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Research in to the basic, epidemiological, preventive, clinical and translational aspects of leukaemia and other hematologic malignancies

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2020 November 16

Dr. Manel Esteller, director of the Josep Carreras Leukaemia Research Institute, recognized among the scientists with the most impact according to Stanford University

Manel Esteller, Director of the Josep Carreras Leukemia Research Institute (IJC), ICREA Researcher and Professor of Genetics at the University of Barcelona is recognized by the prestigious Stanford  University in the United States among the 0.001% of researchers with the most impact on world level in all areas of Science.

Recent publications

Cuatrecasas M, Gorostiaga I, Riera C, Saperas E, Llort G, Costa I, Matias-Guiu X, Carrato C, Navarro M, Pineda M, Dueñas N, Brunet J, Marco V, Trias I, Busteros JI, Mateu G, Balaguer F, Fernández-Figueras MT,, Esteller M, Musulén E.

Complete Loss of EPCAM Immunoexpression Identifies EPCAM Deletion Carriers in MSH2-Negative Colorectal Neoplasia

Cancers (Basel) . 2020 Sep 29;12(10):E2803 29 Sep 2020, .
The use of epithelial cell adhesion molecule (EPCAM) immunohistochemistry (IHC) is not included in the colorectal cancer (CRC) screening algorithm to detect Lynch syndrome (LS) patients. The aim of the present study was to demonstrate that EPCAM IHC is a useful tool to guide the LS germ-line analysis when a loss of MSH2 expression was present. We retrospectively studied MSH2 and EPCAM IHC in a large series of 190 lesions composed of malignant neoplasms (102), precursor lesions of gastrointestinal (71) and extra-gastrointestinal origin (9), and benign neoplasms (8) from different organs of 71 patients suspicious of being LS due to MSH2 alterations. LS was confirmed in 68 patients, 53 with MSH2 mutations and 15 with EPCAM 3'-end deletions. Tissue microarrays were constructed with human normal tissues and their malignant counterparts to assist in the evaluation of EPCAM staining. Among 154 MSH2-negative lesions, 17 were EPCAM-negative, including 10 CRC and 7 colorectal polyps, and 5 of them showed only isolated negative glands. All lesions showing a lack of EPCAM expression belonged to patients with EPCAM 3'-end deletions. EPCAM IHC is a useful screening tool, with 100% specificity to identify LS patients due to EPCAM 3'-end deletions in MSH2-negative CRC and MSH2-negative colorectal polyps.
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Esteve-Puig R, Climent F, Piñeyro D, Domingo-Domènech E, Davalos V, Encuentra M, Rea A, Espejo-Herrera N, Soler M, Lopez M, Ortiz-Barahona V, Tapia G, Navarro T, Cid J, Farré L, Villanueva A, Casanova I, Mangues R, Santamarina-Ojeda P, Fernández AF, Fraga MF, Piris MA, Kol N, Avrahami C, Moshitch-Moshkovitz S, Rechavi G, Sureda A, Esteller M

Epigenetic Loss of m1A RNA Demethylase ALKBH3 in Hodgkin Lymphoma Targets Collagen Conferring Poor Clinical Outcome

Blood 15 Sep 2020, .
No abstract available
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Janin, M, Esteller, M

Epigenetic Awakening of Viral Mimicry in Cancer

Cancer Discov . 2020 Sep;10(9):1258-1260 10 Sep 2020, .
In this issue, Deblois and colleagues show how taxane-resistant triple-negative breast cancer cells evade viral mimicry response as a result of metabolic alteration, DNA hypomethylation, and relocation of histone H3K27 trimethylation (H3K27me3). This adaptation confers a therapeutic vulnerability to the inhibition of the H3K27me3 methyltransferase EZH2 in resistant cells, leading to tumor growth inhibition by viral mimicry reactivation.
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Rosselló-Tortella M, Llinàs-Arias P, Sakaguchi Y, Miyauchi K, Davalos V, Setien F, Calleja-Cervantes ME, Piñeyro D, Martínez-Gómez J, Guil S, Joshi R, Villanueva A, Suzuki T, Esteller M

Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer

Proc Natl Acad Sci U S A. 2020 Aug 25 25 Aug 2020, 117(34):20785-20793 .
Transfer RNA (tRNA) activity is tightly regulated to provide a physiological protein translation, and tRNA chemical modifications control its function in a complex with ribosomes and messenger RNAs (mRNAs). In this regard, the correct hypermodification of position G37 of phenylalanine-tRNA, adjacent to the anticodon, is critical to prevent ribosome frameshifting events. Here we report that the tRNA-yW Synthesizing Protein 2 (TYW2) undergoes promoter hypermethylation-associated transcriptional silencing in human cancer, particularly in colorectal tumors. The epigenetic loss of TYW2 induces guanosine hypomodification in phenylalanine-tRNA, an increase in -1 ribosome frameshift events, and down-regulation of transcripts by mRNA decay, such as of the key cancer gene ROBO1. Importantly, TYW2 epigenetic inactivation is linked to poor overall survival in patients with early-stage colorectal cancer, a finding that could be related to the observed acquisition of enhanced migration properties and epithelial-to-mesenchymal features in the colon cancer cells that harbor TYW2 DNA methylation-associated loss. These findings provide an illustrative example of how epigenetic changes can modify the epitranscriptome and further support a role for tRNA modifications in cancer biology
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SirT7 auto-ADP-ribosylation regulates glucose starvation response through mH2A1

Science Advances 24 Jul 2020, 6 .
Sirtuins are key players of metabolic stress response. Originally described as deacetylases, some sirtuins also exhibit poorly understood mono–adenosine 5′-diphosphate (ADP)–ribosyltransferase (mADPRT) activity. We report that the deacetylase SirT7 is a dual sirtuin, as it also features auto-mADPRT activity. SirT7 mADPRT occurs at a previously undefined active site, and its abrogation alters SirT7 chromatin distribution. We identify an epigenetic pathway by which ADP-ribosyl-SirT7 is recognized by the ADP-ribose reader mH2A1.1 under glucose starvation, inducing SirT7 relocalization to intergenic regions. SirT7 promotes mH2A1 enrichment in a subset of nearby genes, many of them involved in second messenger signaling, resulting in their specific up- or down-regulation. The expression profile of these genes under calorie restriction is consistently abrogated in SirT7-deficient mice, resulting in impaired activation of autophagy. Our work provides a novel perspective on sirtuin duality and suggests a role for SirT7/mH2A1.1 axis in glucose homeostasis and aging.

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