Nuestros investigadores

José Luis Vizmanos Pérez

Bioquímica y Genética
Facultad de Ciencias. Universidad de Navarra
Líneas de investigación
Detección de mutaciones relacionadas con enfermedades genéticas, Filogenia del virus C de la hepatitis, Mecanismos genéticos relacionados con el desarrollo de neoplasias hematológicas, Alteraciones genéticas causantes de las neoplasias mieloproliferativas crónicas, Desarrollo de un modelo en Caenorhabditis elegans para el análisis de los mecanismos genéticos implicados en el desarrollo de neoplasias hematológicas, Análisis de translocaciones cromosómicas implicadas en cáncer, Análisis de compuestos bioactivos con valor nutricional en Caenorhabditis elegans
Índice H
16, (WoS, 02/09/2019)
17, (Scopus, 02/09/2019)
20, (Google Scholar, 02/09/2019)

Publicaciones científicas más recientes (desde 2010)

Autores: De Torre, M.P.; Vizmanos Pérez, José Luis; Cavero Remón, Rita Yolanda; et al.
ISSN 0753-3322  Vol. 129  2020  págs. 110424
Aging-related diseases can be triggered by multiple factors such as oxidative stress. Oxidative stress is an imbalance between free radicals and antioxidants, so today, compounds capable of reducing or neutralizing free radicals are being studied for a therapeutic use. Origanum vulgare L. is a traditional medicinal plant used for a wide number of health problems due to its antimicrobial, carminative and antioxidant activities. However, when administered orally, gastrointestinal digestion can modify some of therapeutical properties. To avoid this, two different solid oral formulations have been designed for an O. vulgare extract evaluating their antioxidant behaviours in vitro and in vivo after a simulation of gastrointestinal digestion. The results showed that the divided powder has a lower antioxidant activity both in vitro and in vivo than the encapsulated extract. The quantitative difference of polyphenols found on HPLC-DAD (especially luteolin, apigenin and caffeic acid) may explain the differences in pharmacological activity. Thus, we propose that the best form to administrate O. vulgare extracts to maintain the antioxidant properties is the encapsulated form, that is, two capsules of 250mg of a hydroalcoholic extract of O. vulgare with a minimum of 33 % of rosmarinic acid as a daily dose.
Autores: Aranaz Oroz, Paula; Zabala Navó, María; Romo Hualde, Ana; et al.
ISSN 2042-6496  Vol. 11  Nº 5  2020  págs. 4512 - 4524
The metabolic properties of omega-6 fatty acid consumption are being increasingly accepted. We had previously observed that supplementation with a borage seed oil (BSO), as a source of linoleic (18:2n-6; LA) and gamma-linolenic (18:3n-6; GLA) acids, reduces body weight and visceral adiposity and improves insulin sensitivity in a diet-induced obesity model of Wistar rats. Here, it was investigated whether the anti-obesogenic properties of BSO could be maintained in a pre-obese model of rats, and if these effects are enhanced by a combination with low doses of quercetin, together with its potential role in the regulation of the adipocyte biology. The combination of BSO and quercetin during 8 weeks was able to ameliorate glucose intolerance and insulin resistance, and to improve liver steatosis. Although no effects were observed on body weight, animals supplemented with this combination exhibited a lower proportion of visceral adiposity. In addition, in vitro differentiation of epididymal adipose-precursor cells of the BSO-treated animals exhibited a down-regulation of Fasn, Glut4, Pparg and Srebp1 genes, in comparison with the control group. Finally, in vitro evaluation of the components of BSO demonstrated that the anti-adipogenic activity of quercetin was significantly potentiated by the combination with both LA and GLA through the down-regulation of different adipogenesis-key genes in 3T3-L1 cells. All these data suggest that omega-6 fatty acids LA and GLA, and their natural sources such as BSO, could be combined with quercetin to potentiate their effects in the prevention of the excess of adiposity and the insulin resistance.
Autores: Aranaz Oroz, Paula; Navarro Herrera, D.; Zabala Navó, María; et al.
ISSN 1424-8247  Vol. 13  Nº 11  2020  págs. 355
Supplementation with bioactive compounds capable of regulating energy homeostasis is a promising strategy to manage obesity. Here, we have screened the ability of different phenolic compounds (myricetin, kaempferol, naringin, hesperidin, apigenin, luteolin, resveratrol, curcumin and epicatechin), and phenolic acids (p-coumaric, ellagic, ferulic, gallic and vanillic acids) regulating C. elegans fat accumulation. Resveratrol exhibited the strongest lipid-reducing activity, which was accompanied by the improvement of lifespan, oxidative stress and ageing, without affecting worm development. Whole-genome expression microarrays demonstrated that resveratrol affected fat mobilization, fatty acid metabolism, and unfolded protein response of the endoplasmic reticulum (UPRER), mimicking the response to calorie restriction. Apigenin induced the oxidative stress response and lipid mobilization, while vanillic acid affected the unfolded-protein response in ER. In summary, our data demonstrates that phenolic compounds exert a lipid-reducing activity in C. elegans through different biological processes and signaling pathways, including those related with lipid mobilization and fatty acid metabolism, oxidative stress, ageing and UPR-ER response. These findings open the door to the possibility of combining them in order to achieve complementary activity against obesity-related disorders.
Autores: Eder-Azanza, L.; Hurtado Rudi, Cristina; Navarro-Herrera, D.; et al.
ISSN 2049-9450  Vol. 10  Nº 6  2019  págs. 639 - 643
In recent years it has been shown that the causes of chronic myeloproliferative neoplasms (MPNs) are more complex than a simple signaling aberration and many other mutated genes affecting different cell processes have been described. For instance, mutations in genes encoding epigenetic regulators are more frequent than expected. One of the latest genes described as mutated is SET binding protein 1 (SETBP1). In silico tools have revealed that there are several human SETBP1 paralogous to nuclear receptor binding SET domain protein 1 (NSD1), NSD2 and NSD3, for example, which are also involved in the development of other hematological malignancies. Therefore, the present study analyzed the mutational status of NSD1, NSD2, NSD3 and SETBP1 in BCR-ABL1 negative MPNs with or without Janus kinase 2 (JAK2) p.V617F mutation. The present study revealed that the NSD genes are not frequently mutated in MPNs. However, a novel SETBP1 mutation was identified in a patient with p.V617F JAK2 positive primary myelofibrosis. These results provide further insight into the genetic complexity of MPNs.
Autores: Aranaz Oroz, Paula; Romo Hualde, Ana; Navarro-Herrera, D.; et al.
ISSN 2042-6496  Vol. 10  Nº 8  2019  págs. 4811 - 4822
Cocoa polyphenols exhibit high antioxidant activity and have been proposed as a potential adjuvant for the treatment of metabolic disturbances. Here, we demonstrate that supplementation with low doses (14 and 140 mg per kg per rat) of a complete cocoa extract induces metabolic benefits in a diet-induced obesity (DIO) model of Wistar rats. After 10 weeks, cocoa extract-supplemented animals exhibited significantly lower body weight gain and food efficiency, with no differences in energy intake. Cocoa significantly reduced visceral (epididymal and retroperitoneal) and subcutaneous fat accumulation accompanied by a significant reduction in the adipocyte size, which was mediated by downregulation of the adipocyte-specific genes Cebpa, Fasn and Adipoq. Additionally, cocoa extract supplementation reduced the triacylglycerol/high density lipoprotein (TAG/HDL) ratio, decreased hepatic triglyceride accumulation, improved insulin sensitivity by reducing HOMA-IR, and significantly ameliorated glucose tolerance after an intraperitoneal glucose tolerance test. Finally, no adverse effect was observed in an in vivo toxicity evaluation of our cocoa extract at doses up to 500 mg kg -1 day -1. Our data demonstrate that low doses of cocoa extract supplementation (14 and 140 mg kg -1 day -1) are safe and sufficient to counteract obesity and type-2 diabetes in rats and provide new insights into the potential application of cocoa supplements in the management of the metabolic syndrome.
Autores: De Torre, M.P.; Cavero Remón, Rita Yolanda; Calvo Martínez, María Isabel (Autor de correspondencia); et al.
ISSN 2076-3921  Vol. 8  Nº 5  2019  págs. 142
The characterization of compounds with antioxidant activity is of great interest due to their ability to reduce reactive oxygen species production and, therefore, prevent some age-related diseases. Its antioxidant capacity can be analyzed by different methods both in vitro and in vivo. Caenorhabditis elegans is an in vivo model widely used in ageing research. Until now, available tests analyze functional effects in the worms, so the antioxidant activity of the compound is indirectly monitored. We have developed a simple and a reliable method to quantify internal antioxidant activity in vivo. To validate this method, we analyzed an aqueous green tea extract and two other compounds with a well-known antioxidant activity and without this activity. The results obtained (EC50 green tea = 21.76 ± 1.28 µg/mL; EC50 positive control = 8.50 ± 0.33 µg/mL; negative control EC50 > 500 µg/mL) can help in the design of further in vivo experiments. Thus, our method can be used as a previous screening capable of reducing the gap between in vitro and in vivo assays.
Autores: Aranaz Oroz, Paula; Navarro-Herrera, D.; Romo Hualde, Ana; et al.
ISSN 1756-4646  Vol. 59  2019  págs. 319 - 328
Brassicaceae contain bioactive compounds with potential positive effects on metabolic syndrome. Here, we evaluated the eventual anti-obesity properties of an ethanolic broccoli extract (BE), selected by a tested ability to reduce Caenorhabditis elegans fat content. Two doses (14 and 140 mg/kg animal) of BE were evaluated in a diet-induced obesity (DIO) Wistar rat model. After 10 weeks of BE supplementation, animals exhibited reduced body weight gain and food efficiency, decreased atherogenic index of plasma and improved glucose tolerance in comparison with non-supplemented rats. BE also reduced the retroperitoneal fat mass and adipocyte size, all associated to down-regulation of Cebpa, Srebp1, Fasn and Adipoq expression in adipocytes. Finally, BE significantly decreased liver steatosis, accompanied by the up-regulation of Acot8 and Acox1, and the down-regulation of Fasn, Fatp4 and Srebf1 expression in hepatocytes. Our data provides new knowledge about the potential role of broccoli components in the prevention of metabolic syndrome.
Autores: Aranaz Oroz, Paula; Navarro Herrera, D.; Zabala Navó, María; et al.
ISSN 1420-3049  Vol. 24  Nº 6  2019  págs. 1 - 21
Phenolic compounds might modulate adiposity. Here, we report our observation that polyphenols and phenolic acids inhibit adipogenesis in 3T3-L1 with different intensity depending on the family and the stage of differentiation. While quercetin and resveratrol inhibited lipid accumulation along the whole process of differentiation, apigenin and myricetin were active during the early and latest stages, but not intermediate, contrary to hesperidin. The activity of phenolic acids was limited to the early stages of the differentiation process, except p-coumaric and ellagic acids. This anti-adipogenic effect was accompanied by down-regulation of Scd1 and Lpl. Molecular docking analysis revealed that the inhibitory activity of these phenolic compounds over the early stages of adipogenesis exhibits a significant correlation (r = 0.7034; p = 0.005) with their binding affinity to the ligand-binding domain of PPAR¿. Results show that polyphenols and phenolic acids would interact with specific residues of the receptor, which could determine their potential anti-adipogenic activity during the early stages of the differentiation. Residues Phe264, His266, Ile281, Cys285 and Met348 are the most frequently involved in these interactions, which might suggest a crucial role for these amino acids modulating the activity of the receptor. These data contribute to elucidate the possible mechanisms of phenolic compounds in the control of adipogenesis.
Autores: Navarro-Herrera, D.; Aranaz Oroz, Paula; Eder-Azanza, L.; et al.
ISSN 2042-6496  Vol. 9  Nº 8  2018  págs. 4340 - 4351
Obesity is a medical condition with increasing prevalence, characterized by an accumulation of excess fat that could be improved using some bioactive compounds. However, many of these compounds with in vitro activity fail to respond in vivo, probably due to the sophistication of the physiological energy regulatory networks. In this context, C. elegans has emerged as a plausible model for the identification and characterization of the effect of such compounds on fat storage in a complete organism. However, the results obtained in such a simple model are not easily extrapolated to more complex organisms such as mammals, which hinders its application in the short term. Therefore, it is necessary to obtain new experimental data about the evolutionary conservation of the mechanisms of fat loss between worms and mammals. Previously, we found that some omega-6 fatty acids promote fat loss in C. elegans by up-regulation of peroxisomal fatty acid ß-oxidation in an omega-3 independent manner. In this work, we prove that the omega-6 fatty acids¿ effects on worms are also seen when they are supplemented with a natural omega-6 source (borage seed oil, BSO). Additionally, we explore the anti-obesity effects of two doses of BSO in a diet-induced obesity rat model, validating the up-regulation of peroxisomal fatty acid ß-oxidation. The supplementation with BSO significantly reduces body weight gain and energy efficiency and prevents white adipose tissue accumulation without affecting food
Autores: Lucio Ollauri, David (Autor de correspondencia); Martínez Oharriz, María Cristina; Gu, Z. W.; et al.
ISSN 0378-5173  Vol. 547  Nº 1 - 2  2018  págs. 97 - 105
The aim of this work was to prepare and evaluate cyclodextrins-modified poly(anhydride) nanoparticles to enhance the oral administration of glibenclamide. A conjugate polymer was synthesized by incorporating hydroxypropyl-beta-cyclodextrin to the backbone of poly(methylvinyl ether-co-maleic anhydride) via Steglich reaction. The degree of substitution of anhydride rings by cyclodextrins molecules was calculated to be 4.9% using H-NMR spectroscopy. A central composite design of experiments was used to optimize the preparative process. Under the optimal conditions, nanoparticles displayed a size of about 170 nm, a surface charge of - 47 mV and a drug loading of 69 mu g GB/mg. X-ray diffraction studies confirmed the loss of the crystalline structure of GB due to its dispersion into the nanoparticles, either included into cyclodextrin cavities or entrapped in the polymer chains. Glibenclamide was mainly release by Fickian-diffusion in simulated intestinal fluid. GB-loaded nanoparticles produced a hypolipidemic effect over C. elegans N2 wild-type and daf-2 mutant. The action mechanism included daf-2 and daf-28 genes, both implicated in the insulin signaling pathway of C. elegans. In summary, the covalent linkage of cyclodextrin to the poly(anhydride) backbone could be an interesting strategy to prepare nanoparticles for the oral administration of glibenclamide.
Autores: Navarro Herrera, D.; Aranaz Oroz, Paula; Eder-Azanza, L.; et al.
ISSN 2042-6496  Vol. 9  Nº 3  2018  págs. 1621 - 1637
Bioactive compounds, including some fatty acids (FAs), can induce beneficial effects on body fat-content and metabolism. In this work, we have used C. elegans as a model to examine the effects of several FAs on body fat accumulation. Both omega-3 and omega-6 fatty acids induced a reduction of fat content in C. elegans, with linoleic, gamma-linolenic and dihomo-gamma-linolenic acids being the most effective ones. These three FAs are sequential metabolites especially in omega-6 PUFA synthesis pathway and the effects seem to be primarily due to dihomo-gamma-linolenic acid, and independent of its transformation into omega-3 or arachidonic acid. Gene expression analyses suggest that peroxisomal beta oxidation is the main mechanism involved in the observed effect. These results point out the importance of further analysis of the activity of these omega-6 FAs, due to their potential application in obesity and related diseases.
Autores: Sánchez Montes, Gregorio; Wang, J.; Ariño Plana, Arturo; et al.
ISSN 2045-7758  Vol. 7  Nº 23  2017  págs. 10301 - 10304
The ratio of the effective number of breeders (Nb) to the adult census size (Na), Nb/Na, approximates the departure from the standard capacity of a population to maintain genetic diversity in one reproductive season. This information is relevant for assessing population status, understanding evolutionary processes operating at local scales, and unraveling how life-history traits affect these processes. However, our knowledge on Nb/Na ratios in nature is limited because estimation of both parameters is challenging. The sibship frequency (SF) method is adequate for reliable Nb estimation because it is based on sibship and parentage reconstruction from genetic marker data, thereby providing demographic inferences that can be compared with field-based information. In addition, capture-mark-recapture (CMR) robust design methods are well suited for Na estimation in seasonal-breeding species. We used tadpole genotypes of three pond-breeding amphibian species (Epidalea calamita, Hyla molleri, and Pelophylax perezi, n = 73-96 single-cohort tadpoles/species genotyped at 15-17 microsatellite loci) and candidate parental genotypes (n = 94-300 adults/species) to estimate Nb by the SF method. To assess the reliability of Nb estimates, we compared sibship and parentage inferences with field-based information and checked for the convergence of results in replicated subsampled analyses. Finally, we used CMR data from a 6-year monitoring program to estimate annual Na in the three species and calculate the Nb/Na ratio. Reliable ratios were obtained for E. calamita (Nb/Na = 0.18-0.28) and P. perezi (0.5), but in H. molleri, Na could not be estimated and genetic information proved insufficient for reliable Nb estimation. Integrative demographic studies taking full advantage of SF and CMR methods can provide accurate estimates of the Nb/Na ratio in seasonal-breeding species. Importantly, the SF method provides results that can be readily evaluated for reliability. This represents a good opportunity for obtaining robust demographic inferences with wide applications for evolutionary and conservation research.
Autores: Eder-Azanza, L.; Hurtado Rudi, Cristina; Navarro-Herrera, D.; et al.
ISSN 0390-6078  Vol. 102  Nº 8  2017  págs. e328 - e331
Autores: Sánchez Montes, Gregorio; Ariño Plana, Arturo; Vizmanos Pérez, José Luis; et al.
ISSN 0022-1503  Vol. 108  Nº 5  2017  págs. 535 - 543
Accurate characterization of genetic diversity is essential for understanding population demography, predicting future trends and implementing efficient conservation policies. For that purpose, molecular markers are routinely developed for nonmodel species, but key questions regarding sampling design, such as calculation of minimum sample sizes or the effect of relatives in the sample, are often neglected. We used accumulation curves and sibship analyses to explore how these 2 factors affect marker performance in the characterization of genetic diversity. We illustrate this approach with the analysis of an empirical dataset including newly optimized microsatellite sets for 3 Iberian amphibian species: Hyla molleri, Epidalea calamita, and Pelophylax perezi. We studied 17¿21 populations per species (total n = 547, 652, and 516 individuals, respectively), including a reference locality in which the effect of sample size was explored using larger samples (77¿96 individuals). As expected, FIS and tests for Hardy¿Weinberg equilibrium and linkage disequilibrium were affected by the presence of full sibs, and most initially inferred disequilibria were no longer statistically significant when full siblings were removed from the sample. We estimated that to obtain reliable estimates, the minimum sample size (potentially including full sibs) was close to 20 for expected heterozygosity, and between 50 and 80 for allelic richness. Our pilot study based on a reference population provided a rigorous assessment of marker properties and the effects of sample size and presence of full sibs in the sample. These examples illustrate the advantages of this approach to produce robust and reliable results for downstream analyses.
Autores: Eder Azanza, L.; Evans, P.; Wickham, C.; et al.
ISSN 0887-6924  Vol. 29  Nº 12  2015  págs. 2410 - 2411
Autores: Erquiaga Martínez, Ignacio; Hurtado Rudi, Cristina; Aranaz Oroz, Paula; et al.
ISSN 0736-6205  Vol. 56  Nº 6  2014  págs. 327 - 329
When studying mutations in DNA samples, determining whether novel sequence changes are somatic mutations or germline polymorphisms can be difficult. Here we describe a novel and very simple approach for identification of somatic mutations and loss of heterozygosity (LoH) events in DNA samples where no matched tissue sample is available. Our method makes use of heterozygous polymorphisms that are located near the putative mutation to trace both germinal alleles.
Autores: Eder Azanza, L.; Navarro Herrera, D.; Aranaz Oroz, Paula; et al.
ISSN 0887-6924  Vol. 28  Nº 10  2014  págs. 2106 - 2109
Autores: Shugay, M.; Ortiz de Mendibil Ayuso, Íñigo; Vizmanos Pérez, José Luis; et al.
ISSN 1367-4803  Vol. 29  Nº 20  2013  págs. 2539 - 2546
Motivation: Gene fusions resulting from chromosomal aberrations are an important cause of cancer. The complexity of genomic changes in certain cancer types has hampered the identification of gene fusions by molecular cytogenetic methods, especially in carcinomas. This is changing with the advent of next-generation sequencing, which is detecting a substantial number of new fusion transcripts in individual cancer genomes. However, this poses the challenge of identifying those fusions with greater oncogenic potential amid a background of 'passenger' fusion sequences. Results: In the present work, we have used some recently identified genomic hallmarks of oncogenic fusion genes to develop a pipeline for the classification of fusion sequences, namely, Oncofuse. The pipeline predicts the oncogenic potential of novel fusion genes, calculating the probability that a fusion sequence behaves as 'driver' of the oncogenic process based on features present in known oncogenic fusions. Cross-validation and extensive validation tests on independent datasets suggest a robust behavior with good precision and recall rates. We believe that Oncofuse could become a useful tool to guide experimental validation studies of novel fusion sequences found during next-generation sequencing analysis of cancer transcriptomes.
Autores: Aranaz Oroz, Paula; Miguéliz Basterra, Itziar; Hurtado Rudi, Cristina; et al.
ISSN 1042-8194  Vol. 54  Nº 2  2013  págs. 428 - 431
Autores: Paris Huguet, Francesc; Hurtado Rudi, Cristina; Azón, Antoni; et al.
ISSN 0906-6705  Vol. 22  Nº 12  2013  págs. 838 - 839
Pachyonychia congenita is a rare, autosomal dominant genetic disease characterized by painful palmoplantar keratoderma and hypertrophic nail dystrophy. This disorder is caused by mutations in any one of five cytoskeletal keratin proteins, K6a, K6b, K6c, K16 and K17. Here, we describe a new p.Leu421Pro (c.1262T>C) mutation in the highly conserved helix termination motif of K16 in a large Spanish family. Bioinformatic analyses as well as previous descriptions in the literature of homologous mutations in other keratin-coding genes show that this mutation is probably causative of the disease.
Autores: Aranaz Oroz, Paula; Hurtado Rudi, Cristina; Erquiaga Martínez, Ignacio; et al.
Revista: Haematologica-journal of Hematology
ISSN 1138-0381  Vol. 97  Nº 8  2012  págs. 1234 -1241
Autores: Shugay, M.; Ortiz de Mendibil Ayuso, Íñigo; Vizmanos Pérez, José Luis; et al.
ISSN 1553-7358  Vol. 8  Nº 12  2012  págs. e1002797
Reciprocal chromosomal translocations (RCTs) leading to the formation of fusion genes are important drivers of hematological cancers. Although the general requirements for breakage and fusion are fairly well understood, quantitative support for a general mechanism of RCT formation is still lacking. The aim of this paper is to analyze available high-throughput datasets with computational and robust statistical methods, in order to identify genomic hallmarks of translocation partner genes (TPGs). Our results show that fusion genes are generally overexpressed due to increased promoter activity of 5' TPGs and to more stable 3'-UTR regions of 3' TPGs. Furthermore, expression profiling of 5' TPGs and of interaction partners of 3' TPGs indicates that these features can help to explain tissue specificity of hematological translocations. Analysis of protein domains retained in fusion proteins shows that the co-occurrence of specific domain combinations is non-random and that distinct functional classes of fusion proteins tend to be associated with different components of the gene fusion network. This indicates that the configuration of fusion proteins plays an important role in determining which 5' and 3' TPGs will combine in specific fusion genes. It is generally accepted that chromosomal proximity in the nucleus can explain the specific pairing of 5' and 3' TPGS and the recurrence of hematological translocations. Using recently available data for chromosomal contact probabilities (Hi-C) we show that TPGs are preferentially located in early replicated regions and occupy distinct clusters in the nucleus. However, our data suggest that, in general, nuclear position of TPGs in hematological cancers explains neither TPG pairing nor clinical frequency. Taken together, our results support a model in which genomic features related to regulation of expression and replication timing determine the set of candidate genes more likely to be translocated in hematological tissues, with functional constraints being responsible for specific gene combinations.
Autores: Cuesta-Dominguez, A.; Ortega, M.; Ormazabal Goicoechea, Cristina; et al.
Revista: PLOS ONE
ISSN 1932-6203  Vol. 7  Nº 2  2012  págs. e32451
Chromosomal translocations in tumors frequently produce fusion genes coding for chimeric proteins with a key role in oncogenesis. Recent reports described a BCR-JAK2 fusion gene in fatal chronic and acute myeloid leukemia, but the functional behavior of the chimeric protein remains uncharacterized. We used fluorescence in situ hybridization and reverse transcription polymerase chain reaction (RT-PCR) assays to describe a BCR-JAK2 fusion gene from a patient with acute lymphoblastic leukemia. The patient has been in complete remission for six years following treatment and autologous transplantation, and minimal residual disease was monitored by real-time RT-PCR. BCR-JAK2 codes for a protein containing the BCR oligomerization domain fused to the JAK2 tyrosine-kinase domain. In vitro analysis of transfected cells showed that BCR-JAK2 is located in the cytoplasm. Transduction of hematopoietic Ba/F3 cells with retroviral vectors carrying BCR-JAK2 induced IL-3-independent cell growth, constitutive activation of the chimeric protein as well as STAT5 phosphorylation and translocation to the nuclei, where Bcl-xL gene expression was elicited. Primary mouse progenitor cells transduced with BCR-JAK2 also showed increased proliferation and survival. Treatment with the JAK2 inhibitor TG101209 abrogated BCR-JAK2 and STAT5 phosphorylation, decreased Bcl-xL expression and triggered apoptosis of transformed Ba/F3 cells. Therefore, BCR-JAK2 is a novel tyrosine-kinase with transforming activity. It deregulates growth factor-dependent proliferation and cell survival, which can be abrogated by the TG101209 inhibitor. Moreover, transformed Ba/F3 cells developed tumors when injected subcutaneously into nude mice, thus proving the tumorigenic capacity of BCR-JAK2 in vivo. Together these findings suggest that adult and pediatric patients with BCR-ABL-negative leukemia and JAK2 overexpression may benefit from targeted therapies.
Autores: Euba Rementeria, Begoña; Vizmanos Pérez, José Luis; García-Granero Marquez, Marta; et al.
Revista: Leukemia & Lymphoma
ISSN 1042-8194  Vol. 53  Nº 6  2011  págs. 1230-1233
Autores: Salas Cintora, Elisa María; García Barchino, María José; Labiano Almiñana, Sara; et al.
Revista: Genes chromosomes & cancer (Print)
ISSN 1045-2257  Vol. 2  Nº 5  2011  págs. 593 - 596
Autores: Hurtado Rudi, Cristina; Erquiaga Martínez, Ignacio; Aranaz Oroz, Paula; et al.
Revista: Leukemia Research
ISSN 0145-2126  Vol. 35  Nº 11  2011  págs. 1537 - 1539
Autores: Erquiaga Martínez, Ignacio; Ormazabal Goicoechea, Cristina; Hurtado Rudi, Cristina; et al.
ISSN 1042-8194  Vol. 51  Nº 9  2010  págs. 1720 - 1726
Hematological malignancies with eosinophilia are often associated with fusions in PDGFRA, PDGFRB, or FGFR1 genes. RT-PCR has proved to be useful for finding new PDGFRA gene fusions, but some studies have shown overexpression of the TK domain which cannot be explained by the existence of such aberrations. This fact could be related to the expression of alternative PDGFRA transcripts. We show that quantification of the expression of three different PDGFRA fragments discriminates between PDGFRA alternative transcripts and fusion genes, and we have tested this novel methodological approach in a group of eosinophilia cases. Our data show that alternative PDGFRA transcripts should be taken into account when screening for PDGFRA aberrations, such as gene fusions, by RT-PCR. Expression from an internal PDGFRA promoter seems to be a frequent event, in both normal and leukemic samples, and is probably related to physiological conditions, but it could have a role in other tumors. Even so, we show that our RQ-PCR methodology can discriminate expression of alternative transcripts from the presence of X-PDGFRA fusion genes.
Autores: Aranaz Oroz, Paula; Ormazabal Goicoechea, Cristina; Hurtado Rudi, Cristina; et al.
ISSN 0165-4608  Vol. 199  Nº 1  2010  págs. 1 - 8
BCR/ABL1-negative chronic myeloproliferative neoplasms (CMPNs) are a heterogeneous group of clonal hematological malignancies. Over recent years, some genetic events in tyrosine lcinase (TK) genes have been described as causal events of these diseases. To identify new genetic aberrations underlying these diseases, we used denaturing high performance liquid chromatography and fluorescence in situ hybridization (FISH) to analyze 17 genes from two receptor-TK families (III and IV) and from three cytoplasmic-TK families (Syk, Abl, and Jak) on samples from 44 BCR/ABL1-negative and JAK2(V617F)-negative CMPN patients with different clinical phenotypes. Although screening by FISH did not reveal novel chromosomal aberrations, several sequence changes were detected. None of them were frequent events, but we identified a new potential activating mutation in the FERM domain of JAK2(R340Q). None of the germline JAK2(V617F) singlenucleotide polymorphisms detected differed in distribution between patients and control subjects. In summary, data presented here show that these genes are not frequently mutated or rearranged in CMPNs, suggesting that molecular events causing these disorders must be located in other genes.
Autores: Martínez López, A. L.; González Navarro, Carlos Javier; Vizmanos Pérez, José Luis; et al.
Libro:  XI International Forum on Advances in Pharmaceutical Technology
2018  págs. 80 - 81
Autores: Vizmanos Pérez, José Luis
Libro:  Biología celular biomédica
2015  págs. 137 - 171
Capítulo 7
Autores: Vizmanos Pérez, José Luis