RESUMEN
The coexistence of multiple myeloma (MM) and mycosis fungoides (MF), and hence of both B- and T-cell neoplastic clones, is a rare event. We describe a case of plaque-stage MF associated with IgG lambda MM. The clinical onset of MF preceded that of MM, supporting the hypothesis that MF predisposed to the development of the B-cell proliferative disorder. The skin tumor cells were found to originate from CD4(+) T-lymphocytes, characterized by a V beta 8 receptor and no proviral human T-lymphotropic virus (HTLV)-I monoclonal integration. They also displayed a polarized Th1-type cytokine profile containing mRNAs for interleukin (IL)-2, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-beta, but not for IL-4, IL-5, or IL-10. The CD8(+)/CD57(+) suppressor-cytotoxic subpopulation was significantly increased in the peripheral blood and was associated with MM progression. Expression of p16INK4A, a gene from the INK family that inhibits cyclin-dependent kinases and regulates the cell cycle, was lacking in MF cells and bone marrow (BM) plasma cells. The p16INK4A gene was silenced by hypermethylation, suggesting that it plays a role in the early phase of the pathogenesis of both diseases. Thus, a lymphoid precursor cell presumably contains aberrations that induce the development of both clonal diseases in a multistep process.
Asunto(s)
Mieloma Múltiple/complicaciones , Micosis Fungoide , Micosis Fungoide/complicaciones , Western Blotting , Linfocitos T CD4-Positivos/química , Linfocitos T CD8-positivos/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Citocinas/análisis , Citocinas/genética , Humanos , Masculino , Metilación , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Micosis Fungoide/genética , Micosis Fungoide/inmunología , Fenotipo , ARN/análisis , Neoplasias Cutáneas/química , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Células TH1/inmunología , Células Th2/inmunologíaAsunto(s)
Proteínas Portadoras/genética , Eliminación de Gen , Genes Supresores de Tumor , Mieloma Múltiple/genética , Secuencia de Bases , Médula Ósea/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Cartilla de ADN , Exones , Humanos , Datos de Secuencia Molecular , Mieloma Múltiple/patología , Paraproteinemias/genética , Paraproteinemias/patología , Reacción en Cadena de la PolimerasaRESUMEN
We studied the molecular alterations of IL-6R, lck and c-myc genes in the tumour cells of 50 patients with multiple myeloma (MM) and 20 patients with monoclonal gammopathies of undetermined significance (MGUS). Southern blot analysis revealed a 5.3 kb IL-6R amplified band by digestion with EcoRI and HindIII in three MGUS patients, but no IL-6R gene alteration was found in MM patients. BamHI digestion revealed a 6.2 kb rearranged band of the lck gene in two MGUS patients with IL-6R amplification. In one MGUS patient we detected a rearrangement upstream of the lck coding region. Myc rearrangement was observed in three MM and two MGUS patients who showed coexistent lck rearrangement and IL-6R amplification. These molecular alterations were detected in the MGUS patients with an IgA monoclonal component, who showed a rapid progression into aggressive MM. Myc rearrangement seems to be associated with a small group of a clinically aggressive MM at diagnosis, secreting IgA or k light chains. Multiple rearrangements and/or molecular alterations are likely to occur at the time of MGUS-IgA transformation into aggressive MM and myc rearrangement may promote a positive pressure for transformation and progression. MM tumourigenesis remains a heterogenous multistep process involving the deregulation of many genes and gene products.
Asunto(s)
Genes myc/genética , Interleucina-6/genética , Mieloma Múltiple/genética , Paraproteinemias/genética , Proteínas Proto-Oncogénicas/genética , Adulto , Anciano , Anciano de 80 o más Años , Northern Blotting , Southern Blotting , Femenino , Reordenamiento Génico , Humanos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito , Masculino , Persona de Mediana EdadRESUMEN
The use of interferon for the induction treatment of multiple myeloma has been shown to be effective in about 20 percent of patients. We studied its effects on long-term survival when it was used for maintenance treatment. Between April 1985 and May 1988, 101 patients with symptomatic multiple myeloma who had had a substantial objective response or a lesser objective response with disappearance of symptoms ("disease stabilization") after 12 courses of induction chemotherapy were randomly assigned to receive recombinant interferon alfa-2b as maintenance therapy (n = 50) or to receive no treatment (n = 51). As of December 1989, 66 of the 101 patients have relapsed (25 given interferon and 41 not treated). The median duration of response (from the time of randomization) was 26 months in the patients given interferon and 14 months in the untreated patients (P = 0.0002). A total of 37 patients have died (14 given interferon and 23 not treated). The median duration of survival (from randomization) was 52 months in the interferon group and 39 months in the control group (P = 0.0526). Among the patients who had had a substantial objective response to induction chemotherapy, the difference in survival time was statistically significant (P = 0.03526). Interferon had to be stopped because of toxic effects in 3 of 12 patients initially treated with 10 MU (megaunits) per square meter of body-surface area. After the dose was reduced to 3 MU per square meter, the only toxic effect was a mild influenza-like syndrome lasting two to three weeks. We conclude that maintenance treatment with interferon prolongs response and survival in patients with multiple myeloma who have responded to conventional induction chemotherapy.
Asunto(s)
Interferón Tipo I/uso terapéutico , Interferón-alfa/uso terapéutico , Mieloma Múltiple/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes , Recurrencia , Inducción de Remisión , Tasa de SupervivenciaRESUMEN
The human T-cell- or lymphocyte-specific gene, lck, encodes a tyrosine kinase and is a member of the src family. In this report we demonstrate that there are two classes of human lck transcripts (types I and II), containing different 5'-untranslated regions, which are expressed from two distinct promoters. No apparent sequence similarity was observed between the 5'-flanking regions of the two promoters. The expression of lck in human T-cell leukemia and carcinoma cell lines and in human peripheral blood T lymphocytes was examined by S1 nuclease and primer extension mapping and by Northern (RNA) blot analysis of total cellular RNA. The following results were obtained. (i) Two RNA start sites in the downstream promoter were used to generate type I transcripts. (ii) The major human type I start site has not been described for the mouse. (iii) At least five RNA start sites in the upstream promoter were used to generate type II transcripts. (iv) In T cells and in two colon carcinoma cell lines, type II transcripts were present in higher amounts than type I transcripts. (v) In T cells treated with phytohemagglutinin, tetradecanoylphorbol acetate, and cyclosporin A, the modulation of lck expression was associated primarily with changes in levels of type II transcripts. The above results suggest that the two human lck promoters are utilized differentially and may be regulated independently during certain physiological states.
Asunto(s)
Regiones Promotoras Genéticas , Proteínas Tirosina Quinasas/genética , Transcripción Genética , Secuencia de Bases , Neoplasias del Colon/enzimología , Neoplasias del Colon/genética , ADN/genética , Humanos , Activación de Linfocitos , Datos de Secuencia Molecular , Mapeo Restrictivo , Linfocitos T/citología , Linfocitos T/enzimología , Linfocitos T/inmunología , Células Tumorales Cultivadas/enzimologíaRESUMEN
The immunologic effects of a year-long therapeutic trial with the synthetic thymic hormone thymopentin were investigated in 29 patients with human immunodeficiency virus--induced lymphadenopathy syndrome. Peripheral T4 and T8 lymphocyte subsets and in vitro immunoglobulin synthesis with pokeweed mitogen (PWM) were monitored before treatment, every 4 months during treatment, and after treatment. Significant increases in circulating T4 cells and a reduction of PWM-induced immunoglobulin suppression were noted in the 21 patients who completed the trial. Furthermore, addition of thymopentin to the in vitro cultures improved the PWM response of T and B cells. After thymopentin treatment, a slight variability of clinical symptoms, including weight loss, diarrhea, night sweats, or a combination of these, was also noted in several subjects.
Asunto(s)
Complejo Relacionado con el SIDA/tratamiento farmacológico , Adyuvantes Inmunológicos/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Timopoyetinas/uso terapéutico , Hormonas del Timo/uso terapéutico , Complejo Relacionado con el SIDA/inmunología , Femenino , Humanos , Inmunoglobulina G/biosíntesis , Activación de Linfocitos , Linfocitos/inmunología , Masculino , TimopentinaRESUMEN
An enzyme-linked immunosorbent assay based on the ability of polyethylene-glycol (PEG) fixed on a solid support to adsorb circulating macromolecules (PEG-solid phase test) was developed in order to provide evidence for the existence of immune complexes of HBeAg/anti-HBe (HBeAg/anti-HBe complex) in sera of HBsAg chronic carriers. The method can detect HBeAg in immune complexes whether antigen or antibody is in excess. In the chronic phase of HBV infection, HBeAg/anti-HBe complexes are formed transiently in the course of the disease, unrelated to the phases of virus replication or peaks of hepatocytolysis, or to the histologic picture of liver disease. Our study indicates that this method offers a new approach to the understanding of biological and clinical problems of the HBeAg/anti-HBe antigenic system in chronic HBV infection.