Publications (13)92.09 Total impact
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Article: Vorinostat interferes with the signaling transduction pathway of T-cell receptor and synergizes with phosphoinositide-3 kinase inhibitors in cutaneous T-cell lymphoma.
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ABSTRACT: Vorinostat (suberoylanilide hydroxamic acid, SAHA), an inhibitor of class I and II histone deacetylases, has been approved for the treatment of cutaneous T-cell lymphoma. In spite of emerging information on the effect of vorinostat in many types of cancer, little is yet known about this drug's mechanism of action, which is essential for its proper use in combination therapy. We investigated alterations in gene expression profile over time in cutaneous T-cell lymphoma cells treated with vorinostat. Subsequently, we evaluated inhibitors of PI3K, PIM and HSP90 as potential combination agents in the treatment of cutaneous T-cell lymphoma. The genes significantly up- or down-regulated by vorinostat over different time periods (2-fold change, false discovery rate corrected P value<0.05) were selected using the short-time series expression miner. Cell viability was assessed in vitro in cutaneous T-cell lymphoma cells through measuring intracellular ATP content. Drug interactions were analyzed by the combination index method with CalcuSyn software. The functional analysis suggests that vorinostat modifies signaling of T-cell receptor, MAPK, and JAK-STAT pathways. The phosphorylation studies of ZAP70 (Tyr319, Tyr493) and its downstream target AKT (Ser473) revealed that vorinostat inhibits phosphorylation of these kinases. With regards to effects on cutaneous T-cell lymphoma cells, combining vorinostat with PI3K inhibitors resulted in synergy while cytotoxic antagonism was observed when vorinostat was combined with HSP90 inhibitor. These results demonstrate the potential targets of vorinostat, underlining the importance of T-cell receptor signaling inhibition following vorinostat treatment. Additionally, we showed that combination therapies involving histone deacetylase inhibitors and inhibitors of PI3K are potentially efficacious for the treatment of cutaneous T-cell lymphoma.Haematologica 04/2010; 95(4):613-21. · 6.42 Impact Factor -
Article: Functional signatures identified in B-cell non-Hodgkin lymphoma profiles.
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ABSTRACT: Gene-expression profiling in B-cell lymphomas has provided crucial data on specific lymphoma types, which can contribute to the identification of essential lymphoma survival genes and pathways. In this study, the gene-expression profiling data of all major B-cell lymphoma types were analyzed by unsupervised clustering. The transcriptome classification so obtained, was explored using gene set enrichment analysis generating a heatmap for B-cell lymphoma that identifies common lymphoma survival mechanisms and potential therapeutic targets, recognizing sets of coregulated genes and functional pathways expressed in different lymphoma types. Some of the most relevant signatures (stroma, cell cycle, B-cell receptor (BCR)) are shared by multiple lymphoma types or subclasses. A specific attention was paid to the analysis of BCR and coregulated pathways, defining molecular heterogeneity within multiple B-cell lymphoma types.Leukemia & lymphoma 10/2009; 50(10):1699-708. · 2.40 Impact Factor -
Article: TCL1A expression delineates biological and clinical variability in B-cell lymphoma.
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ABSTRACT: The assembly of a collection of gene-expression signatures of the major types of B-cell non-Hodgkin's lymphoma has identified increased T-cell leukemia/lymphoma 1A (TCL1) expression in multiple lymphoma types and cases, and has enabled the investigation of the functional and clinical importance of TCL1 expression. Specifically, Burkitt's lymphoma cases show a homogeneously strong expression of TCL1, whereas diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, nodal marginal zone lymphoma, and splenic marginal zone lymphoma display a striking variability in the intensity of TCL1 staining. This was validated in two independent series. A Gene-Set Enrichment Analysis of the genes correlated with TCL1A expression found that variation in the level of expression of TCL1A was significantly associated with some of the most important gene signatures recognizing B-cell lymphoma pathogenesis and heterogeneity, such as germinal center, B-cell receptor, NF-kappaB (and its target genes), death, MAP kinases, TNFR1, TOLL, and IL1R. Additionally, TCL1 expression was correlated with shorter time to treatment in chronic lymphocytic leukemia cases and shorter lymphoma-specific survival in mantle cell lymphoma series, thus indicating the clinical and biological significance of TCL1 expression, and suggesting TCL1A as a potential therapeutic target.Modern Pathology 10/2008; 22(2):206-15. · 4.79 Impact Factor -
Article: Somatic hypermutation signature in B-cell low-grade lymphomas.
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ABSTRACT: Immunoglobulin gene somatic hypermutation is a biologically relevant and clinically useful prognostic factor in different types of low-grade B-cell lymphomas, including chronic lymphocytic leukemia, mantle cell lymphoma and splenic marginal zone lymphoma. With the aim of identifying surrogate markers of somatic hypermutation, a combined investigation of IgV(H) mutational status and expression profiles of 93 samples from patients with small B-cell lymphoma was performed. The analysis identified an somatic hypermutation signature of genes involved in the regulation of gene transcription, DNA repair and replication, and chromosome maintenance. Eight of these genes were subjected to protein analysis using tissue microarrays, for a set of 118 cases. We found a clear link between RAD51C and CDK7 protein expression and somatic hypermutation status, in that positive expression of either marker was significantly associated with a mutated status (p<0.003). We also found that positive expression of TFDP1 and POLA was significantly associated with ongoing somatic hypermutation (p<0.001). To assess the potential clinical applicability of these somatic hypermutation markers, we studied a series of cases of mantle cell lymphoma included in a tissue microarray. The expression of RCC1 and CDK7, separately and together, was found to be significantly associated with longer overall survival. An somatic hypermutation signature has been identified for different types of small B-cell lymphoma. This has a potential mechanistic and diagnostic value.Haematologica 06/2008; 93(8):1186-94. · 6.42 Impact Factor -
Article: Inhibition of poly(ADP-ribose) polymerase modulates tumor-related gene expression, including hypoxia-inducible factor-1 activation, during skin carcinogenesis.
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ABSTRACT: Poly(ADP-ribose) polymerase (PARP)-1, an enzyme that catalyzes the attachment of ADP ribose to target proteins, acts as a component of enhancer/promoter regulatory complexes. In the present study, we show that pharmacologic inhibition of PARP-1 with 3,4-dihydro-5-[4-(1-piperidinyl)butoxyl]-1(2H)-isoquinolinone (DPQ) results in a strong delay in tumor formation and in a dramatic reduction in tumor size and multiplicity during 7,12-dimethylbenz(a)anthracene plus 12-O-tetradecanoylphorbol-13-acetate-induced skin carcinogenesis. This observation was parallel with a reduction in the skin inflammatory infiltrate in DPQ-treated mice and tumor vasculogenesis. Inhibition of PARP also affected activator protein-1 (AP-1) activation but not nuclear factor-kappaB (NF-kappaB). Using cDNA expression array analysis, a substantial difference in key tumor-related gene expression was found between chemically induced mice treated or not with PARP inhibitor and also between wild-type and parp-1 knockout mice. Most important differences were found in gene expression for Nfkbiz, S100a9, Hif-1alpha, and other genes involved in carcinogenesis and inflammation. These results were corroborated by real-time PCR. Moreover, the transcriptional activity of hypoxia-inducible factor-1alpha (HIF-1alpha) was compromised by PARP inhibition or in PARP-1-deficient cells, as measured by gene reporter assays and the expression of key target genes for HIF-1alpha. Tumor vasculature was also strongly inhibited in PARP-1-deficient mice and by DPQ. In summary, this study shows that inhibition of PARP on itself is able to control tumor growth, and PARP inhibition or genetic deletion of PARP-1 prevents from tumor promotion through their ability to cooperate with the activation AP-1, NF-kappaB, and HIF-1alpha.Cancer Research 07/2006; 66(11):5744-56. · 7.86 Impact Factor -
Article: The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells.
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ABSTRACT: One of the most exciting areas of current research in the cannabinoid field is the study of the potential application of these compounds as antitumoral drugs. Here, we describe the signaling pathway that mediates cannabinoid-induced apoptosis of tumor cells. By using a wide array of experimental approaches, we identify the stress-regulated protein p8 (also designated as candidate of metastasis 1) as an essential mediator of cannabinoid antitumoral action and show that p8 upregulation is dependent on de novo-synthesized ceramide. We also observe that p8 mediates its apoptotic effect via upregulation of the endoplasmic reticulum stress-related genes ATF-4, CHOP, and TRB3. Activation of this pathway may constitute a potential therapeutic strategy for inhibiting tumor growth.Cancer Cell 05/2006; 9(4):301-12. · 26.57 Impact Factor -
Article: P53 protein expression in lymphomas and reactive lymphoid tissue
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ABSTRACT: P53 is a tumour suppressor gene, located in the short arm of chromosome 17, which encodes for a nuclear protein involved in the control of cellular growth, regulating the entry of the cell into the S-phase. P53 mutations have been identified in a progressively increasing number of human malignancies. Nuclear p53 protein is usually present in non-tumour cells in minute concentrations, due to its short half-life. In contrast, tumours with p53 mRNA mutations show a higher nuclear protein concentration, detectable by immunohistological techniques, due to stabilization by complexing with other proteins such as heat-shock protein or wild-type p53 protein.Leveis of nuclear p53 protein detected by immunohistochemistry with the monoclonal antibody PAb 1801 were measured with the aid of an image analysis system in 83 non-Hodgkin's lymphomas (NHLs) and 13 cases of Hodgkin's disease, as well as in 14 cases of normal thymus, reactive tonsils, and lymphadenitis. High levels of p53 protein (>5 per cent of the cells) were present only in high-grade lymphomas (in the proportion 13/55), with a peak incidence in Burkitt's lymphoma (5/8 cases). Lower levels (<5 per cent) of p53 protein were detected in low-grade B- and T-cell lymphomas, as well as in most of the cases of Hodgkin's disease, where p53 protein was selectively present in Hodgkin and Reed-Sternberg cells. In 5/14 reactive tonsils or lymph nodes, occasional p53-positive cells were identified.These results suggest a relationship between levels of p53 protein and the aggressiveness of NHL. The sporadic presence of p53-positive cells in human reactive tissues suggests that its expression could depend not only on mutation, but also on stabilization of the protein through complexing with other nuclear proteins. It is not known if this mechanism is also responsible for the p53 nuclear accumulation in high-grade lymphomas.The Journal of Pathology 06/2005; 166(3):235 - 241. · 6.32 Impact Factor -
Article: Transcriptional response of T cells to IFN-alpha: changes induced in IFN-alpha-sensitive and resistant cutaneous T cell lymphoma.
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ABSTRACT: Interferon-alpha (IFN-alpha) therapy is commonly used in the treatment of neoplastic and autoimmune diseases, including cutaneous T cell lymphoma (CTCL). However, the IFN-alpha response is unpredictable, and the IFN-alpha cell targets and pathways are only partially understood. To delineate the molecular mechanisms of IFN-alpha activity, gene expression profiling was performed in a time-course experiment of both IFN-alpha sensitive and IFN-alpha-resistant variants of a CTCL cell line. These experiments revealed that IFN-alpha is responsible for the regulation of hundreds of genes in both variants and predominantly involves genes implicated in signal transduction, cell cycle control, apoptosis, and transcription regulation. Specifically, the IFN-alpha response of tumoral T cells is due to a combination of induction of apoptosis in which TNFSF10 and HSXIAPAF1 may play an important role and cell cycle arrest achieved by downregulation of CDK4 and CCNG2 and upregulation of CDKN2C and tumor suppressor genes (TSGs). Resistance to IFN-alpha appears to be associated with failure to induce IRF1 and IRF7 and deregulation of the apoptotic signals of HSXIAPAF1, TRADD, BAD, and BNIP3. Additionally, cell cycle progression is heralded by upregulation of CDC25A and CDC42. A critical role of NF-kappaB in promoting cell survival in IFN-alpha-resistant cells is indicated by the upregulation of RELB and LTB.Journal of Interferon & Cytokine Research 04/2004; 24(3):185-95. · 3.06 Impact Factor -
Article: Mycosis fungoides shows concurrent deregulation of multiple genes involved in the TNF signaling pathway: an expression profile study.
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ABSTRACT: Mycosis fungoides (MF) is the most frequent type of cutaneous T-cell lymphoma, whose diagnosis and study is hampered by its morphologic similarity to inflammatory dermatoses (ID) and the low proportion of tumoral cells, which often account for only 5% to 10% of the total tissue cells. cDNA microarray studies using the CNIO OncoChip of 29 MF and 11 ID cases revealed a signature of 27 genes implicated in the tumorigenesis of MF, including tumor necrosis factor receptor (TNFR)-dependent apoptosis regulators, STAT4, CD40L, and other oncogenes and apoptosis inhibitors. Subsequently a 6-gene prediction model was constructed that is capable of distinguishing MF and ID cases with unprecedented accuracy. This model correctly predicted the class of 97% of cases in a blind test validation using 24 MF patients with low clinical stages. Unsupervised hierarchic clustering has revealed 2 major subclasses of MF, one of which tends to include more aggressive-type MF cases including tumoral MF forms. Furthermore, signatures associated with abnormal immunophenotype (11 genes) and tumor stage disease (5 genes) were identified.Blood 09/2003; 102(3):1042-50. · 9.90 Impact Factor -
Article: Identification of genes involved in resistance to interferon-alpha in cutaneous T-cell lymphoma.
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ABSTRACT: Interferon-alpha therapy has been shown to be active in the treatment of mycosis fungoides although the individual response to this therapy is unpredictable and dependent on essentially unknown factors. In an effort to better understand the molecular mechanisms of interferon-alpha resistance we have developed an interferon-alpha resistant variant from a sensitive cutaneous T-cell lymphoma cell line. We have performed expression analysis to detect genes differentially expressed between both variants using a cDNA microarray including 6386 cancer-implicated genes. The experiments showed that resistance to interferon-alpha is consistently associated with changes in the expression of a set of 39 genes, involved in signal transduction, apoptosis, transcription regulation, and cell growth. Additional studies performed confirm that STAT1 and STAT3 expression and interferon-alpha induction and activation are not altered between both variants. The gene MAL, highly overexpressed by resistant cells, was also found to be expressed by tumoral cells in a series of cutaneous T-cell lymphoma patients treated with interferon-alpha and/or photochemotherapy. MAL expression was associated with longer time to complete remission. Time-course experiments of the sensitive and resistant cells showed a differential expression of a subset of genes involved in interferon-response (1 to 4 hours), cell growth and apoptosis (24 to 48 hours.), and signal transduction.American Journal Of Pathology 12/2002; 161(5):1825-37. · 4.89 Impact Factor -
Article: Nucleolar p14(ARF) overexpression in Reed-Sternberg cells in Hodgkin's lymphoma: absence of p14(ARF)/Hdm2 complexes is associated with expression of alternatively spliced Hdm2 transcripts.
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ABSTRACT: The development of human cancers is frequently associated with the silencing of the two major tumor suppressor pathways represented by retinoblastoma protein and p53. As the incidence of p53 mutations is significantly lower in Hodgkin's lymphoma than in other neoplasias, we investigated whether the malfunction of other proteins in this pathway could be responsible for its inactivation. Because the existence of nucleolar complexes between p14(ARF) and Hdm2 has been described as having a critical effect on p53 function by inhibiting its degradation, we analyzed the expression and subcellular localization of these proteins in 52 cases and in Hodgkin's cell lines. Two of four cell lines revealed loss of p14(ARF) expression secondary to gene promoter methylation, this being mutually exclusive with p53 mutations (1 of 4), illustrating the existence of selective pressure to inactivate the p53 pathway. The majority of Hodgkin's samples showed a strong nucleolar expression of p14(ARF) that was not associated with Hdm2. They also showed the existence of Hdm2/p53 complexes, and the absence of complexes containing either p14(ARF)/Hdm2 or p14(ARF)/p53. The different localization of Hdm2 (nucleoplasm) and p14(ARF) (nucleoli) observed in Hodgkin's tumors and cell lines is associated with the presence of short alternatively spliced transcripts of Hdm2 lacking the ARF-binding region and the nuclear export signal. The absence of these p14(ARF)/Hdm2 nucleolar complexes could be sufficient to inactivate the pathway and may explain the low frequency of p53 mutations in this tumor.American Journal Of Pathology 03/2002; 160(2):569-78. · 4.89 Impact Factor -
Article: MDM2 AND p21WAF1/CIP1, WILD‐TYPE p53‐INDUCED PROTEINS, ARE REGULARLY EXPRESSED BY STERNBERG–REED CELLS IN HODGKIN'S DISEASE
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ABSTRACT: Mutations in the p53 tumour suppressor gene are the most common genetic alteration found in human cancers. Most of them are accompanied by stabilization of the protein, which renders it detectable through immunohistochemical techniques. Although p53 expression is a very common finding in Hodgkin's disease (HD), the status of the p53 gene is scarcely known, due to the difficulty in sequencing this gene in a lesion in which tumour cells are thought to constitute a very minor subpopulation, diluted in a background of supposedly benign cells. The pattern of expression of two downstream p53 proteins (MDM2 and p21was studied as an indirect way of assessing p53 gene status. MDM2 is a wild-p53 inducible protein which may form a complex with p53, abrogating its function, as has been found in human sarcomas and other malignancies. p21WAF1/CIP1 is another protein inducible by wild-type p53, involved in inhibiting cell-cycle progression, through binding to cyclin/cyclin-dependent-kinase complexes. MDM2 and p21WAF1/CIP1 immunostaining was detected in all the cases analysed, independently of histological type, and were mainly present in Sternberg–Reed and Hodgkin (H SR) cells. These immunohistochemical results were confirmed by Western blotting. To study the cause of MDM2 protein accumulation, MDM2 mRNA expression was also investigated by reverse transcription polymerase chain reaction (RT-PCR). The results show the presence of MDM2 transcripts in all cases of HD, albeit at lower levels than those found in reactive lymphoid tissue. These results seem to support the hypothesis that p53 is transcriptionally active in at least some of the H SR cells in HD, and is able to induce MDM2 and p21WAF1/CIP1 protein expression.The Journal of Pathology 04/1999; 180(1):58 - 64. · 6.32 Impact Factor -
Article: Value of PCR Detection of TCR7 Gene Rearrangement in the Diagnosis ( Cutaneous Lymphocytic Infiltrates
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ABSTRACT: In this study, we analyzed the reliability and usefulness of the polymerase chain reaction (PCR) for the detection of T-cell receptor (TCR)-[gamma] gene monoclonal rearrangement. We first tested for the specificity and sensitivity of this strategy, against the classical criteria of Southern blot analysis (SBA). Of the 27 samples tested, results agreed in all but two. Broader analysis of these cases demonstrated the high specificity (absence of false positives) of the PCR strategy, together with its limited sensitivity (KF? of false negatives). The usefulness of this PCR approach was then tested on a panel of 28 biopsy specimens of cutaneous lymphocytic infiltrates. Monoclonal TCR7 rearrangement was detected in seven of eight cases of early stage mycosis fungoides (MF). one of two Sezary syndrome (SS) cases, two of two non-MF T-cell lymphoma. and two of three lymphomatoid papulosis. Mono-clonality was not detected in any of the 11 benign cases (parapsoriasis and inflammatory dermatosis). Results obtained with this new molecular strategy provide additional support for the hypothesis of a monoclonal origin for most early stage T-cell MF They also suggest the heterogeneous nature of some lymphomatoid papulosis lesions. Therefore, due to the difficulty in detecting T-cell monoclonality by immunohistochemical techniques. PCR can be a useful alternative strategy to SBA. It could also be used as a complementary technique in the routine diagnosis of T-cell cutaneous infiltrates. (C) Lippincott-Raven Publishers.Diagnostic Molecular Pathology 11/1994; 3(4). · 2.26 Impact Factor
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- American Journal Of Pathology (2)
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- Haematologica (2)
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Institutions
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2002–2009
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Centro Nacional de Investigaciones Oncológicas
- Programa de Patología Molecular
Madrid, Madrid, Spain
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