Research publications

Found 141 publicacions matching the indicated search criteria.
Fernandez AF, Bayón GF, Sierra MI, Urdinguio RG, Toraño EG, García M, Carella A, Lopez V, Santamarina P, Pérez RF, Belmonte T, Ramon Tejedor J, Cobo I, Menendez P, Mangas C, Ferrero C, Rodrigo L, Astudillo A, Ortea I, Cueto Díaz S, Rodríguez-Gonzalez P, Ignacio García Alonso J, Mollejo M, Meléndez B, Dominguez G, Bonilla F, Fraga MF

Loss of 5hmC identifies a new type of aberrant DNA hypermethylation in glioma.

Hum. Mol. Genet. 5 Jun 2018, . Epub 5 Jun 2018
Aberrant DNA hypermethylation is a hallmark of cancer although the underlying molecular mechanisms are still poorly understood. To study the possible role of 5-hydroxymethylcytosine (5hmC) in this process we analyzed the global and locus-specific genome-wide levels of 5hmC and 5mC in human primary samples from 12 non-tumoral brains and 53 gliomas. We found that the levels of 5hmC identified in non-tumoral samples were significantly reduced in gliomas. Strikingly, hypo-hydroxymethylation at 4,627 (9.3%) CpG sites was associated with aberrant DNA hypermethylation and was strongly enriched in CpG island (CGI) shores. The DNA regions containing these CpG sites were enriched in H3K4me2 and presented a different genuine chromatin signature to that characteristic of the genes classically aberrantly hypermethylated in cancer. As this 5mC gain is inversely correlated with loss of 5hmC and has not been identified with classical sodium bisulfite-based technologies, we conclude that our data identifies a novel 5hmC-dependent type of aberrant DNA hypermethylation in glioma.
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García-Peydró M, Fuentes P, Mosquera M, García-León MJ, Alcain J, Rodríguez A, de Miguel PG, Menéndez P, Weijer K, Spits H, Scadden DT, Cuesta-Mateos C, Muñoz-Calleja C, Sánchez-Madrid F, Toribio ML

The NOTCH1/CD44 axis drives pathogenesis in a T cell acute lymphoblastic leukemia model.

J. Clin. Invest. 21 May 2018, . Epub 21 May 2018
NOTCH1 is a prevalent signaling pathway in T cell acute lymphoblastic leukemia (T-ALL), but crucial NOTCH1 downstream signals and target genes contributing to T-ALL pathogenesis cannot be retrospectively analyzed in patients and thus remain ill defined. This information is clinically relevant, as initiating lesions that lead to cell transformation and leukemia-initiating cell (LIC) activity are promising therapeutic targets against the major hurdle of T-ALL relapse. Here, we describe the generation in vivo of a human T cell leukemia that recapitulates T-ALL in patients, which arises de novo in immunodeficient mice reconstituted with human hematopoietic progenitors ectopically expressing active NOTCH1. This T-ALL model allowed us to identify CD44 as a direct NOTCH1 transcriptional target and to recognize CD44 overexpression as an early hallmark of preleukemic cells that engraft the BM and finally develop a clonal transplantable T-ALL that infiltrates lymphoid organs and brain. Notably, CD44 is shown to support crucial BM niche interactions necessary for LIC activity of human T-ALL xenografts and disease progression, highlighting the importance of the NOTCH1/CD44 axis in T-ALL pathogenesis. The observed therapeutic benefit of anti-CD44 antibody administration in xenotransplanted mice holds great promise for therapeutic purposes against T-ALL relapse.
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Tejedor JR, Bueno C, Cobo I, Bayón GF, Prieto C, Mangas C, Pérez RF, Santamarina P, Urdinguio RG, Menéndez P, Fraga MF, Fernández AF

Epigenome-wide analysis reveals specific DNA hypermethylation of T cells during human hematopoietic differentiation.

Epigenomics 5 Apr 2018, . Epub 5 Apr 2018
Epigenetic regulation plays an important role in cellular development and differentiation. A detailed map of the DNA methylation dynamics that occur during cell differentiation would contribute to decipher the molecular networks governing cell fate commitment.
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Prieto C, López-Millán B, Roca-Ho H, Stam RW, Romero-Moya D, Rodríguez-Baena FJ, Sanjuan-Pla A, Ayllón V, Ramírez M, Bardini M, De Lorenzo P, Valsecchi MG, Stanulla M, Iglesias M, Ballerini P, Carcaboso ÁM, Mora J, Locatelli F, Bertaina A, Padilla L, Carlos Rodríguez-Manzaneque J, Bueno C, Menéndez P

NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL.

Leukemia Mar 2018, 32 (3) 633-644. Epub 25 Sep 2017
Mixed-lineage leukemia (MLL)-rearranged (MLLr) infant B-cell acute lymphoblastic leukemia (iMLLr-B-ALL) has a dismal prognosis and is associated with a pro-B/mixed phenotype, therapy refractoriness and frequent central nervous system (CNS) disease/relapse. Neuron-glial antigen 2 (NG2) is specifically expressed in MLLr leukemias and is used in leukemia immunophenotyping because of its predictive value for MLLr acute leukemias. NG2 is involved in melanoma metastasis and brain development; however, its role in MLL-mediated leukemogenesis remains elusive. Here we evaluated whether NG2 distinguishes leukemia-initiating/propagating cells (L-ICs) and/or CNS-infiltrating cells (CNS-ICs) in iMLLr-B-ALL. Clinical data from the Interfant cohort of iMLLr-B-ALL demonstrated that high NG2 expression associates with lower event-free survival, higher number of circulating blasts and more frequent CNS disease/relapse. Serial xenotransplantation of primary MLL-AF4
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Meyer C, Burmeister T, Gröger D, Tsaur G, Fechina L, Renneville A, Sutton R, Venn NC, Emerenciano M, Pombo-de-Oliveira MS, Barbieri Blunck C, Almeida Lopes B, Zuna J, Trka J, Ballerini P, Lapillonne H, De Braekeleer M, Cazzaniga G, Corral Abascal L, van der Velden VHJ, Delabesse E, Park TS, Oh SH, Silva MLM, Lund-Aho T, Juvonen V, Moore AS, Heidenreich O, Vormoor J, Zerkalenkova E, Olshanskaya Y, Bueno C, Menendez P, Teigler-Schlegel A, Zur Stadt U, Lentes J, Göhring G, Kustanovich A, Aleinikova O, Schäfer BW, Kubetzko S, Madsen HO, Gruhn B, Duarte X, Gameiro P, Lippert E, Bidet A, Cayuela JM, Clappier E, Alonso CN, Zwaan CM, van den Heuvel-Eibrink MM, Izraeli S, Trakhtenbrot L, Archer P, Hancock J, Möricke A, Alten J, Schrappe M, Stanulla M, Strehl S, Attarbaschi A, Dworzak M, Haas OA, Panzer-Grümayer R, Sedék L, Szczepański T, Caye A, Suarez L, Cavé H, Marschalek R

The MLL recombinome of acute leukemias in 2017.

Leukemia Feb 2018, 32 (2) 273-284. Epub 13 Jul 2017
Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.
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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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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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Body S, Esteve-Arenys A, Miloudi H, Recasens-Zorzo C, Tchakarska G, Moros A, Bustany S, Vidal-Crespo A, Rodriguez V, Lavigne R, Com E, Casanova I, Mangues R, Weigert O, Sanjuan-Pla A, Menéndez P, Marcq B, Picquenot JM, Pérez-Galán P, Jardin F, Roué G, Sola B

Cytoplasmic cyclin D1 controls the migration and invasiveness of mantle lymphoma cells.

Sci Rep 24 Oct 2017, 7 (1) 13946. Epub 24 Oct 2017
Mantle cell lymphoma (MCL) is a hematologic neoplasm characterised by the t(11;14)(q13;q32) translocation leading to aberrant cyclin D1 expression. The cell functions of cyclin D1 depend on its partners and/or subcellular distribution, resulting in different oncogenic properties. We observed the accumulation of cyclin D1 in the cytoplasm of a subset of MCL cell lines and primary cells. In primary cells, this cytoplasmic distribution was correlated with a more frequent blastoid phenotype. We performed immunoprecipitation assays and mass spectrometry on enriched cytosolic fractions from two cell lines. The cyclin D1 interactome was found to include several factors involved in adhesion, migration and invasion. We found that the accumulation of cyclin D1 in the cytoplasm was associated with higher levels of migration and invasiveness. We also showed that MCL cells with high cytoplasmic levels of cyclin D1 engrafted more rapidly into the bone marrow, spleen, and brain in immunodeficient mice. Both migration and invasion processes, both in vivo and in vitro, were counteracted by the exportin 1 inhibitor KPT-330, which retains cyclin D1 in the nucleus. Our data reveal a role of cytoplasmic cyclin D1 in the control of MCL cell migration and invasion, and as a true operator of MCL pathogenesis.
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Prieto C, Marschalek R, Kühn A, Bursen A, Bueno C, Menéndez P

The AF4-MLL fusion transiently augments multilineage hematopoietic engraftment but is not sufficient to initiate leukemia in cord blood CD34

Oncotarget 10 Oct 2017, 8 (47) 81936-81941. Epub 26 Jul 2017
The translocation t(4;11)(q21;q23) is the hallmark genetic abnormality associated with infant pro-B acute lymphoblastic leukemia (B-ALL) and has the highest frequency of rearrangement in Mixed-lineage leukemia (MLL) leukemias. Unlike other MLL translocations, MLL-AF4-induced proB-ALL is exceptionally difficult to model in mice/humans. Previous work has investigated the relevance of the reciprocal translocation fusion protein AF4-MLL for t(4;11) leukemia, finding that AF4-MLL is capable of inducing proB-ALL without requirement for MLL-AF4 when expressed in murine hematopoietic stem/progenitor cells (HSPCs). Therefore, AF4-MLL might represent a key genetic lesion contributing to t(4;11)-driven leukemogenesis. Here, we aimed to establish a humanized mouse model by using AF4-MLL to analyze its transformation potential in human cord blood-derived CD34
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Varela I, Menendez P, Sanjuan-Pla A

Intratumoral heterogeneity and clonal evolution in blood malignancies and solid tumors.

Oncotarget 12 Sep 2017, 8 (39) 66742-66746. Epub 16 Aug 2017
This meeting held at the University of Barcelona in March 2017, brought together scientists and clinicians worldwide to discuss current and future clinico-biological implications of intratumoral heterogeneity (ITH) and subclonal evolution in cancer diagnosis, patient stratification, and treatment resistance in diagnosis, treatment and follow-up. There was consensus that both longitudinal and tumor multi-region studies in matched samples are needed to better understand the dynamics of ITH. The contribution of the epigenome and microenvironment to ITH and subclone evolution remains understudied. It was recommended to combine computational, pathology and imaging tools to study the role of the microenvironment in subclone selection/evolution.
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