sáncez-céspedes + Parra

Impuls a la valorització i transferència de coneixement i tecnologia dels projectes de l’Institut de Recerca contra la Leucèmia Josep Carreras

Dos projectes de l’Institut, dirigits per la Dra. Maribel Parra i la Dra. Montserrat Sanchez-Cespedes junt amb el Dr. Octavio Romero, accedeixen al programa IP Booster, de la Comissió Europea, i al Programa Gínjol, finançat per I-CERCA, per a escalar en el procés de valorització dels seus projectes i explorar la seva capacitat de transferència.

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sanchez-céspedes group

Investigadors de l'Institut Josep Carreras troben una debilitat que podria aprofitar-se per tractar càncers defectius per SMARCA4

La Dra. Montserrat Sánchez-Céspedes i el Dr. Octavio Romero, del grup de Genètica del Càncer de l'Institut de Recerca contra la Leucèmia Josep Carreras, han descobert recentment que els tumors amb una forma genèticament inactivada de la proteïna remodeladora de la cromatina SMARCA4 són molt sensibles als inhibidors de la família de desmetiladores d'histones KDM6.

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La doctora Ana Angulo-Urarte rep una beca d’investigació de la CLOVES Syndrome Community per estudiar els determinants genètics dels PROS

El seu projecte s’enfocarà als aspectes fisiològics i moleculars de l’espectre d’excés de creixement relacionat amb PIK3CA (PROS), per estudiar l’impacte que poden tenir diferents mutacions al gen PIK3CA en el tipus, la gravetat i la progressió de les afeccions relacionades amb CLOVES i PIK3CA, i identificar potencials dianes terapèutiques.

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Últimes publicacions

Patricia Garcia, Rita Fernandez-Hernandez, Ana Cuadrado, Ignacio Coca, Antonio Gomez, Maria Maqueda, Ana Latorre-Pellicer, Beatriz Puisac, Feliciano J. Ramos, Juan Sandoval, Esteller, Manel, Jose Luis Mosquera, Jairo Rodriguez, J. Pié, Ana Losada and Ethel Queralt

Disruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome

Nature Communications 27 Jul 2021, 12, 4551 . Epub 27 Jul 2021
Cornelia de Lange syndrome (CdLS) is a rare disease affecting multiple organs and systems during development. Mutations in the cohesin loader, NIPBL/Scc2, were first described and are the most frequent in clinically diagnosed CdLS patients. The molecular mechanisms driving CdLS phenotypes are not understood. In addition to its canonical role in sister chromatid cohesion, cohesin is implicated in the spatial organization of the genome. Here, we investigate the transcriptome of CdLS patient-derived primary fibroblasts and observe the downregulation of genes involved in development and system skeletal organization, providing a link to the developmental alterations and limb abnormalities characteristic of CdLS patients. Genome-wide distribution studies demonstrate a global reduction of NIPBL at the NIPBL-associated high GC content regions in CdLS-derived cells. In addition, cohesin accumulates at NIPBL-occupied sites at CpG islands potentially due to reduced cohesin translocation along chromosomes, and fewer cohesin peaks colocalize with CTCF.
Xavier Solanich, Gardenia Vargas-Parra, Caspar I. van der Made, Annet Simons, Janneke Schuurs-Hoeijmakers, Arnau Antolí, Jesús del Valle, Gemma Rocamora-Blanch, Fernando Setién, Esteller, Manel, Simon V. van Reijmersdal, Antoni Riera-Mestre, Joan Sabater-Riera, Gabriel Capellá, Frank L. van de Veerdonk, Ben van der Hoven, Xavier Corbella, Alexander Hoischen and Conxi Lázaro

Genetic Screening for TLR7 Variants in Young and Previously Healthy Men With Severe COVID-19

Front. Immunol 23 Jul 2021, 12 . Epub 23 Jul 2021
Introduction: Loss-of-function TLR7 variants have been recently reported in a small number of males to underlie strong predisposition to severe COVID-19. We aimed to determine the presence of these rare variants in young men with severe COVID-19. Methods: We prospectively studied males between 18 and 50 years-old without predisposing comorbidities that required at least high-flow nasal oxygen to treat COVID-19. The coding region of TLR7 was sequenced to assess the presence of potentially deleterious variants. Results: TLR7 missense variants were identified in two out of 14 patients (14.3%). Overall, the median age was 38 (IQR 30-45) years. Both variants were not previously reported in population control databases and were predicted to be damaging by in silico predictors. In a 30-year-old patient a maternally inherited variant [c.644A>G; p.(Asn215Ser)] was identified, co-segregating in his 27-year-old brother who also contracted severe COVID-19. A second variant [c.2797T>C; p.(Trp933Arg)] was found in a 28-year-old patient, co-segregating in his 24-year-old brother who developed mild COVID-19. Functional testing of this variant revealed decreased type I and II interferon responses in peripheral mononuclear blood cells upon stimulation with the TLR7 agonist imiquimod, confirming a loss-of-function effect. Conclusions: This study supports a rationale for the genetic screening for TLR7 variants in young men with severe COVID-19 in the absence of other relevant risk factors. A diagnosis of TLR7 deficiency could not only inform on treatment options for the patient, but also enables pre-symptomatic testing of at-risk male relatives with the possibility of instituting early preventive and therapeutic interventions.
Octavio A. Romero, Andrea Vilarrubi, Juan J. Alburquerque-Bejar, Antonio Gomez, Alvaro Andrades, Deborah Trastulli, Eva Pros, Fernando Setien, Sara Verdura, Lourdes Farré, Juan F. Martín-Tejera, Paula Llabata, Ana Oaknin, Maria Saigi, Josep M. Piulats, Xavier Matias-Guiu, Pedro P. Medina, August Vidal, Alberto Villanueva, Sanchez-Céspedes Montse

SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade

Nat Commun 14 Jul 2021, 12(1):4319 . Epub 14 Jul 2021
Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients.
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Berdasco M, Esteller M

Towards a "druggable" epitranscriptome: Compounds that target RNA modifications in cancer.

Br J Pharmacol 29 Jun 2021, . Epub 29 Jun 2021
Epitranscriptomics is an exciting emerging area that studies biochemical modifications of RNA. The field is boosted by the technical efforts of the last decade to characterize and quantify RNA modifications which have led to a map of post-transcripcional RNA marks in normal cell fate and develoment. However, the scientific interest has been fueled by the discovery of aberrant epitranscriptomes associated with human diseases, mainly cancer. The challenge is now to see whether epitrancriptomics offers a tunable mechanims to be targeted by small- molecule intervention. In this review, we will describe the principal RNA modifications (with a focus on mRNA), summarize the latest scientific evidences of their dysregulation in cancer and provide an overview of the state-of-the-art drug discovery to target the epitranscriptome. Finally, we will discuss the principal challenges in the field of chemical biology and drug development to increase the potential of targeted-RNA for clinical benefit.
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Mallo M, Solé F

Beyond morphology: to be or not to be an MDS.

Br J Haematol 28 Jun 2021, . Epub 28 Jun 2021
No abstract available
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