RESUMEN
BACKGROUND: Plasmablastic lymphoma (PBL) is a rare and aggressive B-cell lymphoma strongly associated with human immunodeficiency virus (HIV) infection. The authors conducted a multi-institutional, retrospective study to describe characteristics and determine prognostic factors in HIV-associated PBL. METHODS: For this study, the investigators included consecutive, HIV-positive patients diagnosed between the years 2000 and 2010 whose tumors had a plasmablastic morphology, were cluster of differentiation 20 (CD20)-negative, and expressed markers of plasmacytic differentiation. RESULTS: Fifty patients from 13 institutions were evaluated. The median age was 43 years, and there was a male predominance. The median count of cells that were positive for CD4 (a glycoprotein expressed on the surface of T-helper cells, monocytes, macrophages, and dendritic cells) was 206 cells/mm(3) . At presentation, 90% of patients had extranodal involvement, 69% presented with advanced stage disease, and 27% had oral involvement. Rearrangements of v-myc myelocytomatosis viral oncogene homolog (MYC) were detected in 41% of the tested patients. Eighty-five percent of patients received chemotherapy, with 63% receiving cyclophosphamide, doxorubicin, vincristine, and prednisone and 37% receiving more intensive regimens. The complete response (CR) rate was 66%. The median overall survival (OS) was 11 months regardless of the intensity of chemotherapy. In the survival analysis, an Eastern Cooperative Oncology Group performance status ≥2, advanced stage, and MYC rearrangements were associated significantly with a worse outcome, whereas attaining a CR with chemotherapy was associated with a better outcome. CONCLUSIONS: The prognosis of PBL in HIV-infected individuals remains poor in the highly active antiretroviral therapy era. Intensive chemotherapy regimens do not seem to increase survival in patients with HIV-associated PBL. Cancer 2012.
Asunto(s)
Infecciones por VIH/complicaciones , Linfoma Relacionado con SIDA/tratamiento farmacológico , Linfoma de Células B/complicaciones , Adulto , Anciano , Terapia Antirretroviral Altamente Activa , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Linfoma Relacionado con SIDA/diagnóstico , Linfoma Relacionado con SIDA/patología , Linfoma de Células B/diagnóstico , Linfoma de Células B/patología , Masculino , Persona de Mediana Edad , Pronóstico , Adulto JovenRESUMEN
Inactivation of Ataxia-telangiectasia mutated (ATM) gene results in an increased risk to develop cancer. We show that ATM deficiency in diffuse large B-cell lymphoma (DLBCL) significantly induce mitochondrial deacetylase sirtuin-3 (SIRT3) activity, disrupted mitochondrial structure, decreased mitochondrial respiration, and compromised TCA flux compared with DLBCL cells expressing wild type (WT)-ATM. This corresponded to enrichment of glutamate receptor and glutamine pathways in ATM deficient background compared to WT-ATM DLBCL cells. ATM-/- DLBCL cells have decreased apoptosis in contrast to radiosensitive non-cancerous A-T cells. In vivo studies using gain and loss of SIRT3 expression showed that SIRT3 promotes growth of ATM CRISPR knockout DLBCL xenografts compared to wild-type ATM control xenografts. Importantly, screening of DLBCL patient samples identified SIRT3 as a putative therapeutic target, and validated an inverse relationship between ATM and SIRT3 expression. Our data predicts SIRT3 as an important therapeutic target for DLBCL patients with ATM null phenotype.
Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/deficiencia , Proteínas de la Ataxia Telangiectasia Mutada/genética , Linfoma de Células B Grandes Difuso/genética , Sirtuina 3/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Línea Celular Tumoral , Ciclo del Ácido Cítrico , Proteína Forkhead Box O3/metabolismo , Humanos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Modelos Biológicos , Consumo de Oxígeno , Sirtuina 1/metabolismoRESUMEN
Systemic mastocytosis is a stem cell disorder characterized histologically by the presence of multifocal compact aggregates of mast cells in at least one extracutaneous organ with or without evidence of skin lesions. The mast cell aggregates are accompanied by fibrosis, which is often significant. However, in spite of its frequent occurrence and severity, little is known about its characteristics. In this study, we evaluated the composition of the fibrotic mast cell aggregates by studying eight bone marrow biopsies and two spleens involved by systemic mastocytosis, and compared the findings with those observed in other fibrotic bone marrow disorders such as primary myelofibrosis and metastatic malignancy. Histochemistry and immunohistochemistry were used to evaluate: (a) extracellular matrix (reticulin, trichrome, collagen IV, laminin); (b) stromal reticulum cells (low-affinity nerve growth factor receptor); (c) presence of myofibroblastic differentiation (smooth muscle actin) and (d) microvessel density (CD34). We found that all cases showed marked reticulin and collagen fibrosis. However, unlike primary myelofibrosis and metastatic malignancy, which are usually associated with increased low-affinity nerve growth factor receptor positivity, its expression was low in all cases of systemic mastocytosis. Myofibroblastic differentiation was only focally detected in two of eight bone marrow biopsies. In all cases, the systemic mastocytosis lesions were largely devoid of type IV collagen and laminin. The latter findings were in contrast with those seen in cases of primary myelofibrosis and metastatic malignancy where smooth muscle actin, collagen IV and laminin were expressed in most cases. Also in contrast with the other two conditions, only minimal vascularity was detectable within the fibrotic mast cell lesions. These findings indicate that systemic mastocytosis exhibits a distinct pattern of stromal change, and suggest that the fibrogenetic mechanism in systemic mastocytosis is most likely different from that of other bone marrow neoplasms which are also associated with fibrosis.
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Médula Ósea/patología , Mastocitos/patología , Mastocitosis Sistémica/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Médula Ósea/irrigación sanguínea , Médula Ósea/metabolismo , Agregación Celular/fisiología , Femenino , Fibrosis , Humanos , Masculino , Mastocitos/metabolismo , Mastocitosis Sistémica/metabolismo , Microvasos/metabolismo , Microvasos/patología , Persona de Mediana Edad , Bazo/irrigación sanguínea , Bazo/metabolismo , Bazo/patología , Células del Estroma/metabolismo , Células del Estroma/patologíaRESUMEN
Altered lipid metabolism and aberrant protein translation are strongly associated with cancerous outgrowth; however, the inter-regulation of these key processes is still underexplored in diffuse large B-cell lymphoma (DLBCL). Although fatty acid synthase (FASN) activity is reported to positively correlate with PI3K-Akt-mTOR pathway that can modulate protein synthesis, the precise impact of FASN inhibition on this process is still unknown. Herein, we demonstrate that attenuating FASN expression or its activity significantly reduces eIF4B (eukaryotic initiation factor 4B) levels and consequently overall protein translation. Through biochemical studies, we identified eIF4B as a bonafide substrate of USP11, which stabilizes and enhances eIF4B activity. Employing both pharmacological and genetic approaches, we establish that FASN-induced PI3K-S6Kinase signaling phosphorylates USP11 enhancing its interaction with eIF4B and thereby promoting oncogenic translation.
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Factores Eucarióticos de Iniciación/genética , Acido Graso Sintasa Tipo I/genética , Regulación Neoplásica de la Expresión Génica , Biosíntesis de Proteínas , Proteínas Quinasas S6 Ribosómicas/genética , Tioléster Hidrolasas/genética , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Línea Celular Tumoral , Factores Eucarióticos de Iniciación/metabolismo , Acido Graso Sintasa Tipo I/metabolismo , Femenino , Humanos , Metabolismo de los Lípidos/genética , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Unión Proteica , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Quinasas S6 Ribosómicas/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Tioléster Hidrolasas/metabolismoRESUMEN
Aggressive natural killer cell leukemia (ANKL) is a systemic NK-cell neoplasm, almost always associated with Epstein-Barr virus (EBV). Rare cases of EBV-negative ANKL have been described, and some reports suggested more indolent behavior. We report the clinicopathologic, immunophenotypic, and molecular characteristics of 7 EBV-negative ANKL. All patients were adults, with a median age of 63 years (range 22 to 83 y) and an M:F ratio of 2.5:1. Five patients were White, 1 Black, and 1 Asian. All patients presented acutely, with fever (6/7), cytopenias (6/7), and splenomegaly (4/7). Four patients had lymphadenopathy, 4 had extranodal disease. Bone marrow involvement was present in 5, with hemophagocytosis in 3. Peripheral blood was involved in 5 with the neoplastic cells containing prominent azurophilic granules. By immunohistochemistry and/or flow cytometry, the tumor cells lacked surface CD3 and were positive for CD56 (7/7), CD2 (5/5), CD8 (3/7), CD30 (4/5), and granzyme-B (6/6). They were negative for CD4, CD5, ßF1, TCRγ, LMP1, and EBV-encoded RNA. Polymerase chain reaction for TCRG clonality was polyclonal. Mutational analysis revealed missense mutations in the STAT3 gene in both cases studied. Median survival was 8 weeks from the onset of disease. One patient received allogeneic bone marrow transplant and is alive with no disease (follow-up 15 mo). EBV-negative ANKL exists but is rare. It tends to occur in older patients and is indistinguishable clinically and pathologically from EBV-positive ANKL, with a similar fulminant clinical course. The high prevalence of Asian patients seen with EBV-positive disease seems less evident with EBV-negative cases.
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Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/patología , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Infecciones por Virus de Epstein-Barr , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Inmunofenotipificación , Hibridación in Situ , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Adulto JovenRESUMEN
BACKGROUND: Localized amyloidosis of the larynx is a rare entity of unclear etiology. Surgical debulking is the primary treatment modality but often is not curative. METHODS AND RESULTS: A 41-year-old woman presenting with increasing hoarseness, dysphagia, dyspnea, and weight loss was found to have a submucosal mass in the left false vocal fold. Biopsy of the specimen revealed amyloid. After negative work-up for systemic disease, the patient underwent surgical debulking. Specimens revealed a population of clonal plasma cells demonstrating lambda restriction. The patient was treated with adjuvant external beam radiation to a dose of 45 Gy. At 11 months, the patient's voice, breathing, and swallowing have all improved substantially. CONCLUSIONS: Recent pathologic studies suggest that localized amyloidosis of the larynx is caused by a localized, nonmalignant plasma cell disorder. Because full resection is difficult, we recommend a combination of surgery and radiation therapy to cure this disease.