Publicació científica

S'han trobat 1304 publicacions amb els criteris indicats.
Luscieti S, Galy B, Gutierrez L, Reinke M, Couso J, Shvartsman M, Di Pascale A, Witke W, Hentze MW, Pilo Boyl P, Sanchez M

The actin-binding protein profilin 2 is a novel regulator of iron homeostasis.

Blood 26 Oct 2017, 130 (17) 1934-1945. Epub 3 Ago 2017
Cellular iron homeostasis is controlled by the iron regulatory proteins (IRPs) 1 and 2 that bind cis-regulatory iron-responsive elements (IRE) on target messenger RNAs (mRNA). We identified profilin 2 (Pfn2) mRNA, which encodes an actin-binding protein involved in endocytosis and neurotransmitter release, as a novel IRP-interacting transcript, and studied its role in iron metabolism. A combination of electrophoretic mobility shift assay experiments and bioinformatic analyses led to the identification of an atypical and conserved IRE in the 3' untranslated region of Pfn2 mRNA. Pfn2 mRNA levels were significantly reduced in duodenal samples from mice with intestinal IRP ablation, suggesting that IRPs exert a positive effect on Pfn2 mRNA expression in vivo. Overexpression of Pfn2 in HeLa and Hepa1-6 cells reduced their metabolically active iron pool. Importantly, Pfn2-deficient mice showed iron accumulation in discrete areas of the brain (olfactory bulb, hippocampus, and midbrain) and reduction of the hepatic iron store without anemia. Despite low liver iron levels, hepatic hepcidin expression remained high, likely because of compensatory activation of hepcidin by mild inflammation. Splenic ferroportin was increased probably to sustain hematopoiesis. Overall, our results indicate that Pfn2 expression is controlled by the IRPs in vivo and that Pfn2 contributes to maintaining iron homeostasis in cell lines and mice.
Més informació
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.
Més informació
Baptista MJ, Tapia G, Hernández-Rivas JÁ, Martínez-Trillos A, Mate JL, Navarro JT

MYC-rearranged lymphomas other than Burkitt: Comparison between R-CHOP and Burkitt-type immunochemotherapy.

Med Clin (Barc) 23 Oct 2017, 149 (8) 339-342. Epub 23 Jun 2017
MYC-rearranged (MYC-R) lymphomas other than Burkitt lymphoma (BL) are very aggressive, with poor prognosis when treated with standard regimens. We aimed to study the characteristics and outcome of a series of MYC-R lymphomas comparing the treatment results between R-CHOP based and a specific intensive regimen for BL (BURKIMAB).
Més informació
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
Més informació
Marjanović MP, Hurtado-Bagès S, Lassi M, Valero V, Malinverni R, Delage H, Navarro M, Corujo D, Guberovic I, Douet J, Gama-Perez P, Garcia-Roves PM, Ahel I, Ladurner AG, Yanes O, Bouvet P, Suelves M, Teperino R, Pospisilik JA, Buschbeck M

MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD(+) consumption.

Nat. Struct. Mol. Biol. 9 Oct 2017, . Epub 9 Oct 2017
Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD(+)-derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain was essential for sustained optimal mitochondrial function but dispensable for gene regulation. Through direct binding, macroH2A1.1 inhibits basal poly-ADP ribose polymerase 1 (PARP-1) activity and thus reduces nuclear NAD(+) consumption. The resultant accumulation of the NAD(+) precursor NMN allows for maintenance of mitochondrial NAD(+) pools that are critical for respiration. Our data indicate that macroH2A1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD(+) consumption and establishing a buffer of NAD(+) precursors in differentiated cells.
Més informació
Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, Orlowski RZ, Ludwig H, Facon T, Hajek R, Weisel K, Hungria V, Minuk L, Feng S, Zahlten-Kumeli A, Kimball AS, Moreau P

Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial.

Lancet Oncol. Oct 2017, 18 (10) 1327-1337. Epub 23 Ago 2017
The phase 3 ENDEAVOR trial was a head-to-head comparison of two proteasome inhibitors in patients with relapsed or refractory multiple myeloma. Progression-free survival was previously reported to be significantly longer with carfilzomib administered in combination with dexamethasone than with bortezomib and dexamethasone in an interim analysis. The aim of this second interim analysis was to compare overall survival between the two treatment groups.
Més informació
Molina O, Kouprina N, Masumoto H, Larionov V, Earnshaw WC

Using human artificial chromosomes to study centromere assembly and function.

Chromosoma Oct 2017, 126 (5) 559-575. Epub 7 Jul 2017
Centromeres are the site of assembly of the kinetochore, which directs chromosome segregation during cell division. Active centromeres are characterized by the presence of nucleosomes containing CENP-A and a specific chromatin environment that resembles that of active genes. Recent work using human artificial chromosomes (HAC) sheds light on the fine balance of different histone post-translational modifications and transcription that exists at centromeres for kinetochore assembly and maintenance. Here, we review the use of HAC technology to understand centromere assembly and function. We put particular emphasis on studies using the alphoid
Més informació
Manils J, Fischer H, Climent J, Casas E, García-Martínez C, Bas J, Sukseree S, Vavouri T, Ciruela F, de Anta JM, Tschachler E, Eckhart L, Soler C

Double deficiency of Trex2 and DNase1L2 nucleases leads to accumulation of DNA in lingual cornifying keratinocytes without activating inflammatory responses.

Sci Rep 19 Set 2017, 7 (1) 11902. Epub 19 Set 2017
The cornification of keratinocytes on the surface of skin and oral epithelia is associated with the degradation of nuclear DNA. The endonuclease DNase1L2 and the exonuclease Trex2 are expressed specifically in cornifying keratinocytes. Deletion of DNase1L2 causes retention of nuclear DNA in the tongue epithelium but not in the skin. Here we report that lack of Trex2 results in the accumulation of DNA fragments in the cytoplasm of cornifying lingual keratinocytes and co-deletion of DNase1L2 and Trex2 causes massive accumulation of DNA fragments throughout the cornified layers of the tongue epithelium. By contrast, cornification-associated DNA breakdown was not compromised in the epidermis. Aberrant retention of DNA in the tongue epithelium was associated neither with enhanced expression of DNA-driven response genes, such as Ifnb, Irf7 and Cxcl10, nor with inflammation. Of note, the expression of Tlr9, Aim2 and Tmem173, key DNA sensor genes, was markedly lower in keratinocytes and keratinocyte-built tissues than in macrophages and immune tissues, and DNA-driven response genes were not induced by introduction of DNA in keratinocytes. Altogether, our results indicate that DNase1L2 and Trex2 cooperate in the breakdown and degradation of DNA during cornification of lingual keratinocytes and aberrant DNA retention is tolerated in the oral epithelium.
Més informació
Lo Re O, Fusilli C, Rappa F, Van Haele M, Douet J, Pindjakova J, Rocha SW, Pata I, Valčíková B, Uldrijan S, Yeung RS, Peixoto CA, Roskams T, Buschbeck M, Mazza T, Vinciguerra M

Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma.

Hepatology 15 Set 2017, . Epub 15 Set 2017
Hepatocellular carcinomas (HCC) contain a sub-population of cancer stem cells (CSCs), which exhibit stem-cell like features and are responsible for tumor relapse, metastasis, and chemoresistance. The development of effective treatments for HCC will depend on a molecular-level understanding of the specific pathways driving CSC emergence and stemness. MacroH2A1 is a variant of the histone H2A and an epigenetic regulator of stem cell function, where it promotes differentiation and, conversely, acts as a barrier to somatic cell reprogramming. Here we focused on the role played by the histone variant macroH2A1 as a potential epigenetic factor promoting CSC differentiation. In human HCC sections we uncovered a significant correlation between low frequencies of macroH2A1 staining and advanced, aggressive HCC subtypes with poorly-differentiated tumor phenotypes. Using HCC cell lines we found that shRNA-mediated macroH2A1 knock-down induces acquisition of CSC-like features, including the growth of significantly larger and less-differentiated tumors when injected into nude mice. MacroH2A1-depleted HCC cells also exhibited reduced proliferation, resistance to chemotherapeutic agents, and stem-like metabolic changes consistent with enhanced hypoxia responses and increased glycolysis. The loss of macroH2A1 increased expression of a panel of stemness-associated genes, and drove hyper-activation of the NF-κBp65 pathway. Blocking phosphorylation of NF-κBp65 on Ser536 inhibited the emergence of CSC-like features in HCC cells knocked-down for macroH2A1.
Més informació
Varela I, Menendez P, Sanjuan-Pla A

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

Oncotarget 12 Set 2017, 8 (39) 66742-66746. Epub 16 Ago 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.
Més informació