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INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome characterized by an excessive immune activation. Glycosylated ferritin (GF) level has been proposed as highly specific of HLH. METHODS: We have studied 12 subjects with HLH according to the HLH-04 trial criteria and 11 patients with a clinical and laboratoristic suspicion of HLH. The percentage of GF was measured by an in-house assay. RESULTS: The only biomarkers that were significantly different in the two groups were fraction of GF (P<.001) and the presence of hemophagocytosis in bone marrow (P=.006). Subjects with HLH had significantly lower percentage of GF than patients with other inflammatory conditions mimicking HLH. A fraction of GF ≤20% was strongly consistent with a diagnosis of HLH. CONCLUSIONS: Fraction of GF is useful to identify subjects at high risk for early death and therefore in need of early treatment.
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Ferritinas/sangre , Linfohistiocitosis Hemofagocítica/sangre , Linfohistiocitosis Hemofagocítica/diagnóstico , Adulto , Anciano , Femenino , Glicosilación , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Protein kinase CK2 sustains acute myeloid leukemia cell growth, but its role in leukemia stem cells is largely unknown. Here, we discovered that the CK2 catalytic α and regulatory ß subunits are consistently expressed in leukemia stem cells isolated from acute myeloid leukemia patients and cell lines. CK2 inactivation with the selective inhibitor CX-4945 or RNA interference induced an accumulation of leukemia stem cells in the late S-G2-M phases of the cell cycle and triggered late-onset apoptosis. As a result, leukemia stem cells displayed an increased sensitivity to the chemotherapeutic agent doxorubicin. From a molecular standpoint, CK2 blockade was associated with a downmodulation of the stem cell-regulating protein BMI-1 and a marked impairment of AKT, nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) activation, whereas FOXO3a nuclear activity was induced. Notably, combined CK2 and either NF-κB or STAT3 inhibition resulted in a superior cytotoxic effect on leukemia stem cells. This study suggests that CK2 blockade could be a rational approach to minimize the persistence of residual leukemia cells.
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Quinasa de la Caseína II/metabolismo , Leucemia Mieloide Aguda/metabolismo , FN-kappa B/metabolismo , Células Madre Neoplásicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/metabolismo , Adenosina Trifosfato/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Biomarcadores , Quinasa de la Caseína II/antagonistas & inhibidores , Quinasa de la Caseína II/genética , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Expresión Génica , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Complejo Represivo Polycomb 1/genética , Complejo Represivo Polycomb 1/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Transducción de SeñalRESUMEN
Genetic mutations of oncogenes often underlie deranged cell growth and altered differentiation pathways leading to malignant transformation of B-lymphocytes. However, addiction to oncogenes is not the only drive to lymphoid tumor pathogenesis. Dependence on non-oncogenes, which act by propelling basic mechanisms of cell proliferation and survival, has also been recognized in the pathobiology of lymphoid leukemias, lymphomas and multiple myeloma. Among the growing number of molecules that may uphold non-oncogene addiction, a key place is increasingly being recognized to the serine-threonine kinase CK2. This enzyme is overexpressed and overactive in B-acute lymphoblastic leukemia, multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin lymphomas, such as mantle cell, follicular, Burkitt's and diffuse large B-cell lymphomas. In these tumors, CK2 may serve the activity of oncogenes, similar to BCR-ABL and c-MYC, control the activation of critical signaling cascades, such as NF-κB (nuclear factor-κB), STAT3 (signal transducer and activator of transcription 3) and PTEN/PI3K/AKT (phosphatase and tensin homolog protein/phosphoinositide 3-kinase/AKR thymoma), and sustain multiple cellular stress-elicited pathways, such as the proteotoxic stress, unfolded protein and DNA-damage responses. CK2 has also been shown to have an essential role in tuning signals derived from the stromal tumor microenvironment. Not surprisingly, targeting CK2 in lymphoid tumor cell lines or mouse xenograft models can boost the cytotoxic effects of both conventional chemotherapeutics and novel agents, similar to heat-shock protein 90, proteasome and tyrosine kinases inhibitors. In this review, we summarize the evidence indicating how CK2 embodies most of the features of a cancer growth-promoting non-oncogene, focusing on lymphoid tumors. We further discuss the preclinical data of the use of small ATP-competitive CK2 inhibitors, which hold the promise to be additional options in novel drug combinations for the therapy of lymphoid and plasmacellular malignancies.
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Quinasa de la Caseína II/genética , Quinasa de la Caseína II/metabolismo , Leucemia de Células B/genética , Leucemia de Células B/metabolismo , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Animales , Linfocitos B/metabolismo , Linfocitos B/patología , Biomarcadores de Tumor , Proliferación Celular , Supervivencia Celular/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Oncogenes , Transducción de SeñalRESUMEN
Salinomycin, isolated from Streptomyces albus, displays antimicrobial activity. Recently, a large-scale screening approach identified salinomycin and nigericin as selective apoptosis inducers of cancer stem cells. Growing evidence suggests that salinomycin is able to kill different types of non-stem tumor cells that usually display resistance to common therapeutic approaches, but the mechanism of action of this molecule is still poorly understood. Since salinomycin has been suggested to act as a K(+) ionophore, we explored its impact on mitochondrial bioenergetic performance at an early time point following drug application. In contrast to the K(+) ionophore valinomycin, salinomycin induced a rapid hyperpolarization. In addition, mitochondrial matrix acidification and a significant decrease of respiration were observed in intact mouse embryonic fibroblasts (MEFs) and in cancer stem cell-like HMLE cells within tens of minutes, while increased production of reactive oxygen species was not detected. By comparing the chemical structures and cellular effects of this drug with those of valinomycin (K(+) ionophore) and nigericin (K(+)/H(+) exchanger), we conclude that salinomycin mediates K(+)/H(+) exchange across the inner mitochondrial membrane. Compatible with its direct modulation of mitochondrial function, salinomycin was able to induce cell death also in Bax/Bak-less double-knockout MEF cells. Since at the concentration range used in most studies (around 10 µM) salinomycin exerts its effect at the level of mitochondria and alters bioenergetic performance, the specificity of its action on pathologic B cells isolated from patients with chronic lymphocytic leukemia (CLL) versus B cells from healthy subjects was investigated. Mesenchymal stromal cells (MSCs), proposed to mimic the tumor environment, attenuated the apoptotic effect of salinomycin on B-CLL cells. Apoptosis occurred to a significant extent in healthy B cells as well as in MSCs and human primary fibroblasts. The results indicate that salinomycin, when used above µM concentrations, exerts direct, mitochondrial effects, thus compromising cell survival.
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Antibióticos Antineoplásicos/farmacología , Mitocondrias/efectos de los fármacos , Piranos/farmacología , Equilibrio Ácido-Base , Animales , Respiración de la Célula , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Fibroblastos/efectos de los fármacos , Fibroblastos/fisiología , Humanos , Células Jurkat , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Nigericina/farmacología , Consumo de Oxígeno , Valinomicina/farmacologíaRESUMEN
BACKGROUND: TNF-like ligand 1A (TL1A), a recently recognized member of the TNF superfamily, and its death domain receptor 3 (DR3), firstly identified for their relevant role in T lymphocyte homeostasis, are now well-known mediators of several immune-inflammatory diseases, ranging from rheumatoid arthritis to inflammatory bowel diseases to psoriasis, whereas no data are available on their involvement in sarcoidosis, a multisystemic granulomatous disease where a deregulated T helper (Th)1/Th17 response takes place. METHODS: In this study, by flow cytometry, real-time PCR, confocal microscopy and immunohistochemistry analyses, TL1A and DR3 were investigated in the pulmonary cells and the peripheral blood of 43 patients affected by sarcoidosis in different phases of the disease (29 patients with active sarcoidosis, 14 with the inactive form) and in 8 control subjects. RESULTS: Our results demonstrated a significant higher expression, both at protein and mRNA levels, of TL1A and DR3 in pulmonary T cells and alveolar macrophages of patients with active sarcoidosis as compared to patients with the inactive form of the disease and to controls. In patients with sarcoidosis TL1A was strongly more expressed in the lung than the blood, i.e., at the site of the involved organ. Additionally, zymography assays showed that TL1A is able to increase the production of matrix metalloproteinase 9 by sarcoid alveolar macrophages characterized, in patients with the active form of the disease, by reduced mRNA levels of the tissue inhibitor of metalloproteinase (TIMP)-1. CONCLUSIONS: These data suggest that TL1A/DR3 interactions are part of the extended and complex immune-inflammatory network that characterizes sarcoidosis during its active phase and may contribute to the pathogenesis and to the progression of the disease.
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BACKGROUND: The 2008 World Health Organization (WHO) classification distinguishes three entities among the large granular lymphocytic leukemia (LGL leukemia): T-cell LGL leukemia (T-LGL leukemia), aggressive natural killer (NK) cell leukemia, and chronic NK lymphoproliferative disorders (LPD), the later considered as a provisional entity. Only a few and small cohorts of chronic NK LPD have been published. PATIENTS AND METHODS: We report here clinicobiological features collected retrospectively from 70 cases of chronic NK LPD, and compared with those of T-LGL leukemia. RESULTS: There were no statistical differences between chronic NK LPD and T-LGL leukemia concerning median age [61 years (range 23-82 years)], organomegaly (26%), associated autoimmune diseases (24%), and associated hematological malignancies (11%). Patients with chronic NK LPD were significantly less symptomatic (49% versus 18%, P < 0.001) and the association with rheumatoid arthritis was more rarely observed (7% versus 17%, P = 0.03). The neutropenia (<0.5 × 10(9)/l) was less severe in chronic NK LPD (33% versus 61%, P < 0.001) without difference in the rate of recurrent infections. STAT3 mutation was detected in 12% of the cohort, which is lower than the frequency observed in T-LGL leukemia. Thirty-seven percent of the patients required specific therapy. Good results were obtained with cyclophosphamide. Overall and complete response rates were, respectively, 69% and 56%. Overall survival was 94% at 5 years. CONCLUSION: This study suggests very high similarities between chronic NK LPD and T-LGL leukemias. Since chronic NK LPD is still a provisional entity, our findings should be helpful when considering further revisions of the WHO classification.
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Células Asesinas Naturales/patología , Leucemia Linfocítica Granular Grande/patología , Trastornos Linfoproliferativos/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Leucemia Linfocítica Granular Grande/clasificación , Leucemia Linfocítica Granular Grande/genética , Trastornos Linfoproliferativos/clasificación , Trastornos Linfoproliferativos/genética , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factor de Transcripción STAT3/genética , Organización Mundial de la SaludAsunto(s)
Células de la Médula Ósea/citología , Quinasa de la Caseína II/metabolismo , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/metabolismo , Osteoclastos/citología , Antineoplásicos/química , Supervivencia Celular , Citocinas/metabolismo , Silenciador del Gen , Humanos , Interleucina-6/metabolismo , Osteoblastos/citología , Fosforilación , Receptores CXCR4/metabolismo , Células del Estroma/citología , Factor de Necrosis Tumoral alfa/metabolismoAsunto(s)
Clofazimina/uso terapéutico , Ficusina/uso terapéutico , Canal de Potasio Kv1.3/antagonistas & inhibidores , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Bloqueadores de los Canales de Potasio/uso terapéutico , Clofazimina/farmacología , Ficusina/farmacología , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Proteínas Asociadas a Pancreatitis , Bloqueadores de los Canales de Potasio/farmacologíaRESUMEN
CK2 is a multitask kinase whose role is essential for a countless number of cellular processes, many of which are critical for blood cell development. A prevailing task for this kinase rests on counteracting programmed cell death triggered by multiple stimuli. CK2 is overexpressed in many solid tumors and in vivo mouse models have proven its tumorigenic potential. Recent data have suggested that CK2 may also have a significant role in the pathogenesis of hematopoietic tumors, such as multiple myeloma, chronic lymphocytic leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia and chronic myeloproliferative neoplasms. CK2 regulates hematopoiesis-associated signaling pathways and seems to reinforce biochemical cascades indispensable for tumor growth, proliferation and resistance to conventional and novel cytotoxic agents. Although its activity is multifold, recent evidence supports the rationale of CK2 inhibition as a therapeutic strategy in solid and hematological tumors and phase-I clinical trials are in progress to test the efficacy of this innovative therapeutic approach. In this review, we will summarize the data supporting CK2 as an oncogenic kinase in blood tumors and we will describe some critical signaling pathways, whose regulation by this protein kinase may be implicated in tumorigenesis.
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Quinasa de la Caseína II/metabolismo , Transformación Celular Neoplásica/patología , Neoplasias Hematológicas/etiología , Neoplasias Hematológicas/patología , Oncogenes/fisiología , Transducción de Señal , Animales , Supervivencia Celular , Neoplasias Hematológicas/enzimología , Humanos , RatonesRESUMEN
The recently updated World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, published in 2008, has made great advances in revising the disorders previously included in the pool of natural killer (NK) cell tumors. Although NK cell neoplasms represent a relatively rare group of diseases, accounting for <5% of all lymphoid neoplasms, they include very distinctive conditions both clinically and pathologically. This family of diseases includes the most indolent clinical forms, such as the provisional new entry of chronic lymphoproliferative disorder of NK cells (CLPD-NK) in the WHO classification, as well as one of the most fatal diseases recognized in medical oncology, aggressive NK cell leukemia (ANKL), which is characterized by a prognosis of weeks, or even days. In addition, some disorders previously identified as blastic NK cell lymphoma within the NK cell system have been more properly defined and included in the blastic plasmacytoid dentritic cell neoplasms, although rare cases of bona fide immature NK lymphoid tumors (now classified as NK cell lymphoblastic leukemia/lymphoma) have been reported in the literature. This paper focuses on recent concepts and progress in morphology, pathogenesis, clinicopathological features, treatment approaches, and outcomes of NK cell malignancies.
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Células Asesinas Naturales/patología , Leucemia Linfoide/patología , Linfoma/patología , Humanos , Leucemia Linfoide/clasificación , Linfoma/clasificación , Pronóstico , Organización Mundial de la SaludRESUMEN
BACKGROUND: The best therapeutic approach for primary plasma cell leukemia (PPCL) remains unknown so far. In very limited studies, the poor clinical outcome of this aggressive variant of multiple myeloma seemed to be ameliorated by the use of the proteasome inhibitor bortezomib. Aiming to provide more consolidated data, this multicenter retrospective survey focused on unselected and previously untreated PPCL patients who had received bortezomib as frontline therapy. PATIENTS AND METHODS: Twenty-nine patients with PPCL were collected. Bortezomib was given at standard doses and schedules, in various combinations with dexamethasone, thalidomide, doxorubicin, melphalan, prednisone, vincristine, and cyclophosphamide. RESULTS: An overall response rate of 79% was observed, with 38% of at least very good partial remission. Grade 3-4 hematological, neurological, infectious, and renal toxic effects occurred in 20%, 21%, 16%, and 4% of patients, respectively. After a median follow-up of 24 months, 16 patients were alive (55%), 12 of whom were in remission phase and 4 relapsed. The best long-term results were achieved in patients who received stem-cell transplantation after bortezomib induction. CONCLUSION: Bortezomib, used as initial therapy, is able to increase the percentage and the quality of responses in PPCL patients, producing a significant improvement of survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia de Células Plasmáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Ácidos Borónicos/administración & dosificación , Bortezomib , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia de Células Plasmáticas/mortalidad , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Prednisona/administración & dosificación , Pirazinas/administración & dosificación , Estudios Retrospectivos , Talidomida/administración & dosificación , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
In B-cell chronic lymphocytic leukemia (B-CLL) cells, Lyn, a tyrosine kinase belonging to the Src family, is overexpressed and atypically localized in an aberrant cytosolic complex in an active conformation, contributing to the unbalance between cell survival and pro-apoptotic signals. In this study, we demonstrate that Lyn constitutively phosphorylates the immunoreceptor tyrosine inhibitory motifs of the inhibitory cell surface co-receptor CD5, a marker of B-CLL. As a result, CD5 provides an anchoring site to Src homology 2 domain-containing phosphatase 1 (SHP-1), a known negative regulator of hematopoietic cell function, thereby triggering the negative B-cell receptor (BCR) signaling. The subsequent segregation of SHP-1 into two pools, one bound to the inhibitory co-receptor CD5 in an active form, the other in the cytosol in an inhibited conformation, proves crucial for withstanding apoptosis, as shown by the use of phosphotyrosine phosphatase-I-I, a direct inhibitor of SHP-1, or SHP-1 knockdown. These results confirm that Lyn exhibits the unique ability to negatively regulate BCR signaling, in addition to positively regulating effectors downstream of the BCR, and identify SHP-1 as a novel player in the deranged signaling network and as a potential attractive target for new therapeutic strategies in B-CLL.
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Apoptosis , Antígenos CD5/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Familia-src Quinasas/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Compartimento Celular , Femenino , Citometría de Flujo , Humanos , Inmunoprecipitación , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Persona de Mediana Edad , Fosforilación , Fracciones Subcelulares/metabolismo , Dominios Homologos srcRESUMEN
B-chronic lymphocytic leukemia (B-CLL) is a malignant disorder characterized by the accumulation of the leukemic cells in the G0-G1 phase of the cell cycle and expressing high levels of the anti-apoptotic protein Bcl-2. Since we observed that the treatment of autoimmune complications with Cyclosporine A (CsA) determined in some CLL patients an improvement not only of the autoimmune phenomena, but also of the leukemic process, we evaluated the in vitro cytotoxicity of CsA as compared to Dexamethasone (Dex) on leukemic cells. Leukemic cells obtained from 32 B-CLL patients showed a heterogeneous pattern of spontaneous apoptosis at 24 h interval and this pattern permitted to identify: Group 1 (14/32) with high (>20%) apoptotic rate and Group 2 (18/32) with low cell death. CsA and Dex increased cell death in both groups with a different timing by an apoptotic mechanism that does not involve Bcl-2. Furthermore, in Group 2, CsA-induced apoptosis was significant higher than that observed with Dex both at 4 and 24 h. We suggest that, in B-CLL, CsA has a significant pro-apoptotic activity manifested also in patients with low spontaneous apoptosis. Our observations might be taken into account to consider new therapeutic strategies in B-CLL.
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Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Ciclosporina/farmacología , Dexametasona/farmacología , Inmunosupresores/farmacología , Leucemia Linfocítica Crónica de Células B/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fase G1/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Fase de Descanso del Ciclo Celular/efectos de los fármacos , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
OBJECTIVES: We tested whether Behçet's disease (BD) is characterized by alterations of circulating endothelial progenitor cells (EPCs),which are involved in vascular homeostasis and repair. METHODS: We enrolled 30 BD patients and 27 matched healthy controls. EPCs were defined and measured by flow cytometry according to the expression of CD34, CD133 and KDR. RESULTS: We show that BD patients had significantly lower levels of CD34+KDR+ and CD34+CD133+KDR+ EPCs than controls. We found significant negative correlations between EPC phenotypes and BD duration, while there were positive correlations between CD34+KDR+ EPCs and both BD activity scores and C-reactive protein. The lower EPC levels with increasing disease duration was shown in univariate analysis and in multivariable analysis adjusted for possible confounders. CONCLUSION: This is the first report that BD is associated with progressive EPC decline. Reduction of EPCs may represent a mechanism of induction and/or progression of vascular injury in these patients.
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Síndrome de Behçet/sangre , Células Endoteliales/metabolismo , Células Madre/metabolismo , Antígeno AC133 , Adulto , Antígenos CD , Antígenos CD34 , Recuento de Células Sanguíneas , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Citometría de Flujo , Glicoproteínas , Humanos , Masculino , Péptidos , Índice de Severidad de la Enfermedad , Receptor 2 de Factores de Crecimiento Endotelial VascularRESUMEN
We report on the clinico-biological characteristics of 20 cases of gammadelta T cell large granular lymphocyte (LGL) leukemia. All the data were compared to that of 196 cases with alphabeta T cell subtype, which represents the majority of T cell LGL leukemias. Clinical findings were quite similar in the two groups regarding age, sex ratio, recurrent infections, and association with auto-immune diseases especially rheumatoid arthritis. Gammadelta LGL predominantly expressed a CD3+/CD4-/CD8+/CD16+/CD57+ phenotype, in 50% of cases. Clinical outcome was favorable for these patients with overall survival of 85% at 3 years. Fifty percent of gammadelta patients required treatment and the response to therapy was estimated at 55%. gammadelta and alphabeta T cell LGL leukemia harbor a very similar clinico-biological behavior and represent part of an antigen-driven T cell lymphoproliferation.
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Leucemia de Células T/diagnóstico , Receptores de Antígenos de Linfocitos T gamma-delta , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/complicaciones , Células Clonales , Femenino , Reordenamiento Génico de la Cadena gamma de los Receptores de Antígenos de los Linfocitos T , Humanos , Inmunofenotipificación , Leucemia de Células T/inmunología , Leucopenia/diagnóstico , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T alfa-beta , Esplenomegalia/diagnósticoAsunto(s)
Endocardio/patología , Neoplasias Cardíacas/patología , Leucemia Prolinfocítica de Células T/patología , Infiltración Leucémica/patología , Trombosis/patología , Anciano , Biopsia , Ecocardiografía , Electrocardiografía , Femenino , Atrios Cardíacos/patología , Neoplasias Cardíacas/diagnóstico por imagen , Humanos , Leucemia Prolinfocítica de Células T/diagnóstico por imagen , Infiltración Leucémica/diagnóstico por imagen , Trombosis/diagnóstico por imagenRESUMEN
Activation of telomerase reverse transcriptase (hTERT) is essential for unlimited cell growth and plays a critical role in tumorigenesis. We investigated hTERT gene expression in 134 B-cell chronic lymphocytic leukemia (B-CLL) cases and evaluated its prognostic value with other prognostic markers (IgVH mutation status, CD38 and ZAP-70 expression). Real-time PCR assays to quantify either all hTERT transcripts (AT) or only the full length (FL) transcript encoding the functional protein were developed. hTERT-AT levels strongly correlated with hTERT-FT levels (r=0.743, P<0.0001); both inversely correlated with the percentage of IgVH mutation (P<0.005) and were significantly higher in unmutated than in mutated cases (P=0.004 and P=0.001, respectively). The hTERT values which best discriminated between the unmutated and mutated IgVH cases were 150 and 40 copies for hTERT-AT and hTERT-FL, respectively. Using these cut-off values, there was a significant difference in the survival of patients with high or low hTERT levels (P<0.0001). Unmutated cases with low hTERT levels had an overall survival close to mutated cases with high hTERT levels. Thus, this work identifies hTERT-RNA level as a new prognostic marker in B-CLL, and may be used to identify previously unrecognized patient groups with the same IgVH mutation status and different disease outcomes.
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Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Telomerasa/genética , ADP-Ribosil Ciclasa 1/análisis , Adulto , Anciano , Linfocitos B/enzimología , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/enzimología , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Proteína Tirosina Quinasa ZAP-70/análisisRESUMEN
Using polymerase chain reaction (PCR)-based sequence-specific primers, the killer immunoglobulin-like receptor (KIR) genotypes of 35 patients with natural killer (NK)-type lymphoproliferative disease of granular lymphocytes and of 50 normal subjects were investigated to evaluate whether genes coding for activating KIRs were more frequently detected in patients with NK-lymphoproliferative disease of granular lymphocytes (LDGL). Genotype frequency indicated that the most frequently found gene content was eight genes in controls and 14 in patients (P<0.05). The KIR genotype analysis revealed that patient and, surprisingly, control KIR genotypes preferentially consisted of type B haplotypes characterized by the presence of multiple-activating KIRs. Evidence was also provided that the same KIR genotype was shared by a variable number of patients. Interestingly, the recurrent genotypes observed in the patient group were not found in controls. Concerning inhibitory genes, KIR2DL5a and 2DL5b were more frequently detected in patients than in controls (P<0.01), likely representing a discrete feature of the genetic repertoire of the patients. KIR gene repertoire analysis in patients suggests that the susceptibility to NK-LDGL might be related to the presence of activating KIR genes and supports the concept that these receptors may be involved in the priming of granular lymphocytes (GL) proliferation. Population analysis might disclose a genetic background predisposing to this disease.