RESUMO
Various histological subtypes of leukaemia and lymphoma are associated with diagnostic chromosome translocations, and substantial strides have been made in determining the specific oncogenes targetted by those translocations. We report the cloning of a novel fusion oncogene associated with a unique leukaemia/lymphoma syndrome. Patients afflicted with this syndrome present with lymphoblastic lymphoma and a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow, which generally progress to full-blown acute myelogenous leukaemia within a year of diagnosis. A specific chromosome translocation, t(8;13)(p11;q11-12), is found in both lymphoma and myeloid leukaemia cells from these patients, supporting bi-lineage differentiation from a transformed stem cell. We find that the 8p11 translocation breakpoints, in each of four patients, interrupt intron 8 of the fibroblast growth factor receptor 1 gene (FGFR1). These translocations are associated with aberrant transcripts in which four predicted zinc-finger domains, contributed by a novel and widely expressed chromosome-13 gene (ZNF198), are fused to the FGFR1 tyrosine-kinase domain. Transient expression studies show that the ZNF198-FGFR1 fusion transcript directs the synthesis of an approximately 87-kD polypeptide, localizing predominantly to the cytoplasm. Our studies demonstrate an FGFR1 oncogenic role and suggest a tumorigenic mechanism in which ZNF198-FGFR1 activation results from ZNF198 zinc-finger-mediated homodimerization.
Assuntos
Proteínas de Transporte , Cromossomos Humanos Par 13 , Cromossomos Humanos Par 8 , Proteínas de Ligação a DNA/genética , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores Proteína Tirosina Quinases , Receptores de Fatores de Crescimento de Fibroblastos/genética , Translocação Genética , Dedos de Zinco/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Transformação Celular Neoplásica , Humanos , Camundongos , Dados de Sequência Molecular , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Síndrome , Fatores de TranscriçãoRESUMO
BACKGROUND: The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with diffuse large-B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of diffuse large-B-cell lymphoma is unclear. METHODS: We profiled gene expression in pretreatment biopsy specimens from 181 patients with diffuse large-B-cell lymphoma who received CHOP and 233 patients with this disease who received R-CHOP. A multivariate gene-expression-based survival-predictor model derived from a training group was tested in a validation group. RESULTS: A multivariate model created from three gene-expression signatures--termed "germinal-center B-cell," "stromal-1," and "stromal-2"--predicted survival both in patients who received CHOP and patients who received R-CHOP. The prognostically favorable stromal-1 signature reflected extracellular-matrix deposition and histiocytic infiltration. By contrast, the prognostically unfavorable stromal-2 signature reflected tumor blood-vessel density. CONCLUSIONS: Survival after treatment of diffuse large-B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment.
Assuntos
Perfilação da Expressão Gênica , Expressão Gênica , Linfoma Difuso de Grandes Células B/genética , Células Estromais/metabolismo , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida , Progressão da Doença , Doxorrubicina , Matriz Extracelular/genética , Regulação Neoplásica da Expressão Gênica , Genes MHC da Classe II , Centro Germinativo , Humanos , Fatores Imunológicos/administração & dosagem , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Pessoa de Meia-Idade , Análise Multivariada , Neovascularização Patológica/genética , Prednisona , Prognóstico , Rituximab , Células Estromais/patologia , VincristinaRESUMO
Lymphomas express a tumor-specific antigen which can be targeted by cancer vaccination. We evaluated the ability of a new idiotype protein vaccine formulation to eradicate residual t(14;18)+ lymphoma cells in 20 patients in a homogeneous, chemotherapy-induced first clinical complete remission. All 11 patients with detectable translocations in their primary tumors had cells from the malignant clone detectable in their blood by PCR both at diagnosis and after chemotherapy, despite being in complete remission. However, 8 of 11 patients converted to lacking cells in their blood from the malignant clone detectable by PCR after vaccination and sustained their molecular remissions. Tumor-specific cytotoxic CD8+ and CD4+ T cells were uniformly found (19 of 20 patients), whereas antibodies were detected, but apparently were not required for molecular remission. Vaccination was thus associated with clearance of residual tumor cells from blood and long-term disease-free survival. The demonstration of molecular remissions, analysis of cytotoxic T lymphocytes against autologous tumor targets, and addition of granulocyte-monocyte colony-stimulating factor to the vaccine formulation provide principles relevant to the design of future clinical trials of other cancer vaccines administered in a minimal residual disease setting.
Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Idiótipos de Imunoglobulinas/uso terapêutico , Linfoma Folicular/terapia , Adulto , Idoso , Anticorpos Antineoplásicos/sangue , Antineoplásicos/uso terapêutico , Vacinas Anticâncer/imunologia , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 18 , DNA de Neoplasias/sangue , Quimioterapia Combinada , Feminino , Humanos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/genética , Linfoma Folicular/imunologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Indução de Remissão , Translocação GenéticaRESUMO
BACKGROUND: Recently novel Epstein-Barr virus (EBV) lymphoproliferative diseases (LPDs) have been identified in non-immunocompromised hosts, both in Asia and Western countries. These include aggressive T-cell and NK-cell LPDs often subsumed under the heading of chronic active Epstein-Barr virus (CAEBV) infection and EBV-driven B-cell LPDs mainly affecting the elderly. DESIGN: To better define the pathogenesis, classification, and treatment of these disorders, participants from Asia, The Americas, Europe, and Australia presented clinical and experimental data at an international meeting. RESULTS: The term systemic EBV-positive T-cell LPD, as adopted by the WHO classification, is preferred as a pathological classification over CAEBV (the favored clinical term) for those cases that are clonal. The disease has an aggressive clinical course, but may arise in the background of CAEBV. Hydroa vacciniforme (HV) and HV-like lymphoma represent a spectrum of clonal EBV-positive T-cell LPDs, which have a more protracted clinical course; spontaneous regression may occur in adult life. Severe mosquito bite allergy is a related syndrome usually of NK cell origin. Immune senescence in the elderly is associated with both reactive and neoplastic EBV-driven LPDs, including EBV-positive diffuse large B-cell lymphomas. CONCLUSION: The participants proposed an international consortium to facilitate further clinical and biological studies of novel EBV-driven LPDs.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/virologia , Infecções por Vírus Epstein-Barr/terapia , Humanos , Transtornos Linfoproliferativos/terapiaRESUMO
Myeloid progenitor cells were highly purified from normal human bone marrow by positive immunoselection with high-affinity monoclonal antibodies linked to magnetic beads and were successfully infected in vitro with the human immunodeficiency virus type 1 (HIV-1). From 99 to 100 percent pure bone marrow cells expressing the CD34 phenotypic marker were obtained. These cells were devoid of mature myeloid or T cell surface and intracellular markers as analyzed by immunohistochemical staining and flow cytometry. HIV-1 particles were detected by supernatant reverse transcriptase activity and transmission electron microscopy 40 to 60 days after infection. Viral particles were predominantly observed assembling and accumulating from within intracellular membranes, while phenotypically the cells were observed to have differentiated into CD4+ monocytes. These studies have important implications in understanding the pathogenesis of HIV-1 as well as the possible cause of certain of the observed hematologic abnormalities in HIV-1 infection. They also indicate that the bone marrow may serve as a potentially important reservoir of HIV-1 in the body.
Assuntos
Células da Medula Óssea , HIV/fisiologia , Células-Tronco Hematopoéticas/microbiologia , Replicação Viral , Antígenos de Diferenciação de Linfócitos T/análise , Antígenos de Superfície/análise , Membrana Celular/microbiologia , Separação Celular , Citometria de Fluxo , Imunofluorescência , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/ultraestrutura , Humanos , Imuno-Histoquímica , Microscopia Eletrônica , Fenótipo , DNA Polimerase Dirigida por RNA/metabolismoRESUMO
AIMS: Light-chain-restricted germinal centres are generally associated with the existence of a neoplastic lymphoproliferative disorder. The aim was to present a series of cases with persistent lymph node enlargement that featured some germinal centres showing light chain immunoglobulin restriction. METHODS AND RESULTS: A series of six reactive lymphadenitis and two Castleman's disease cases was analysed by immunohistochemistry, IgH-polymerase chain reaction (PCR) and microdissected PCR. In all cases some germinal centres contained a population of plasma cells and plasmacytoid germinal centre cells showing light chain immunoglobulin restriction. In three cases the monotypic cells also showed distinct Bcl-2 expression. Two of the cases showed a predominant IgH rearrangement on a florid polyclonal background and one had an IgH monoclonal rearrangement, as revealed by PCR. Microdissected germinal centre PCR revealed a dominant repeated band in one of three cases and in another case a non-repeated clonal peak was observed. One of the patients developed a follicular lymphoma, which became evident from a subsequent biopsy. CONCLUSIONS: These findings may be a manifestation of an underlying disorder in the regulation of the immune response, or an exaggeration of the germinal centre oligoclonal nature. This should be taken into account in the differential diagnosis of follicular hyperplasia.
Assuntos
Hiperplasia do Linfonodo Gigante/imunologia , Centro Germinativo/imunologia , Cadeias Leves de Imunoglobulina/imunologia , Linfadenite/imunologia , Adulto , Idoso , Hiperplasia do Linfonodo Gigante/genética , Hiperplasia do Linfonodo Gigante/patologia , Feminino , Rearranjo Gênico , Genes de Imunoglobulinas/genética , Genes bcl-2/genética , Centro Germinativo/patologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Leves de Imunoglobulina/genética , Linfadenite/genética , Linfadenite/patologia , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Plasmócitos/patologia , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-bcl-2/imunologiaRESUMO
Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed biologically and prognostically distinct subgroups: germinal center B-cell-like (GCB), activated B-cell-like (ABC) and primary mediastinal (PM) DLBCL. The BCL6 gene is often translocated and/or mutated in DLBCL. Therefore, we examined the BCL6 molecular alterations in these DLBCL subgroups, and their impact on BCL6 expression and BCL6 target gene repression. BCL6 translocations at the major breakpoint region (MBR) were detected in 25 (18.8%) of 133 DLBCL cases, with a higher frequency in the PM (33%) and ABC (24%) subgroups than in the GCB (10%) subgroup. Translocations at the alternative breakpoint region (ABR) were detected in five (6.4%) of 78 DLBCL cases, with three cases in ABC and one case each in the GCB and the unclassifiable subgroups. The translocated cases involved IgH and non-IgH partners in about equal frequency and were not associated with different levels of BCL6 mRNA and protein expression. BCL6 mutations were detected in 61% of DLBCL cases, with a significantly higher frequency in the GCB and PM subgroups (>70%) than in the ABC subgroup (44%). Exon-1 mutations were mostly observed in the GCB subgroup. The repression of known BCL6 target genes correlated with the level of BCL6 mRNA and protein expression in GCB and ABC subgroups but not with BCL6 translocation and intronic mutations. No clear inverse correlation between BCL6 expression and p53 expression was observed. Patients with higher BCL6 mRNA or protein expression had a significantly better overall survival. The biological role of BCL6 in translocated cases where repression of known target genes is not demonstrated is intriguing and warrants further investigation.
Assuntos
Proteínas de Ligação a DNA/biossíntese , Linfoma Difuso de Grandes Células B/genética , Mutação , Análise Mutacional de DNA , Éxons , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Íntrons , Linfoma Difuso de Grandes Células B/metabolismo , Modelos Genéticos , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-6 , RNA Mensageiro/metabolismo , Fatores de Tempo , Translocação Genética , Resultado do TratamentoRESUMO
To investigate the relationship of the lymphoid hyperplasia of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) to supervening malignant lymphoma, we subjected DNA from lymph nodes and peripheral blood mononuclear cells from five AILD patients to Southern blot analysis to detect clonal rearrangements of immunoglobulin and T-cell receptor genes. Lymph nodes and peripheral blood from AILD patients were found to contain clones of lymphoid cells harboring either immunoglobulin or T-cell receptor gene rearrangements that, in some instances, regressed during the course of disease. A lymph node from one patient was involved by immunoblastic lymphoma and manifested an additional gene rearrangement pattern not seen in premalignant specimens from that patient. In contrast, DNA obtained from normal peripheral blood mononuclear cells and 11 examples of other forms of lymphoid hyperplasia showed no gene rearrangements. As a disorder of cellular immunoregulation in which lymphoid cells may escape normal growth controls, AILD provides a natural model to dissect stages of lymphomagenesis in man.
Assuntos
Linfadenopatia Imunoblástica/patologia , Linfonodos/patologia , Linfoma/patologia , Células Cultivadas , Células Clonais , DNA/análise , Genes , Humanos , Linfadenopatia Imunoblástica/complicações , Linfadenopatia Imunoblástica/genética , Linfoma/etiologia , Linfoma/genéticaRESUMO
In mice, the two distinct autosomal recessive genes lpr and gld can induce a syndrome characterized by autoantibody formation and the progressive accumulation of an unusual CD4-CD8- T cell population in peripheral lymphoid tissue. This phenotype does not precisely mirror any human disease. In this report we describe two patients with a progressive lymphoproliferative disorder associated with autoimmunity. The peripheral blood and lymph nodes of these patients contained large numbers of an unusual CD4-CD8- T cell population. These CD4-CD8- T cells express surface markers characteristic of mature peripheral blood T cells (CD3, CD2, CD5), express the alpha/beta form of the T cell receptor, and do not express surface markers characteristic of immature thymocytes (CD1) or NK cells (CD16, CD56). Functionally, these cells exhibited deficient proliferation and lymphokine production upon stimulation with mitogenic antibodies to CD3 or CD2. Both proliferation and lymphokine production could be augmented by co-stimulation with an antibody directed at the CD28 determinant. The clinical and immunological features of this syndrome resemble the lymphoproliferative/autoimmune disease seen in lpr and gld mice.
Assuntos
Doenças Autoimunes/imunologia , Transtornos Linfoproliferativos/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Doenças Autoimunes/patologia , Antígenos CD4/análise , Antígenos CD8/análise , Citometria de Fluxo , Humanos , Hipergamaglobulinemia/patologia , Interferon gama/biossíntese , Interleucina-2/biossíntese , Linfonodos/patologia , Ativação Linfocitária , Transtornos Linfoproliferativos/patologia , Camundongos , Camundongos Mutantes , Receptores de Antígenos de Linfócitos T alfa-beta/análiseRESUMO
Treatment of HL-60 cells with dibutyryl cyclic AMP induced rapid transcriptional inactivation of c-myc and the transferrin receptor. Transcriptional inactivation was followed by loss of c-myc and transferrin receptor mRNA and protein. Treated cells completed one round of proliferation, followed by growth arrest, G1 synchronization, and monocytic differentiation. These data suggest that cyclic AMP-mediated control of growth and differentiation may be achieved, at least in part, by transcriptional regulation of certain growth-associated proto-oncogenes and growth factor receptor genes.
Assuntos
Bucladesina/farmacologia , Proto-Oncogenes/efeitos dos fármacos , Receptores da Transferrina/genética , Transcrição Gênica/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-myc , Receptores da Transferrina/biossíntese , Receptores da Transferrina/efeitos dos fármacosRESUMO
Follicular lymphoma (FL) is typically an indolent disease, but 30-40% of FL cases transform into an aggressive lymphoma (tFL) with a poor prognosis. To identify the genetic changes that drive this transformation, we sequenced the exomes of 12 cases with paired FL and tFL biopsies and identified 45 recurrently mutated genes in the FL-tFL data set and 39 in the tFL cases. We selected 496 genes of potential importance in transformation and sequenced them in 23 additional tFL cases. Integration of the mutation data with copy-number abnormality (CNA) data provided complementary information. We found recurrent mutations of miR-142, which has not been previously been reported to be mutated in FL/tFL. The genes most frequently mutated in tFL included KMT2D (MLL2), CREBBP, EZH2, BCL2 and MEF2B. Many recurrently mutated genes are involved in epigenetic regulation, the Janus-activated kinase-signal transducer and activator of transcription (STAT) or the nuclear factor-κB pathways, immune surveillance and cell cycle regulation or are TFs involved in B-cell development. Of particular interest are mutations and CNAs affecting S1P-activated pathways through S1PR1 or S1PR2, which likely regulate lymphoma cell migration and survival outside of follicles. Our custom gene enrichment panel provides high depth of coverage for the study of clonal evolution or divergence.
Assuntos
Carcinogênese/genética , Transformação Celular Neoplásica/genética , Dosagem de Genes , Linfoma Folicular/genética , Evolução Clonal/genética , Análise Mutacional de DNA , Epigênese Genética/genética , Exoma/genética , Humanos , OncogenesRESUMO
Diffuse intermediately differentiated lymphocytic lymphoma (IDL) is a rare (approximately 2.5%) histologic subtype of malignant lymphoma. We have reviewed the morphologic, immunophenotypic, and clinical features of this disease in 23 patients treated at the National Cancer Institute in the 25-year period between 1963 and 1988. These tumors are uniformly of B-cell origin, but most of them express the T-cell antigen CD5; lambda light chain was expressed nearly twice as frequently as kappa. Median age at diagnosis was 58 years; all patients presented with stage III or IV disease, and the natural history of disease in these patients was heterogeneous. Median survival of patients was more than 5 years, but those with liver involvement documented by biopsy had a significantly shorter survival. No other prognostic factor or combination of prognostic factors significantly affected survival in this small series; however, patients with high expression of the proliferation-associated nuclear antigen Ki-67, absence of cell-surface antigens CD9 and CD10, and blastic morphology appeared to have poorer survival. Treatment was heterogeneous, but patients who achieved a complete response to combination chemotherapy survived longer than patients who failed to achieve a complete response. Only two patients had complete responses lasting longer than 2 years. Unlike patients with follicular lymphoma, those with relapsed IDL did not undergo histologic progression of the disease to an aggressive lymphoma. However, as with patients with follicular lymphoma, it was possible to observe patients with IDL without therapy for periods up to 5 years. Although a significant minority of patients may have very aggressive disease, it appears that, in most patients, IDL behaves similarly to other lymphomas with indolent histology, and thus, an optimal therapeutic approach has not yet been defined.
Assuntos
Leucemia Linfocítica Crônica de Células B/patologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prednisona/administração & dosagem , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Taxa de Sobrevida , Vincristina/administração & dosagem , Irradiação Corporal TotalRESUMO
Cytogenetic studies were conducted on fresh and cultured cells from 11 patients with human T-cell leukemia virus-associated adult T-cell leukemia-lymphoma. Clones with abnormal karyotypes were detected in 9 of the 11 patients. Chromosome numbers were near-diploid in cells from all but 1 patient who also had a tetraploid clone. The chromosome abnormalities in these cells were extensive; numerous complex structural changes were seen in every chromosome pair. Structural abnormalities occurred most frequently in chromosome 6. The 6 patients with chromosome 6 deletions had breakpoints at bands q11, q13, q16q23, q21q23, q22q24, and q23q24. The characteristic clinical features of these 6 patients were aggressive course, short survival, poor response to chemotherapy, high white blood cell counts, hypercalcemia, and bone lesions, whereas cytogenetically abnormal patients without chromosome 6q deletions tended to have a more indolent course. The precise role of the 6q deletion cannot be established with certainty from these data. However, this abnormality appears to occur with a greater than expected frequency in this large cell aggressive lymphoma, in association with hypercalcemia and lytic bone lesions.
Assuntos
Aberrações Cromossômicas , Deltaretrovirus , Leucemia/genética , Linfoma/genética , Infecções por Retroviridae/genética , Adulto , Células Cultivadas , Feminino , Humanos , Cariotipagem , Masculino , Pessoa de Meia-IdadeRESUMO
An analysis of trends in the incidence of non-Hodgkin's lymphoma requires an understanding of individual disease entities within this broad group. The non-Hodgkin's lymphomas represent a diverse group of malignancies that have in common an origin from lymphoid cells. Nevertheless, these disorders are heterogeneous in their clinical behavior, morphological appearance, cellular origin, etiology, and pathogenesis. A modern classification of non-Hodgkin's lymphomas must include an integration of morphological, immunophenotypical, and molecular concepts in order to delineate individual diseases within this broad group. Existing classification schemes such as the working formulation, while they may be useful in providing a guide to clinical management, cannot provide this information in the absence of other data. This point is most readily made with the low-grade B-cell lymphomas which include follicular lymphomas, mantle cell lymphomas, small lymphocytic lymphomas, immunosecretory disorders, and lymphomas of mucosa-associated lymphoid tissues. Each of these malignancies has a distinct phenotype and genotype, and indubitably each has a different etiology. The postthymic T-cell tumors are equally diverse. Analysis of epidemiological data from cancer registries must include a recognition that our ability to recognize individual diseases from historical data is limited. Studies of trends in the non-Hodgkin's lymphomas should attempt to delineate biological markers that may be of relevance to pathogenesis in both historical and prospectively accrued cases.
Assuntos
Linfoma não Hodgkin/classificação , Linfoma não Hodgkin/patologia , Humanos , FenótipoRESUMO
CDKN2 (p16INK4A/MTS1) and p15INK4B/MTS2 have been shown recently to be potent inhibitors of the cyclin D/cyclin-dependent kinase 4 complex. Both genes are candidates for the putative tumor suppressor gene located at chromosome 9p21. We examined a series of 14 hematopoietic cell lines and 117 primary lymphoid tumors for deletion and mutation of these genes. The primary tumors included 65 T-cell malignancies and 52 B-cell malignancies. The cell line study revealed 4 of 4 T-ALL lines to have homozygous deletions of CDKN2. Two of the 4 lines also showed homozygous deletions of MTS2, while the remaining 2 lines retained both MTS2 alleles. In the primary tumors, homozygous deletions of both CDKN2 and MTS2 were found in 35% of the T-ALL/lymphoblastic lymphoma (8 of 23). Homozygous deletions of both genes also occurred in 1 of 3 precursor B-ALLs. PCR-single strand conformational polymorphism analysis of CDKN2 exons 2 and 3 and MTS2 exon 2 failed to demonstrate mutations in either CDKN2 or MTS2 in any of the T- or B-cell malignancies, with two possible exceptions. These results are consistent with a role for CDKN2 and/or MTS2 in the pathogenesis of some lymphoid leukemia/lymphomas, particularly in T-ALL/lymphoblastic lymphoma.
Assuntos
Deleção de Genes , Leucemia Linfocítica Crônica de Células B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Sequência de Bases , Southern Blotting , DNA de Neoplasias/análise , DNA de Neoplasias/genética , Humanos , Linfoma de Células B/genética , Linfoma de Células T/genética , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Células Tumorais CultivadasRESUMO
Our previous studies of the translocated MYC gene in Burkitt's lymphoma showed the existence of clustered somatic mutations located in the transcriptional activation domain. We now report that aggressive lymphomas arising in the acquired immunodeficiency syndrome (AIDS) contain similar mutations and that the presence of mutations is correlated with the rearrangement of the oncogene. Mutations were also found in other de novo non-AIDS, non-Burkitt's aggressive lymphomas with MYC rearrangements. An unusual asparagine to serine mutation at codon 11 was identified in several transformed follicular lymphomas without MYC rearrangement but not in normal tissues from patients with this mutation. These findings indicate that AIDS-associated and other de novo aggressive lymphomas with the MYC gene rearrangement are subject to the same mutation and selection process that affects Burkitt's lymphomas.
Assuntos
Genes myc/genética , Linfoma Relacionado a AIDS/genética , Linfoma não Hodgkin/genética , Mutação Puntual/genética , Sequência de Aminoácidos , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Imunoblástico de Células Grandes/genética , Dados de Sequência MolecularRESUMO
We have conducted a clinical trial utilizing anti-thymocyte globulin (ATG) for the treatment of patients with non-Hodgkin's lymphomas. Six patients were treated; 50% reductions in tumor mass of short duration were observed in one patient with a T-cell lymphoma and two patients with B-cell lymphomas. In vitro assays have been performed in an attempt to study the reactivity and potential mechanism of antitumor action of the ATG. The ATG bound to essentially all normal blood mononuclear leukocytes as well as tumor cells from patients with T-, B-, or null cell lymphomas demonstrating its lack of specificity. Furthermore, complement-mediated lysis of normal mononuclear leukocytes, normal T- or B-cells, and tumor cells from two unresponsive patients were all comparable; moreover, since this lysis occurred only at concentrations of ATG that are not attainable in vivo, it is unlikely that complement-mediated cytotoxicity accounts for the responses observed. Peripheral blood lymphocyte counts and total erythrocyte rosettes did decrease during ATG treatment. Thus, objective tumor responses in both B- and T-cell non-Hodgkin's lymphomas can be achieved with a very nonspecific antiserum although significant toxicity resulted. Whether the magnitude or duration of response can be increased with monoclonal antibodies remains to be determined. Future success with serotherapy might require use of either a battery of different monoclonal antibodies or a single monoclonal antibody that can deliver radioisotopes, chemotherapy, or toxins to the tumor cells.
Assuntos
Soro Antilinfocitário/uso terapêutico , Linfoma/terapia , Adolescente , Adulto , Citotoxicidade Celular Dependente de Anticorpos , Linfócitos B/imunologia , Membrana Celular/imunologia , Ensaios Clínicos como Assunto , Feminino , Imunofluorescência , Seguimentos , Humanos , Imunoglobulinas/análise , Linfoma/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Linfócitos T/imunologiaRESUMO
Eleven cases of lymphoblastic malignancy, presenting as lymphoma, were investigated for immunological and differentiation markers prior to the onset of therapy. Biopsy specimens exhibited the typical morphological features of lymphoblastic lymphoma (convoluted T-cell lymphoma). Intranuclear terminal deoxynucleotidyl transferase was detected in the neoplastic cells from each case by indirect antibody staining of cytocentrifuge preparations. Eight cases were T-cell type as evidenced by unsensitized sheep erythrocyte rosette formation and staining with the monoclonal antibody OKT11. Three T-cell cases were OKT4 positive, two were OKT8 positive, and none were positive with both OKT4 and OKT8. Three cases failed to react with any monoclonal antibodies specific for T-cells and did not form unsensitized sheep erythrocyte rosettes or stain for surface immunoglobulin. However, these three cases were Ia positive and J5 (common acute lymphoblastic leukemia antigen) positive. Cells from two of these erythrocyte rosette-negative, Ia-positive, common acute lymphoblastic leukemia-positive cases contained intracytoplasmic mu heavy chains and were therefore of pre-B-cell phenotype. These cases were histologically indistinguishable from the T-cell cases. However, clinically, they were distinguished by the absence of mediastinal masses and by a clinical presentation as isolated lytic lesions of bone in two of the three. OKT9 and OKT10 stained neoplastic cells from T-cell, as well as pre-B-lymphoblastic, lymphoma. Although morphologically homogeneous, lymphoblastic lymphomas are comprised of an immunologically diverse group of neoplasms which include cells of "common" and "mature" thymocyte, non-T, non-B, and pre-B phenotypes and are closely related to the cells of acute lymphoblastic leukemia. In addition, intratumor heterogeneity was observed in most instances and may reflect growth or differentiation differences between subpopulations of individual neoplastic clones.
Assuntos
Epitopos/análise , Linfoma não Hodgkin/imunologia , Adolescente , Adulto , Anticorpos Monoclonais , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Linfonodos/imunologia , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Fenótipo , Linfócitos T/imunologiaRESUMO
Cells from spleens and lymph nodes infiltrated with neoplastic well-differentiated lymphocytes (WDLT) were investigated for the presence of receptors for unsensitized sheep red blood cells, complement (IgM EAC), and antigen-antibody complexes, as well as for the presence of surface immunoglobulins. In addition, the cells were examined by scanning electron microscopy (SEM). The surface markers and ultrastructure of WDLT cells were compared with those of cells obtained from peripheral blood of patients with chronic lymphocytic leukemia (CLL). Like the CLL populations, most WDLT samples showed a low percentage of unsensitized sheep red blood cell-binding cells and a concomitantly high percentage of IgM EAC-binding cells. Furthermore, a substantial number of WDLT cells in several instances showed a lower binding affinity for IgM EAC than normal lymphocytes, as demonstrated by the poor attachment of the IgM EAC reagent to the WDLT cells in suspension and to frozen tissue sections. Weak IgM EAC binding capacity was demonstrated in the CLL cells as well. WDLT and CLL cells bound the IgG EA complex only when certain sensitive techniques were applied (pelleting). A variable percentage of cells with surface immunoglobulins was found among WDLT and DLL populations. However, accurate counting of surface immunoglobulin-bearing neoplastic cells was very difficult in most cases due to the extremely faint surface fluorescence as compared to normal. SEM did not reveal specific changes in WDLT or CLL cells that would permit their identification as neoplastic lymphocytes. No major differences were found between WDLT and CLL cells and no correlation could be established between SEM appearances and surface markers. As previously observed with other cell populations, the conditions under which the cells were manipulated before fixation (in particular the environmental temperature) seemed to play a major role in the final SEM appearance of both WDLT and CLL cells. The results of our studies indicate that WDLT cells represent a population of B-cells whose surface properties are very similar to those of circulating CLL cells. The poor capacity of WDLT cells and CLL cells to bind IGM EAC or to stain with fluorescein-conjugated antihuman immunoglobulin suggests low density or poor affinity of the surface receptors. In this regard, these neoplastic cells are different from those of follicular lymphomas, also of B-cell origin.