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Buschbeck Lab 2021

Investigadors de l’Institut Josep Carreras troben que la inhibició de CBP/p300 pot augmentar la sensibilitat de les cèl·lules MDS a l’azacitidina

Científics de l'Institut de Recerca contra la Leucèmia Josep Carreras han descobert que és possible potenciar l'activitat antitumoral de la azacitidina, un dels medicaments més habituals per als pacients amb síndrome mielodisplàstica d'alt risc, mitjançant la inhibició de les proteïnes CBP i p300. Aquesta troballa obre la porta a combatre de manera sinèrgica aquests tipus de càncer, especialment en pacients amb risc de desenvolupar leucèmia mieloide aguda.

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informe REDECAN 2021

REDECAN publica les últimes dades de la incidència de neoplàsies hematològiques a Espanya

El Dr. Rafael Marcos-Gragera, membre de l'Institut de Recerca contra la Leucèmia Josep Carreras i líder del grup de el Registre del Càncer de Girona, de l'Institut Català d'Oncologia / Pla director d'oncologia, ha coordinat l'informe publicat per la Xarxa Espanyola de Registres de el Càncer (REDECAN) sobre la incidència de neoplàsies hematològiques que pronostica el diagnòstic de 26.000 nous casos el 2021. 

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sanchez-céspedes group

Noves dades sobre el paper de la proteïna MAX en el càncer de pulmó

Un equip científic liderat per la Dra. Montse Sanchez-Cespedes, líder de grup de l'Institut de Recerca contra la Leucèmia Josep Carreras, prova les característiques i la funció supressora de tumors de MAX i el seu paper en el desenvolupament de el càncer de pulmó de cèl·lules petites, un tipus de càncer de pulmó molt agressiu. Els resultats mostren que les cèl·lules canceroses que no tenen MAX presenten característiques neuroendocrines (tipus ASLC1 o NEUROD1) i que la seva capacitat oncogènica, independent de l'oncogèn MYC, implica una funció anormal del complex repressiu ncPRC1.6. 

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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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Últimes publicacions

Jeannine Diesch, Marguerite-Marie Le Pannérer, René Winkler, Raquel Casquero, Matthias Muhar, Mark van der Garde, Michael Maher, Carolina Martínez Herráez, Joan J. Bech-Serra, Michaela Fellner, Philipp Rathert, Nigel Brooks, Lurdes Zamora, Antonio Gentilella, Carolina de la Torre, Johannes Zuber, Katharina S. Götze & Marcus Buschbeck

Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis

Nat Commun 12, 6060 (2021). https://doi.org/10.1038/s41467-021-26258-z 18 Oct 2021, .
The nucleotide analogue azacitidine (AZA) is currently the best treatment option for patients with high-risk myelodysplastic syndromes (MDS). However, only half of treated patients respond and of these almost all eventually relapse. New treatment options are urgently needed to improve the clinical management of these patients. Here, we perform a loss-of-function shRNA screen and identify the histone acetyl transferase and transcriptional co-activator, CREB binding protein (CBP), as a major regulator of AZA sensitivity. Compounds inhibiting the activity of CBP and the closely related p300 synergistically reduce viability of MDS-derived AML cell lines when combined with AZA. Importantly, this effect is specific for the RNA-dependent functions of AZA and not observed with the related compound decitabine that is only incorporated into DNA. The identification of immediate target genes leads us to the unexpected finding that the effect of CBP/p300 inhibition is mediated by globally down regulating protein synthesis.
Laura G.Rico, Roser Salvia, Michael D.Ward, JordiPetriz

Flow-cytometry-based protocols for human blood/marrow immunophenotyping with minimal sample perturbation

STAR Protocols, Volume 2, Issue 4, 2021 11 Oct 2021, .
This protocol provides instructions to improve flow cytometry analysis of marrow/peripheral blood cells by avoiding erythrolytic solutions, density gradients, and washing steps. We describe two basic approaches for identifying cell surface antigens with minimal sample perturbation, which have been successfully used to identify healthy and pathologically rare cells. The greatest advantage of these approaches is that they minimize the unwanted effect caused by sample preparation, allowing for improved study of live cells at the point of analysis.
Garcia-Prieto CA, Villanueva L, Bueno-Costa A, Davalos V, González-Navarro EA, Juan M, Urbano-Ispizua Á, Delgado J, Ortíz-Maldonado V, Del Bufalo F, Locatelli F, Quintarelli C, Sinibaldi M, Soler M, Castro de Moura M, Ferrer G, Urdinguio RG, Fernandez AF, Fraga MF, Bar D, Meir A, Itzhaki O, Besser MJ, Avigdor A, Jacoby E, Esteller M

Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies.

J Natl Cancer Inst 28 Set 2021, . Epub 28 Set 2021
Background: Chimeric antigen receptor (CAR) T-cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course. Methods: We recruited 114 patients with B-cell malignancies, comprising 77 acute lymphoblastic leukemia (ALL) and 37 non-Hodgkin lymphoma (NHL) patients, who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T-cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), event-free survival (EFS) and overall survival (OS) were assessed. All statistical tests were 2-sided. Results: We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T-cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR) adjusting by multiple testing. Using the sites linked to CR, the EPICART signature was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher's exact test, P<.001) and enhanced EFS (HR = 0.36, 95% CI = 0.19 to 0.70, P=.002; log-rank P=.003) and OS (HR = 0.45, 95% CI = 0.20 to 0.99, P=.047; log-rank P=.04;). Most important the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35) where it was associated with CR (Fisher's exact test, P<.001) and enhanced OS (HR = 0.31, 95% CI = 0.11 to 0.84, P=.02; log-rank P=.02). Conclusions: We show that the DNA methylation landscape of patient CART19 cells influences the efficacy of the cellular immunotherapy treatment in patients with B-cell malignancy.
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Ribeiro ML, Reyes-Garau D, Vinyoles M, Profitos-Peleja N, Santos JC, Armengol M, Fernández-Serrano M, Sedo Mor A, Bech-Serra JJ, Blecua P, Musulen E, De La Torre C, Miskin HP, Esteller M, Bosch F, Menéndez P, Normant E, Roué G

Antitumor activity of the novel BTK inhibitor TG-1701 is associated with disruption of Ikaros signaling in patients with B-cell non-Hodgkin lymphoma.

Clin Cancer Res 22 Set 2021, . Epub 22 Set 2021
Purpose: Despite the remarkable activity of BTK inhibitors (BTKi) in relapsed B-cell non-Hodgkin lymphoma (B-NHL), no clinically-relevant biomarker has been associated to these agents so far. The relevance of phosphoproteomic profiling for the early identification of BTKi responders remains underexplored. Experimental design: A set of six clinical samples from an ongoing phase 1 trial dosing chronic lymphocytic leukemia (CLL) patients with TG-1701, a novel irreversible and highly specific BTKi, were characterized by phosphoproteomic and RNA-seq analysis. The activity of TG-1701 was evaluated in a panel of eleven B-NHL cell lines and mouse xenografts, including two NFκB- and BTKC481S-driven BTKi resistant models. Biomarker validation and signal transduction analysis were conducted through real-time PCR, western blot, immunostaining and gene knock-out (KO) experiments. Results: A non-supervised, phosphoproteomic-based clustering did match the early clinical outcomes of CLL patients and separated a group of "early-responders" from a group of "late-responders". This clustering was based on a selected list of 96 phosphosites with Ikaros-pSer442/445 as a potential biomarker for TG-1701 efficacy. TG-1701 treatment was further shown to blunt Ikaros gene signature, including YES1 and MYC, in early-responder patients as well as in BTKi-sensitive B-NHL cell lines and xenografts. In contrast, Ikaros nuclear activity and signaling remained unaffected by the drug in vitro and in vivo, in late-responder patients and in BTKC481S, BTKKO and non-canonical NFκB models. Conclusions: These data validate phosphoproteomic as a valuable tool for the early detection of response to BTK inhibition in the clinic, and for the determination of drug mechanism of action.
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Llabata P, Torres-Diz M, Gomez A, Tomas-Daza L, Romero OA, Grego-Bessa J, Llinas-Arias P, Valencia A, Esteller M, Javierre BM, Zhang X, Sanchez-Cespedes M

MAX mutant small-cell lung cancers exhibit impaired activities of MGA-dependent noncanonical polycomb repressive complex.

Proc Natl Acad Sci U S A 14 Set 2021, 118 (37) .
The MYC axis is disrupted in cancer, predominantly through activation of the MYC family oncogenes but also through inactivation of the MYC partner MAX or of the MAX partner MGA. MGA and MAX are also members of the polycomb repressive complex, ncPRC1.6. Here, we use genetically modified MAX-deficient small-cell lung cancer (SCLC) cells and carry out genome-wide and proteomics analyses to study the tumor suppressor function of MAX. We find that MAX mutant SCLCs have ASCL1 or NEUROD1 or combined ASCL1/NEUROD1 characteristics and lack MYC transcriptional activity. MAX restitution triggers prodifferentiation expression profiles that shift when MAX and oncogenic MYC are coexpressed. Although ncPRC1.6 can be formed, the lack of MAX restricts global MGA occupancy, selectively driving its recruitment toward E2F6-binding motifs. Conversely, MAX restitution enhances MGA occupancy to repress genes involved in different functions, including stem cell and DNA repair/replication. Collectively, these findings reveal that MAX mutant SCLCs have either ASCL1 or NEUROD1 or combined characteristics and are MYC independent and exhibit deficient ncPRC1.6-mediated gene repression.
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