Buschbeck Lab 2021

Researchers at the Josep Carreras Institute find inhibition of CBP/p300 may enhance sensitivity of MDS cells to azacytidine

Scientists at the Josep Carreras Leukaemia Research Institute have found that it is possible to enhance the antitumor activity of azacytidine, one of the most common treatment option for patients with high-risk myelodysplastic syndrome, by inhibiting the CBP and p300 proteins. This finding opens the door to synergistically fight these kind of cancers, especially in patients at risk of developing acute myeloid leukemia.

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Recent publications

Morante-Palacios O, Lorente-Sorolla C, Ciudad L, Calafell-Segura J, Garcia-Gomez A, Català-Moll F, Ruiz-Sanmartín A, Martínez-Gallo M, Ferrer R, Ruiz-Rodriguez JC, Álvarez-Errico D, Ballestar E

JAK2-STAT Epigenetically Regulates Tolerized Genes in Monocytes in the First Encounter With Gram-Negative Bacterial Endotoxins in Sepsis

Front. Immunol. 12:734652. 17 Nov 2021, . Epub 17 Nov 2021
Microbial challenges, such as widespread bacterial infection in sepsis, induce endotoxin tolerance, a state of hyporesponsiveness to subsequent infections. The participation of DNA methylation in this process is poorly known. In this study, we perform integrated analysis of DNA methylation and transcriptional changes following in vitro exposure to gram-negative bacterial lipopolysaccharide, together with analysis of ex vivo monocytes from septic patients. We identify TET2-mediated demethylation and transcriptional activation of inflammation-related genes that is specific to toll-like receptor stimulation. Changes also involve phosphorylation of STAT1, STAT3 and STAT5, elements of the JAK2 pathway. JAK2 pathway inhibition impairs the activation of tolerized genes on the first encounter with lipopolysaccharide. We then confirm the implication of the JAK2-STAT pathway in the aberrant DNA methylome of patients with sepsis caused by gram-negative bacteria. Finally, JAK2 inhibition in monocytes partially recapitulates the expression changes produced in the immunosuppressive cellular state acquired by monocytes from gram-negative sepsis, as described by single cell-RNA-sequencing. Our study evidences both the crucial role the JAK2-STAT pathway in epigenetic regulation and initial response of the tolerized genes to gram-negative bacterial endotoxins and provides a pharmacological target to prevent exacerbated responses.
Cid E, Yamamoto M, Yamamoto F

Mixed-Up Sugars: Glycosyltransferase Cross-Reactivity in Cancerous Tissues and Their Therapeutic Targeting.

Chembiochem 2 Nov 2021, . Epub 2 Nov 2021
The main categories of glycan changes in cancer are: (1) decreased expression of histo-blood group A and/or B antigens and increased Lewis-related antigens, (2) appearance of cryptic antigens, such as Tn and T, (3) emergence of genetically incompatible glycans, such as A antigen expressed in tumors of individuals of group B or O and heterophilic expression of Forssman antigen (FORS1), and (4) appearance of neoglycans. This review focuses on the expression of genetically incompatible A/B/FORS1 antigens in cancer. Several possible molecular mechanisms are exemplified, including missense mutations that alter the sugar specificity of A and B glycosyltransferases (AT and BT, respectively), restoration of the correct codon reading frame of O alleles, and modification of acceptor specificity of AT to synthesize the FORS1 antigen by missense mutations and/or altered splicing. Taking advantage of pre-existing natural immunity, the potential uses of these glycans for immunotherapeutic targeting will also be discussed.
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Rodriguez-Cortez VC, Navarrete-Meneses MP, Molina O, Velasco-Hernandez T, Gonzalez J, Romecin P, Gutierrez-Aguera F, Roca-Ho H, Vinyoles M, Kowarz E, Marin P, Rodriguez-Perales S, Gomez-Marin C, Perez-Vera P, Cortes-Ledesma F, Bigas A, Terron A, Bueno C, Menendez P

The insecticides permethrin and chlorpyriphos show limited genotoxicity and no leukemogenic potential in human and murine hematopoietic stem progenitor cells.

Haematologica 28 Oct 2021, . Epub 28 Oct 2021
Not available.
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Soler M, Davalos V, Sánchez-Castillo A, Mora-Martinez C, Setién F, Siqueira E, Castro de Moura M, Esteller M, Guil S

The transcribed ultraconserved region uc.160+ enhances processing and A-to-I editing of the miR-376 cluster: hypermethylation improves glioma prognosis.

Mol Oncol 19 Oct 2021, . Epub 19 Oct 2021
Transcribed ultraconserved regions (T-UCRs) are noncoding RNAs derived from DNA sequences that are entirely conserved across species. Their expression is altered in many tumor types, and, although a role for T-UCRs as regulators of gene expression has been proposed, their functions remain largely unknown. Herein, we describe the epigenetic silencing of the uc.160+ T-UCR in gliomas and mechanistically define a novel RNA-RNA regulatory network in which uc.160+ modulates the biogenesis of several members of the miR-376 cluster. This includes the positive regulation of primary microRNA (pri-miRNA) cleavage and an enhanced A-to-I editing on its mature sequence. As a consequence, the expression of uc.160+ affects the downstream, miR-376-regulated genes, including the transcriptional coregulators RING1 and YY1-binding protein (RYBP) and forkhead box P2 (FOXP2). Finally, we elucidate the clinical impact of our findings, showing that hypermethylation of the uc.160+ CpG island is an independent prognostic factor associated with better overall survival in lower-grade gliomas, highlighting the importance of T-UCRs in cancer pathophysiology.
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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). 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.