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A new project aims to shed new light on a frequent form of leukemia in Down Syndrome children

The American Society of Hematology (ASH) has selected a project led by Dr. Sergi Cuartero, researcher at the Josep Carreras Leukaemia Research Institute, to receive the 2022 ASH Global Research Award. Dr. Cuartero is one of 13 talented early-career investigators selected for this honor. The project aims to better understand the molecular basis of myeloid leukemia of Down Syndrome (ML-DS) and contribute to the identification of novel actionable targets for therapeutic use in ML-DS.

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Oscar Molina 2021

A new method developed by researchers from the Josep Carreras Institute predicts childhood hyperdiploid B-ALL relapse risk

An international research team coordinated by Dr. Oscar Molina and Dr. Pablo Menéndez, from the Josep Carreras Leukaemia Research Institute, identifies chromosomal abnormalities associated to relapse in a frequent subset of B-cell Acute Lymphoblastic Leukemia (B-ALL), a severe condition affecting especially children. This finding may help identify those patients at a higher risk of relapse at diagnosis to direct them to more appropriate treatment options and anticipate the cancer comeback.

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Laura Mondragón

Researchers at the Josep Carreras Institute will study a rare T-cell lymphoma thanks to the Leukemia Research Foundation

Dr. Laura Mondragón, “T-cell lymphoma” group leader at the Josep Carreras Leukaemia Research Institute, has been granted a new project to fight against angioimmunoblastic T cell lymphoma (AITL). The project, starting October 1st 2022, is funded by the Leukemia Research Foundation based in Northfield, Illinois (USA) and aims to exploit the latest generation of animal models for AITL, to better understand this type of adult lymphoma and open the door to new therapeutic approaches.

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Dr. Esteller & Dra. Pujol (IDIBELL)

Discovered epigenetic alterations associated with the COVID-19 related severe inflammatory syndrome in childhood

Researchers from the Cancer Epigenetics group led by Dr. Manel Esteller at the Josep Carreras Leukaemia Research Institute and Dr. Aurora Pujol, from the Bellvitge Biomedical Research Institute, have identified an epigenetic signature associated to the development of the Multisystem Inflammatory Syndrome in Children (MIS-C) after a SARS-CoV-2 virus infection. The signature has been named EPIMISC, in line with previous studies on the epigenetics of COVID-19 from the same team.

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David Corujo

Cancer vs. the immune system: macroH2A, a chromatin protein, can turn cancer cells deaf to immune commands

Researchers from the Buschbeck lab and IGTP are pushing forward our understanding of the role of the macroH2A histone variants in the progression of cancer and the crosstalk of cancer cells with the immune system. In a research paper recently published at the journal Cell Reports, the team identified two different areas where macroH2As can act when cancer cells are exposed to cytokines, the immune signaling machinery: chromatin regulation of gene expression and autocrine signaling secretion.

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Francesc Solé 2022

Genetic information from myelodysplastic syndromes’ patients incorporated in the latest update of the international standard risk assessment metric: the IPSS-M

Researchers from the Josep Carreras Leukaemia Research Institute, Dr. Francesc Solé and Dr. Laura Palomo from the Myelodysplastic Syndromes Group, and Dr. Lurdes Zamora from the Myeloid Neoplasms Group, participated in the international consortium that developed the new molecular-based prognostic index for Myelodysplastic Syndromes, the IPSS-M. This new tool, recently published at NEJM Evidence, a new journal from the New England Journal of Medicine Publishing Group, will allow a better risk stratification of patients and, thus, a better treatment, tailored to their individual needs.

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Recent publications

M Graupera, A Angulo-Urarte

When, where and which PIK3CA mutations are pathogenic in congenital disorders

Nature Cardiovascular Research 8 Aug 2022, 2022 . Epub 8 Aug 2022
PIK3CA encodes the class I PI3Kα isoform and is frequently mutated in cancer. Activating mutations in PIK3CA also cause a range of congenital disorders featuring asymmetric tissue overgrowth, known as the PIK3CA-related overgrowth spectrum (PROS), with frequent vascular involvement. In PROS, PIK3CA mutations arise postzygotically, during embryonic development, leading to a mosaic body pattern distribution resulting in a variety of phenotypic features. A clear skewed pattern of overgrowth favoring some mesoderm-derived and ectoderm-derived tissues is observed but not understood. Here, we summarize our current knowledge of the determinants of PIK3CA-related pathogenesis in PROS, including intrinsic factors such as cell lineage susceptibility and PIK3CA variant bias, and extrinsic factors, which refers to environmental modifiers. We also include a section on PIK3CA-related vascular malformations given that the vasculature is frequently affected in PROS. Increasing our biological understanding of PIK3CA mutations in PROS will contribute toward unraveling the onset and progression of these conditions and ultimately impact on their treatment. Given that PIK3CA mutations are similar in PROS and cancer, deeper insights into one will also inform about the other.
Adema V, Ma F, Kanagal-Shamanna R, Thongon N, Montalban-Bravo G, Yang H, Peslak SA, Wang F, Acha P, Sole F, Lockyer P, Cassari M, Maciejewski JP, Visconte V, Ganan-Gomez I, Song Y, Bueso-Ramos C, Pellegrini M, Tan TM, Bejar R, Carew JS, Halene S, Santini V, Al-Atrash G, Clise-Dwyer K, Garcia-Manero G, Blobel GA, Colla S

Targeting the EIF2AK1 signaling pathway rescues red blood cell production in SF3B1-mutant myelodysplastic syndromes with ringed sideroblasts.

Blood Cancer Discov 4 Aug 2022, . Epub 4 Aug 2022
SF3B1 mutations, which occur in 20% of patients with myelodysplastic syndromes (MDS), are the hallmarks of a specific MDS subtype, MDS with ringed sideroblasts (MDS-RS), which is characterized by the accumulation of erythroid precursors in the bone marrow and primarily affects the elderly population. Here, using single-cell technologies and functional validation studies of primary SF3B1-mutant MDS-RS samples, we show that SF3B1 mutations lead to the activation of the EIF2AK1 pathway in response to heme deficiency and that targeting this pathway rescues aberrant erythroid differentiation and enables the red blood cell maturation of MDS-RS erythroblasts. These data support the development of EIF2AK1 inhibitors to overcome transfusion dependency in patients with SF3B1-mutant MDS-RS with impaired red blood cell production.
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Lucas Pontel, Alberto Bueno-Costa, Agustín E. Morellato, Juliana Carvalho Santos, Gaël Roué, Manel Esteller

Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing

Redox Biology 31 Jul 2022, 2022 (102408) 2213-2317. Epub 31 Jul 2022
Ferroptosis is a form of cell death triggered by phospholipid hydroperoxides (PLOOH) generated from the iron-dependent oxidation of polyunsaturated fatty acids (PUFAs). To prevent ferroptosis, cells rely on the antioxidant glutathione (GSH), which serves as cofactor of the glutathione peroxidase 4 (GPX4) for the neutralization of PLOOHs. Some cancer cells can also limit ferroptosis through a GSH-independent axis, centered mainly on the ferroptosis suppressor protein 1 (FSP1). The significance of these two anti-ferroptosis pathways is still poorly understood in cancers from hematopoietic origin. Here, we report that blood-derived cancer cells are selectively sensitive to compounds that block the GSH-dependent anti-ferroptosis axis. In T and B acute lymphoblastic leukemia (ALL) cell lines and patient biopsies, the promoter of the gene coding for FSP1 is hypermethylated, silencing the expression of FSP1 and creating a selective dependency on GSH-centered anti-ferroptosis defenses. In-trans expression of FSP1 increases the resistance of leukemic cells to compounds targeting the GSH-dependent anti-ferroptosis pathway. FSP1 over-expression also favors ALL-tumor growth in an in vivo chick chorioallantoic membrane (CAM) model. Hence, our results reveal a metabolic vulnerability of ALL that might be of therapeutic interest.
Azagra A, Meler A, de Barrios O, Tomás-Daza L, Collazo O, Monterde B, Obiols M, Rovirosa L, Vila-Casadesús M, Cabrera-Pasadas M, Gusi-Vives M, Graf T, Varela I, Sardina JL, Javierre BM, Parra M

The HDAC7-TET2 epigenetic axis is essential during early B lymphocyte development.

Nucleic Acids Res 29 Jul 2022, . Epub 29 Jul 2022
Correct B cell identity at each stage of cellular differentiation during B lymphocyte development is critically dependent on a tightly controlled epigenomic landscape. We previously identified HDAC7 as an essential regulator of early B cell development and its absence leads to a drastic block at the pro-B to pre-B cell transition. More recently, we demonstrated that HDAC7 loss in pro-B-ALL in infants associates with a worse prognosis. Here we delineate the molecular mechanisms by which HDAC7 modulates early B cell development. We find that HDAC7 deficiency drives global chromatin de-condensation, histone marks deposition and deregulates other epigenetic regulators and mobile elements. Specifically, the absence of HDAC7 induces TET2 expression, which promotes DNA 5-hydroxymethylation and chromatin de-condensation. HDAC7 deficiency also results in the aberrant expression of microRNAs and LINE-1 transposable elements. These findings shed light on the mechanisms by which HDAC7 loss or misregulation may lead to B cell-based hematological malignancies.
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Robles-Rebollo I, Cuartero S, Canellas-Socias A, Wells S, Karimi MM, Mereu E, Chivu AG, Heyn H, Whilding C, Dormann D, Marguerat S, Rioja I, Prinjha RK, Stumpf MPH, Fisher AG, Merkenschlager M

Cohesin couples transcriptional bursting probabilities of inducible enhancers and promoters.

Nat Commun 27 Jul 2022, 13 (1) 4342. Epub 27 Jul 2022
Innate immune responses rely on inducible gene expression programmes which, in contrast to steady-state transcription, are highly dependent on cohesin. Here we address transcriptional parameters underlying this cohesin-dependence by single-molecule RNA-FISH and single-cell RNA-sequencing. We show that inducible innate immune genes are regulated predominantly by an increase in the probability of active transcription, and that probabilities of enhancer and promoter transcription are coordinated. Cohesin has no major impact on the fraction of transcribed inducible enhancers, or the number of mature mRNAs produced per transcribing cell. Cohesin is, however, required for coupling the probabilities of enhancer and promoter transcription. Enhancer-promoter coupling may not be explained by spatial proximity alone, and at the model locus Il12b can be disrupted by selective inhibition of the cohesinopathy-associated BET bromodomain BD2. Our data identify discrete steps in enhancer-mediated inducible gene expression that differ in cohesin-dependence, and suggest that cohesin and BD2 may act on shared pathways.
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