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Research centers throughout Spain collaborate to deploy the latest genomic analysis technologies and identify therapeutic targets in childhood cancer.

  • The study, the outcome of a multicenter collaboration, unravels molecular vulnerabilities of acute pediatric leukemias from multiple perspectives, for the first time.

  • The results are based on genomic and epigenomic sequencing and whole transcriptome of 69 babies with a poor prognosis type of leukemia and their computational analysis.

  • The research was led by researchers from the Josep Carreras Leukemia Research Institute, the CSIC and the Principado de Asturias Health Research Institute.

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PIPgen visual 02

PIPgen: a new Innovative Training Network to put PI3K/PTEN related diseases under the spotlight

The PIPgen Training Programme seeks to train the next generation of PI3K/PTEN experts and envisions to empower PI3K/PTEN related disease research in Europe towards clinical translation.

Dr. Mariona Graupera, group leader at the Josep Carreras Leukaemia Research Institute, coordinates the Innovative Training Network (ITN) PIPgen, a Marie Skłodowska Curie Action funded by the European Commission under Horizon 2020 (H2020) framework programme.

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Recent publications

Chen-Jen Hsu, Oliver Meers, Marcus Buschbeck, Florian H. Heidel

The Role of MacroH2A Histone Variants in Cancer

Cancers 2021, 13(12), 3003 15 Jun 2021, . Epub 15 Jun 2021
The epigenome regulates gene expression and provides a molecular memory of cellular events. A growing body of evidence has highlighted the importance of epigenetic regulation in physiological tissue homeostasis and malignant transformation. Among epigenetic mechanisms, the replacement of replication-coupled histones with histone variants is the least understood. Due to differences in protein sequence and genomic distribution, histone variants contribute to the plasticity of the epigenome. Here, we focus on the family of macroH2A histone variants that are particular in having a tripartite structure consisting of a histone fold, an intrinsically disordered linker and a globular macrodomain. We discuss how these domains mediate different molecular functions related to chromatin architecture, transcription and DNA repair. Dysregulated expression of macroH2A histone variants has been observed in different subtypes of cancer and has variable prognostic impact, depending on cellular context and molecular background. We aim to provide a concise review regarding the context- and isoform-dependent contributions of macroH2A histone variants to cancer development and progression.
Rossi M, Meggendorfer M, Zampini M, Tettamanti M, Riva E, Travaglino E, Bersanelli M, Mandelli S, Galbussera AA, Mosca E, Saba E, Chiereghin C, Manes N, Milanesi C, Ubezio M, Morabito L, Peano C, Soldà G, Asselta R, Duga S, Selmi C, De Santis M, Malik K, Maggioni G, Bicchieri ME, Campagna A, Tentori CA, Russo A, Civilini E, Allavena P, Piazza R, Corrao G, Sala C, Termanini A, Giordano L, Detoma P, Malabaila A, Sala L, Rosso S, Zanetti R, Saitta C, Riva E, Condorelli G, Passamonti F, Santoro A, Sole F, Platzbecker U, Fenaux P, Bolli N, Castellani G, Kern W, Vassiliou G, Haferlach T, Lucca U, Della Porta MG

Clinical relevance of clonal hematopoiesis in the oldest-old population.

Blood 14 Jun 2021, . Epub 14 Jun 2021
Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes very common in oldest-old individuals, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 oldest-old individuals enrolled in two population-based studies and investigate the relationships between CHIP and associated pathologies. Clonal mutations were observed in one third of oldest-old individuals and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, ASXL1 with additional genetic lesions) and variant allele frequency ≥0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1 or JAK2 (most occurring as single lesion) were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was a common finding in oldest-old population, the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly-specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of oldest-old subjects with cytopenia had presumptive evidence of myeloid neoplasm. In conclusion, specific mutational patterns define different risk of developing myeloid neoplasms vs. inflammatory-associated diseases in oldest-old population. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.
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Palomo L, Santiago-Vacas E, Pascual-Figal D, Fuster JJ, Solé F, Bayés-Genís A

Prevalence and characteristics of clonal hematopoiesis in heart failure.

Rev Esp Cardiol (Engl Ed) 9 Jun 2021, . Epub 9 Jun 2021
No abstract available.
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Genescà E, Morgades M, González-Gil C, Fuster-Tormo F, Haferlach C, Meggendorfer M, Montesinos P, Barba P, Gil C, Coll R, Moreno MJ, Martínez-Carballeira D, García-Cadenas I, Vives S, Ribera J, González-Campos J, Díaz-Beya M, Mercadal S, Artola MT, Cladera A, Tormo M, Bermúdez A, Vall-Llovera F, Martínez-Sánchez P, Amigo ML, Monsalvo S, Novo A, Cervera M, García-Guiñon A, Ciudad J, Cervera J, Hernández-Rivas JM, Granada I, Haferlach T, Orfao A, Solé F, Ribera JM

Adverse prognostic impact of complex karyotype (≥3 cytogenetic alterations) in adult T-cell acute lymphoblastic leukemia (T-ALL).

Leuk Res 8 Jun 2021, 109 106612. Epub 8 Jun 2021
The potential prognostic value of conventional karyotyping in adult T-cell acute lymphoblastic leukemia (T-ALL) remains an open question. We hypothesized that a modified cytogenetic classification, based on the number and type of cytogenetic abnormalities, would allow the identification of high-risk adult T-ALL patients. Complex karyotype defined by the presence of ≥3 cytogenetic alterations identified T-ALL patients with poor prognosis in this study. Karyotypes with ≥3 abnormalities accounted for 16 % (22/139) of all evaluable karyotypes, corresponding to the largest poor prognosis cytogenetic subgroup of T-ALL identified so far. Patients carrying karyotypes with ≥3 cytogenetic alterations showed a significantly inferior response to therapy, and a poor outcome in terms of event-free survival (EFS), overall survival (OS) and cumulative incidence of relapse (CIR), independently of other baseline characteristics and the end-induction minimal residual disease (MRD) level. Additional molecular analyses of patients carrying ≥3 cytogenetic alterations showed a unique molecular profile that could contribute to understand the underlying molecular mechanisms of resistance and to evaluate novel targeted therapies (e.g. IL7R directed) with potential impact on outcome of adult T-ALL patients.
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Castro P, Palomo M, Moreno-Castaño AB, Fernández S, Torramadé-Moix S, Pascual G, Martinez-Sanchez J, Richardson E, Téllez A, Nicolas JM, Carreras E, Richardson PG, Badimon JJ, Escolar G, Diaz-Ricart M

Is the Endothelium the Missing Link in the Pathophysiology and Treatment of COVID-19 Complications?

Cardiovasc Drugs Ther 7 Jun 2021, . Epub 7 Jun 2021
Patients with COVID-19 present a wide spectrum of disease severity, from asymptomatic cases in the majority to serious disease leading to critical care and even death. Clinically, four different scenarios occur within the typical disease timeline: first, an incubation and asymptomatic period; second, a stage with mild symptoms due mainly to the virus itself; third, in up to 20% of the patients, a stage with severe symptoms where a hyperinflammatory response with a cytokine storm driven by host immunity induces acute respiratory distress syndrome; and finally, a post-acute sequelae (PASC) phase, which present symptoms that can range from mild or annoying to actually quite incapacitating. Although the most common manifestation is acute respiratory failure of the lungs, other organs are also frequently involved. The clinical manifestations of the COVID-19 infection support a key role for endothelial dysfunction in the pathobiology of this condition. The virus enters into the organism via its interaction with angiotensin-converting enzyme 2-receptor that is present prominently in the alveoli, but also in endothelial cells, which can be directly infected by the virus. Cytokine release syndrome can also drive endothelial damage independently. Consequently, a distinctive feature of SARS-CoV-2 infection is vascular harm, with severe endothelial injury, widespread thrombosis, microangiopathy, and neo-angiogenesis in response to endothelial damage. Therefore, endothelial dysfunction seems to be the pathophysiological substrate for severe COVID-19 complications. Biomarkers of endothelial injury could constitute strong indicators of disease progression and severity. In addition, the endothelium could represent a very attractive target to both prevent and treat these complications. To establish an adequate therapy, the underlying pathophysiology and corresponding clinical stage should be clearly identified. In this review, the clinical features of COVID-19, the central role of the endothelium in COVID-19 and in other pathologies, and the potential of specific therapies aimed at protecting the endothelium in COVID-19 patients are addressed.
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