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Manel Esteller Credit Sonia Troncoso

Dr. Manel Esteller receives the Admirables Award in Biomedical Research

The director of the Josep Carreras Leukaemia Research Institute, Dr. Manel Esteller, has been awarded the Admirables prize for his scientific career in biomedical research. Diario Médico and Correo Farmacéutico awarded this prize to Dr. Esteller in recognition of his research in epigenetics and its alterations in human diseases, especially in cancer.

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Manel Esteller & Vanessa Ortiz

Epigenetic weaknesses discovered in liver cancer capable of improving its treatment

Researchers at the Josep Carreras Leukaemia Research Institute, led by Dr. Manel Esteller, have discovered a key epigenetic alteration that anticipates the clinical course of liver cancer. This is the deactivation of the NSUN7 gene, which is an epigenetic editor of RNA. Tumors with this alteration tend to have a poor clinical prognosis, although the research indicates that they are more vulnerable to bromodomain inhibitors, a family of anticancer drugs.

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Manel Esteller i Salvador Macip

Researcher Salvador Macip joins the Josep Carreras Leukaemia Research Institute

Researcher Salvador Macip, an expert in the study of cancer and senescence, joins the Josep Carreras Leukaemia Research Institute to lead the "Mechanisms of Cancer and Ageing" group. Dr. Macip will collaborate with specialists in epigenetics and senescence at the Josep Carreras Institute and will keep his current affiliations as professor, researcher and Director of Health Sciences Studies at the Universitat Oberta de Catalunya and the University of Leicester (UK).

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Genescà i Solé

Genomic studies gain importance in the diagnosis of new generation in hematologic cancer

The researchers Eulàlia Genescà and Francesc Solé, from the Josep Carreras Leukaemia Research Institute, have organized the third edition of the course "NEXT, New Generation Diagnosis in Leukemia" together with the Spanish Society of Hematology and Hemotherapy (SEHH). The course, which has the support of the Spanish Program for Hematology Treatments (PETHEMA) of the SEHH, has shown that the diagnosis of leukemia, and of hematological cancer in general, "is at the same level in Spain as in countries with a recognized track record", according to both experts.

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Visita Pedro Sánchez

The President of the Government of Spain, Pedro Sánchez, visits the Josep Carreras Institute and praises its research against cancer

The President Pedro Sánchez has visited the Josep Carreras Leukaemia Research Institute this Thursday, May 4, where he has been able to learn more about the research carried out to advance the fight against diseases such as leukemia and cancer. The head of the Spanish Chief Executive was accompanied by Josep Carreras, President of the Institute’s Board of Trustees and the Josep Carreras Foundation, and Miquel Iceta, Minister of Culture and Sports.

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Javier Briones

Launch of a clinical trial with CAR-T against lymphoma, developed by Dr. Briones, member of the Josep Carreras Institute

The first patients are being treated with a CAR-T drug against B lymphomas in a Phase I study. This new advanced therapy drug offers a therapeutic proposal, unique in Spain, for patients with some types of lymphatic cancer that have not responded well to conventional treatments. CAR-T 19 SP is the second drug of this type produced and developed entirely at the Research Institute of the Hospital de la Santa Creu i Sant Pau - IIB-Sant Pau, which already has two academic CAR-Ts of its own production. The research project is led by Dr. Javier Briones, head of the Cellular Immunotherapy and Gene Therapy Research Group at IIB-Sant Pau, member of the Josep Carreras Leukaemia Research Institute and head of the Clinical Hematology Unit of the Hematology Service of the Hospital de Sant Pau.

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Ainara Meler Premi Immunologia

The researcher Ainara Meler receives the award for the best scientific publication in immunology

On April 27, in the framework of the International Day of Immunology (April 29), the Catalan Society of Immunology celebrated its traditional Awards in recognition of those researchers who have made significant contributions in the field of immunology. This year the award for the best scientific publication in the category of new researcher was given to Ainara Meler, researcher of the Development and Lymphocytic Diseases group of the Josep Carreras Leukaemia Research Institute.

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Grup Genética del Cáncer Sanchez-Cespedes

Researchers find out why some lung tumors avoid immunotherapy and how to predict it in advance

The oncogenic activation of MYC, a critical gene in cancer progression, has the potential to identify lung cancer patients who may respond poorly to immunotherapy (ICB). This is the main conclusion of a study recently published by a team of researchers led by Dr. Montse Sanchez-Cespedes, Principal Investigator of the Cancer Genetics group at the Josep Carreras Leukaemia Research Institute. Their findings highlight a major contributor to poor response and suggest a new approach to selecting patients who will benefit from ICB or require alternative treatments well in advance.

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Recent publications

Ortiz-Barahona V, Soler M, Davalos V, García-Prieto CA, Janin M, Setien F, Fernández-Rebollo I, Bech-Serra JJ, De La Torre C, Guil S, Villanueva A, Zhang PH, Yang L, Guarnacci M, Schumann U, Preiss T, Balaseviciute U, Montal R, Llovet JM, Esteller M

Epigenetic inactivation of the 5-methylcytosine RNA methyltransferase NSUN7 is associated with clinical outcome and therapeutic vulnerability in liver cancer.

Molecular Cancer 12 May 2023, 22 (1) 83. Epub 12 May 2023
Background: RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggests that the epitranscriptome and its associated enzymes are altered in human tumors. Methods: Combining data mining and conventional experimental procedures, NSUN7 methylation and expression status was assessed in liver cancer cell lines and primary tumors. Loss-of-function and transfection-mediated recovery experiments coupled with RNA bisulfite sequencing and proteomics determined the activity of NSUN7 in downstream targets and drug sensitivity. Results: In this study, the initial screening for genetic and epigenetic defects of 5-methylcytosine RNA methyltransferases in transformed cell lines, identified that the NOL1/NOP2/Sun domain family member 7 (NSUN7) undergoes promoter CpG island hypermethylation-associated with transcriptional silencing in a cancer-specific manner. NSUN7 epigenetic inactivation was common in liver malignant cells and we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) to find the RNA targets of this poorly characterized putative RNA methyltransferase. Using knock-out and restoration-of-function models, we observed that the mRNA of the coiled-coil domain containing 9B (CCDC9B) gene required NSUN7-mediated methylation for transcript stability. Most importantly, proteomic analyses determined that CCDC9B loss impaired protein levels of its partner, the MYC-regulator Influenza Virus NS1A Binding Protein (IVNS1ABP), creating sensitivity to bromodomain inhibitors in liver cancer cells exhibiting NSUN7 epigenetic silencing. The DNA methylation-associated loss of NSUN7 was also observed in primary liver tumors where it was associated with poor overall survival. Interestingly, NSUN7 unmethylated status was enriched in the immune active subclass of liver tumors. Conclusion: The 5-methylcytosine RNA methyltransferase NSUN7 undergoes epigenetic inactivation in liver cancer that prevents correct mRNA methylation. Furthermore, NSUN7 DNA methylation-associated silencing is associated with clinical outcome and distinct therapeutic vulnerability.
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Mohty M, Malard F, Alaskar AS, Aljurf M, Arat M, Bader P, Baron F, Bazarbachi A, Blaise D, Brissot E, Ciceri F, Corbacioglu S, Dalle JH, Dignan F, Huynh A, Kenyon M, Nagler A, Pagliuca A, Perić Z, Richardson PG, Ruggeri A, Ruutu T, Yakoub-Agha I, Duarte RF, Carreras E

Diagnosis and severity criteria for sinusoidal obstruction syndrome/veno-occlusive disease in adult patients: a refined classification from the European society for blood and marrow transplantation (EBMT).

Bone Marrow Transplantation 24 Apr 2023, . Epub 24 Apr 2023
Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life-threatening complication that can develop after hematopoietic cell transplantation (HCT). A new definition for diagnosis, and a severity grading system for SOS/VOD in adult patients, was reported a few years ago on behalf of the European Society for Blood and Marrow Transplantation (EBMT). The aim of this work is to update knowledge regarding diagnosis and severity assessment of SOS/VOD in adult patients, and also its pathophysiology and treatment. In particular, we now propose to refine the previous classification and distinguish probable, clinical and proven SOS/VOD at diagnosis. We also provide an accurate definition of multiorgan dysfunction (MOD) for SOS/VOD severity grading based on Sequential Organ Failure Assessment (SOFA) score.
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Auñón C, Sanvisens A, Turon E, Vidal-Vila A, Puigdemont M, Osca-Gelis G, Eraso A, Marcos-Gragera R

Time trends and survival of marginal zone lymphoma over 25 years in Girona, Spain (1994-2018).

Cancer Medicine 19 Apr 2023, . Epub 19 Apr 2023
Objective: To analyze the incidence, incidence trends, and survival of marginal zone lymphomas (MZLs) in Girona and to describe these indicators based on the location in the case of extranodal MZLs. Methods: Population-based study of MZL collected in the Girona Cancer Registry, 1994-2018. Sociodemographic data, tumor location, and stage were obtained from clinical records. Crude (CR) and age-adjusted (ASRE ) incidence rates expressed per 100,000 person-years (p-y) were calculated. Joinpoint regression models were used for the trend analysis according to the MZL group. Five-year observed and net survival were analyzed. Results: A total of 472 MZLs were included, 44 (9.3%) were nodal, 288 (61.0%) extranodal, 122 (25.9%) splenic, and the rest (n = 18) MZL, NOS. The CR for the MZL was 2.89 × 100,000 p-y (95% CI: 2.63-3.15), the ASRE was 3.26 × 100,000 p-y (95% CI: 2.97-3.57), and the annual percentage change (APC) was 1.6 (95% CI: 0.5-2.7). The ASRE for nodal MZL was 0.30 × 100,000 p-y (95% CI: 0.22-0.41) and showed an APC of 2.9% (95% CI: -16.4-26.6). For extranodal MZL, the ASRE was 1.98 × 100,000 p-y (95% CI: 1.76-2.23) and the APC was -0.4 (95% CI: -2.0-1.2). The most frequent locations of this type of MZL were the gastric (35.4%), skin (13.2%), and respiratory system (11.8%). The ASRE of the splenic MZL was 0.85 (95% CI: 0.71-1.02) with an APC of 12.8 (95% CI: 2.5-24.0). The 5-year net survival of MZL was 82.1% (95% CI: 76.3-86.5). Conclusions: This study reveals differences in the incidence and trend of the incidence of MZL according to the subgroup, showing a significant increase in the overall MZL mainly due to splenic MZL type.
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Janin M, Esteller M

Global Shift in Alternative Splicing and Therapeutic Susceptibilities in Leukemia Driven by METTL3 Overexpression

Blood Cancer Discovery 17 Apr 2023, OF1-OF4. Epub 17 Apr 2023
Mutations in splicing factors are commonly observed in chronic lymphocytic leukemia (CLL); however, other mechanisms can also contribute to the dysregulation of alternative splicing. One example is the overexpression of the m6A RNA methyltransferase METTL3, that by depositing the epitranscriptomic mark in spliceosome transcripts leads to aberrant splicing, but at the same time creates vulnerability to METTL3 inhibitors. See related article by Wu et al., (8) .
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Meyer C, Larghero P, Almeida Lopes B, Burmeister T, Gröger D, Sutton R, Venn NC, Cazzaniga G, Corral Abascal L, Tsaur G, Fechina L, Emerenciano M, Pombo-de-Oliveira MS, Lund-Aho T, Lundán T, Montonen M, Juvonen V, Zuna J, Trka J, Ballerini P, Lapillonne H, Van der Velden VHJ, Sonneveld E, Delabesse E, de Matos RRC, Silva MLM, Bomken S, Katsibardi K, Keernik M, Grardel N, Mason J, Price R, Kim J, Eckert C, Lo Nigro L, Bueno C, Menendez P, Zur Stadt U, Gameiro P, Sedék L, Szczepański T, Bidet A, Marcu V, Shichrur K, Izraeli S, Madsen HO, Schäfer BW, Kubetzko S, Kim R, Clappier E, Trautmann H, Brüggemann M, Archer P, Hancock J, Alten J, Möricke A, Stanulla M, Lentes J, Bergmann AK, Strehl S, Köhrer S, Nebral K, Dworzak MN, Haas OA, Arfeuille C, Caye-Eude A, Cavé H, Marschalek R

The KMT2A recombinome of acute leukemias in 2023.

Leukemia 5 Apr 2023, . Epub 5 Apr 2023
Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from 3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.
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