Research publications

Found 1304 publicacions matching the indicated search criteria.
Van de Sompele S, Pécheux L, Couso J, Meunier A, Sanchez M, De Baere E

Functional characterization of a novel non-coding mutation "Ghent +49A > G" in the iron-responsive element of L-ferritin causing hereditary hyperferritinaemia-cataract syndrome.

Sci Rep 21 Dec 2017, 7 (1) 18025. Epub 21 Dec 2017
Hereditary hyperferritinaemia-cataract syndrome (HHCS) is a rare disorder usually caused by heterozygous mutations in the iron-responsive element (IRE) in the 5' untranslated region (5'UTR) of the L-ferritin gene (FTL), disturbing the binding of iron regulatory proteins (IRPs) and the post-transcriptional regulation of ferritin expression. Here, the proband of a consanguineous family displayed moderate bilateral cataracts and elevated serum ferritin in the absence of iron overload. The parents and siblings showed variable degrees of mild bilateral cataracts combined with elevated levels of circulating ferritin. Sequencing of FTL identified a novel 5'UTR mutation c.-151A > G, also named "Ghent +49A > G". The zygosity of the mutation, occurring in homozygous and heterozygous state in the proband and other affected family members respectively, correlated well with severity of ophthalmological and hematological manifestations. The substitution is expected to impair the secondary structure of the upper IRE stem. Functional characterization of +49A > G by electrophoretic mobility shift assays demonstrated a reduced binding affinity for IRP1 compared to the wild-type IRE of FTL. Overall, we have expanded the repertoire of deleterious biallelic FTL IRE mutations in HHCS with this novel +49A > G mutation, the zygosity of which correlated well with the disease expression.
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Rovó A, Kulasekararaj A, Medinger M, Chevallier P, Ribera JM, Peffault de Latour R, Knol C, Iacobelli S, Kanfer E, Bruno B, Maury S, Quarello P, Koh MBC, Schouten H, Blau IW, Tichelli A, Hill A, Risitano A, Passweg J, Marsh J, Dreger P, Dufour C

Association of aplastic anaemia and lymphoma: a report from the severe aplastic anaemia working party of the European Society of Blood and Bone Marrow Transplantation.

Br. J. Haematol. 19 Dec 2017, . Epub 19 Dec 2017More information
Nomdedeu M, Pereira A, Calvo X, Colomer J, Sole F, Arias A, Gomez C, Luño E, Cervera J, Arnan M, Pomares H, Ramos F, Oiartzabal I, Espinet B, Pedro C, Arrizabalaga B, Blanco ML, Tormo M, Hernandez-Rivas JM, Díez-Campelo M, Ortega M, Valcárcel D, Cedena MT, Collado R, Grau J, Granada I, Sanz G, Campo E, Esteve J, Costa D

Clinical and biological significance of isolated Y chromosome loss in myelodysplastic syndromes and chronic myelomonocytic leukemia. A report from the Spanish MDS Group.

Leuk. Res. Dec 2017, 63 85-89. Epub 28 Oct 2017
Isolate loss of chromosome Y (-Y) in myelodysplastic syndromes (MDS) is associated to a better outcome but it is also well described as an age-related phenomenon. In this study we aimed to analyze the prognostic impact of -Y in the context of the IPSS-R cytogenetic classification, evaluate the clinical significance of the percentage of metaphases with isolated -Y, and test whether finding -Y may predispose to over-diagnose MDS in patients with borderline morphological features. We evaluated 3581 male patients from the Spanish MDS Registry with a diagnosis of MDS or chronic myelomonocytic leukemia (CMML). -Y was identified in 177 patients (4.9%). Compared with the 2246 male patients with normal karyotype, -Y group showed a reduced risk of leukemic transformation that did not translate into a survival advantage. The overall survival and the risk of leukemic transformation were not influenced by the percentage of metaphases with -Y. The -Y group was not enriched in patients with minor morphologic traits of dysplasia, suggesting that the better outcome in the -Y group cannot be explained by enrichment in cases misdiagnosed as MDS. In conclusion, our results support the current recommendation of classifying patients with -Y within the very good risk category of the IPSS-R for MDS and rule out a selection bias as a possible explanation of this better outcome. An analysis of the molecular basis of MDS with isolated -Y would be of interest as it may provide a biological basis of protection against progression to acute leukemia.
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García-Sanz R, Corchete LA, Alcoceba M, Chillon MC, Jiménez C, Prieto I, García-Álvarez M, Puig N, Rapado I, Barrio S, Oriol A, Blanchard MJ, de la Rubia J, Martínez R, Lahuerta JJ, González Díaz M, Mateos MV, San Miguel JF, Martínez-López J, Sarasquete ME

Prediction of peripheral neuropathy in multiple myeloma patients receiving bortezomib and thalidomide: a genetic study based on a single nucleotide polymorphism array.

Hematol Oncol Dec 2017, 35 (4) 746-751. Epub 8 Sep 2016
Bortezomib- and thalidomide-based therapies have significantly contributed to improved survival of multiple myeloma (MM) patients. However, treatment-induced peripheral neuropathy (TiPN) is a common adverse event associated with them. Risk factors for TiPN in MM patients include advanced age, prior neuropathy, and other drugs, but there are conflicting results about the role of genetics in predicting the risk of TiPN. Thus, we carried out a genome-wide association study based on more than 300 000 exome single nucleotide polymorphisms in 172 MM patients receiving therapy involving bortezomib and thalidomide. We compared patients developing and not developing TiPN under similar treatment conditions (GEM05MAS65, NCT00443235). The highest-ranking single nucleotide polymorphism was rs45443101, located in the PLCG2 gene, but no significant differences were found after multiple comparison correction (adjusted P = .1708). Prediction analyses, cytoband enrichment, and pathway analyses were also performed, but none yielded any significant findings. A copy number approach was also explored, but this gave no significant results either. In summary, our study did not find a consistent genetic component associated with TiPN under bortezomib and thalidomide therapies that could be used for prediction, which makes clinical judgment essential in the practical management of MM treatment.
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Domingo-Reines J, López-Ornelas A, Montes R, Romero T, Rodriguez-Llamas JL, Lara-Rodarte R, González-Pozas F, Ayllon V, Menendez P, Velasco I, Ramos-Mejia V

Hoxa9 and EGFP reporter expression in human Embryonic Stem Cells (hESC) as useful tools for studying human development.

Stem Cell Res Dec 2017, 25 286-290. Epub 5 Aug 2017
HoxA9 is an evolutionarily conserved homeobox gene implicated in embryo development. To study the roles of Hoxa9 during human development we generated a transgenic H9 (hESC) line that overexpresses HoxA9 and the Enhanced Green Fluorescent Protein (EGFP), and a control H9 with a stable expression of the EGFP. The resulting H9-HoxA9-EGFP and H9-EGFP cell lines allow an efficient visualization of hESCs by fluorescent microscopy, quantification by flow cytometry and cell differentiation tracking. Both transgenic cell lines maintained the pluripotent phenotype, the ability to differentiate into all three germ layers and a normal karyotype.
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Ribera JM

Efficacy and safety of bispecific T-cell engager blinatumomab and the potential to improve leukemia-free survival in B-cell acute lymphoblastic leukemia.

Expert Rev Hematol Dec 2017, 10 (12) 1057-1067. Epub 1 Nov 2017
Immunotherapy is a promising modality of treatment of neoplastic diseases, including acute lymphoblastic leukemia (ALL). The CD19/CD3-bispecific T cell-engaging (BiTE®) monoclonal antibody blinatumomab can transiently bind cytotoxic T cells to CD19
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Collado R, Puiggros A, López-Guerrero JA, Calasanz MJ, Larráyoz MJ, Ivars D, García-Casado Z, Abella E, Orero MT, Talavera E, Oliveira AC, Hernández-Rivas JM, Hernández-Sánchez M, Luño E, Valiente A, Grau J, Portal I, Gardella S, Salgado AC, Giménez MT, Ardanaz MT, Campeny A, Hernández JJ, Álvarez S, Espinet B, Carbonell F

Chronic lymphocytic leukemia with isochromosome 17q: An aggressive subgroup associated with TP53 mutations and complex karyotypes.

Cancer Lett. 28 Nov 2017, 409 42-48. Epub 6 Sep 2017
Although i(17q) [i(17q)] is frequently detected in hematological malignancies, few studies have assessed its clinical role in chronic lymphocytic leukemia (CLL). We recruited a cohort of 22 CLL patients with i(17q) and described their biological characteristics, mutational status of the genes TP53 and IGHV and genomic complexity. Furthermore, we analyzed the impact of the type of cytogenetic anomaly bearing the TP53 defect on the outcome of CLL patients and compared the progression-free survival (PFS) and overall survival (OS) of i(17q) cases with those of a group of 38 CLL patients harboring other 17p aberrations. We detected IGHV somatic hypermutation in all assessed patients, and TP53 mutations were observed in 71.4% of the cases. Patients with i(17q) were more commonly associated with complex karyotypes (CK) and tended to have a poorer OS than patients with other anomalies affecting 17p13 (median OS, 44 vs 120 months, P = 0.084). Regarding chromosomal alterations, significant differences in the median OS were found among groups (P = 0.044). In conclusion, our findings provide new insights regarding i(17q) in CLL and show a subgroup with adverse prognostic features.
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Ribera JM, Morgades M, Montesinos P, Martino R, Barba P, Soria B, Bermúdez A, Moreno MJ, González-Campos J, Vives S, Gil C, Abella E, Guàrdia R, Martínez-Carballeira D, Martínez-Sánchez P, Amigo ML, Mercadal S, Serrano A, López-Martínez A, Vall-Llovera F, Sánchez-Sánchez MJ, Peñarrubia MJ, Calbacho M, Méndez JA, Bergua J, Cladera A, Tormo M, García-Belmonte D, Feliu E, Ciudad J, Orfao A

Efficacy and safety of native versus pegylated Escherichia coli asparaginase for treatment of adults with high-risk, Philadelphia chromosome-negative acute lymphoblastic leukemia.

Leuk. Lymphoma 22 Nov 2017, 1-10. Epub 22 Nov 2017
Native or pegylated (PEG) asparaginase (ASP) are commonly used in treatment of acute lymphoblastic leukemia (ALL), but have been scarcely compared in the same trial in adult patients. Native vs. PEG-ASP administered according to availability in each center were prospectively evaluated in adults with high-risk ALL. Ninety-one patients received native ASP and 35 PEG-ASP in induction. No significant differences were observed in complete remission, minimal residual disease levels after induction and after consolidation, disease-free survival, and overall survival. No significant differences in grades 3-4 toxicity were observed in the induction period, although a trend for higher hepatic toxicity was observed in patients receiving PEG-ASP. In this trial the type of ASP did not influence patient response and outcome.
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Navarro-Montero O, Ayllon V, Lamolda M, López-Onieva L, Montes R, Bueno C, Ng E, Guerrero-Carreno X, Romero T, Romero-Moya D, Stanley E, Elefanty A, Ramos-Mejia V, Menendez P, Real PJ

RUNX1c Regulates Hematopoietic Differentiation of Human Pluripotent Stem Cells Possibly in Cooperation with Proinflammatory Signaling.

Stem Cells Nov 2017, 35 (11) 2253-2266. Epub 23 Sep 2017
Runt-related transcription factor 1 (Runx1) is a master hematopoietic transcription factor essential for hematopoietic stem cell (HSC) emergence. Runx1-deficient mice die during early embryogenesis due to the inability to establish definitive hematopoiesis. Here, we have used human pluripotent stem cells (hPSCs) as model to study the role of RUNX1 in human embryonic hematopoiesis. Although the three RUNX1 isoforms a, b, and c were induced in CD45+ hematopoietic cells, RUNX1c was the only isoform induced in hematoendothelial progenitors (HEPs)/hemogenic endothelium. Constitutive expression of RUNX1c in human embryonic stem cells enhanced the appearance of HEPs, including hemogenic (CD43+) HEPs and promoted subsequent differentiation into blood cells. Conversely, specific deletion of RUNX1c dramatically reduced the generation of hematopoietic cells from HEPs, indicating that RUNX1c is a master regulator of human hematopoietic development. Gene expression profiling of HEPs revealed a RUNX1c-induced proinflammatory molecular signature, supporting previous studies demonstrating proinflammatory signaling as a regulator of HSC emergence. Collectively, RUNX1c orchestrates hematopoietic specification of hPSCs, possibly in cooperation with proinflammatory signaling. Stem Cells 2017;35:2253-2266.
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Ribera J, Zamora L, Morgades M, Mallo M, Solanes N, Batlle M, Vives S, Granada I, Juncà J, Malinverni R, Genescà E, Guàrdia R, Mercadal S, Escoda L, Martinez-Lopez J, Tormo M, Esteve J, Pratcorona M, Martinez-Losada C, Solé F, Feliu E, Ribera JM

Copy number profiling of adult relapsed B-cell precursor acute lymphoblastic leukemia reveals potential leukemia progression mechanisms.

Genes Chromosomes Cancer Nov 2017, 56 (11) 810-820. Epub 26 Aug 2017
The outcome of relapsed adult acute lymphoblastic leukemia (ALL) remains dismal despite new therapeutic approaches. Previous studies analyzing relapse samples have shown a high degree of heterogeneity regarding gene alterations without an evident relapse signature. Bone marrow or peripheral blood samples from 31 adult B-cell precursor ALL patients at first relapse, and 21 paired diagnostic samples were analyzed by multiplex ligation probe-dependent amplification (MLPA). Nineteen paired diagnostic and relapse samples of these 21 patients were also analyzed by SNP arrays. A trend to acquire homozygous CDKN2A/B deletions and a significant increase in the number of copy number alterations (CNA) was observed from diagnosis to first relapse. Evolution from an ancestral clone was the main pattern of clonal evolution. Relapse samples were extremely heterogeneous regarding CNA frequencies. However, CDKN2A/B, PAX5, ETV6, ATM, IKZF1, VPREB1, and TP53 deletions and duplications of 1q, 8q, 17q, 21, X/Y PAR1, and Xp were frequently detected at relapse. Duplications of genes involved in cell proliferation, drug resistance and stem cell homeostasis regulation, as well as deletions of KDM6A and STAG2 genes emerged as specific alterations at relapse. Genomics of relapsed adult B-cell precursor ALL is highly heterogeneous, although some recurrent lesions involved in essential pathways deregulation were frequently observed. Selective and simultaneous targeting of these deregulated pathways may improve the results of current salvage therapies.
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