymphocytic leukemia (CLL). MATERIALS AND METHODS: Twenty-nine patients who had relapsed after an initial response (n = 8) or were refractory (n = 21) to chemotherapy were treated with CAMPATH-1H administered as a 30-mg 2-hour intravenous (IV) infusion thrice weekly for a maximum period of 12 weeks. RESULTS: Eleven patients (38%) achieved a partial remission (PR) and one (4%) a complete remission (CR) (response rate, 42%; 95% confidence interval [CI], 23% to 61%). Three of eight patients (38%) with a relapse and nine of 21 refractory patients (43%) responded to CAMPATH-1H therapy. CLL cells were rapidly eliminated from blood in 28 of 29 patients (97%). CR in the bone marrow was obtained in 36% and splenomegaly resolved completely in 32%. Lymphadenopathy was normalized in only two patients (7%). The median response duration was 12 months (range, 6 to 25+). World Health Organization (WHO) grade IV neutropenia and thrombocytopenia developed in three (10%) and two patients (7%), respectively. Neutropenia and thrombocytopenia recovered in most responding patients during continued CAMPATH-1H treatment. Lymphopenia (< 0.5 x 10(9)/L) occurred in all patients. Two patients had opportunistic infections and four had bacterial septicemia. CONCLUSION: CAMPATH-1H had significant activity in patients with advanced and chemotherapy-resistant CLL. The most pronounced effects were noted in blood, bone marrow, and spleen. Preferential clearance of blood may allow harvesting of uncontaminated blood stem cells for use in high-dose chemotherapy protocols.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Antígenos CD/inmunología , Antígenos de Neoplasias , Antineoplásicos/uso terapéutico , Glicoproteínas , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/terapia , Adulto , Anciano , Alemtuzumab , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/administración & dosificación , Anticuerpos Antineoplásicos/efectos adversos , Antineoplásicos/efectos adversos , Plaquetas , Antígeno CD52 , Europa (Continente) , Humanos , Cinética , Linfocitos , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
PURPOSE: T-prolymphocytic leukemia (T-PLL) is an aggressive malignancy of mature T cells refractory to conventional chemotherapy, with a median survival duration of 7.5 months. We report here promising results with the use of a genetically reshaped human CD52 antibody, CAMPATH-1H. PATIENTS AND METHODS: Fifteen patients with T-PLL, most of whom had received the purine analog deoxycoformycin (DCF), were treated with CAMPATH-1H. Results were compared with those of 25 patients treated with DCF. RESULTS: Major responses occurred in 11 patients (73%) treated with CAMPATH-1H compared with 40% with DCF. Complete remissions (CRs) were documented in nine (60%) of the CAMPATH-1H cases and only three (12%) were obtained with DCF. CRs with CAMPATH-1H were durable, and re-treatment with the antibody resulted in second CRs in three relapsed patients. Two of them were successfully autografted with peripheral-blood and bone marrow stem cells collected during the first CR. Apart from first-dose reactions, infusions of CAMPATH-1H were well tolerated. However, two responding patients developed severe bone marrow aplasia that was fatal in one; the second remained moderately pancytopenic 21 weeks after stopping CAMPATH-1H therapy. The cause of this adverse effect is unknown. CONCLUSION: CAMPATH-1H is an effective agent in T-PLL and represents a significant improvement over other types of therapy. However, CAMPATH-1H alone is not sufficient for long-term remissions, and the role of autologous stem-cell transplantation needs further investigation.