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Patients, doctors and researchers in an interdisciplinary and privileged environment

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Patients, at the center of research

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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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News

2021 January 11

The INTERCEPT-MDS PhD fellowships to train Europe’s first experts in the emerging field of disease interception are open for applications.

Three of the twelve positions at the forefront of research into myeloid diseases will be based at the Josep Carreras Leukaemia Research Institute as part of the Innovative Training Network (ITN) entitled INTERCEPT-MDS. The Josep Carreras Institute coordinates this Marie Skłodowska Curie Action funded by the European Commission under the H2020 framework.

intercept call

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Recent publications

Antonio Garcia-Gomez, Tianlu Li, Carlos de la Calle-Fabregat, Javier Rodríguez-Ubreva, Laura Ciudad, Francesc Català-Moll, Gerard Godoy-Tena, Montserrat Martín-Sánchez, Laura San-Segundo, Sandra Muntión, Xabier Morales, Carlos Ortiz-de-Solórzano, Julen Oyarzabal, Edurne San José-Enériz, Manel Esteller, Xabier Agirre, Felipe Prosper, Mercedes Garayoa, Esteban Ballestar

Targeting aberrant DNA methylation in mesenchymal stromal cells as a treatment for myeloma bone disease

Nat Commun 12, 421 (2021) 18 Jan 2021, .
Multiple myeloma (MM) progression and myeloma-associated bone disease (MBD) are highly dependent on bone marrow mesenchymal stromal cells (MSCs). MM-MSCs exhibit abnormal transcriptomes, suggesting the involvement of epigenetic mechanisms governing their tumor-promoting functions and prolonged osteoblast suppression. Here, we identify widespread DNA methylation alterations of bone marrow-isolated MSCs from distinct MM stages, particularly in Homeobox genes involved in osteogenic differentiation that associate with their aberrant expression. Moreover, these DNA methylation changes are recapitulated in vitro by exposing MSCs from healthy individuals to MM cells. Pharmacological targeting of DNMTs and G9a with dual inhibitor CM-272 reverts the expression of hypermethylated osteogenic regulators and promotes osteoblast differentiation of myeloma MSCs. Most importantly, CM-272 treatment prevents tumor-associated bone loss and reduces tumor burden in a murine myeloma model. Our results demonstrate that epigenetic aberrancies mediate the impairment of bone formation in MM, and its targeting by CM-272 is able to reverse MBD.
M Cabezón, R Malinverni, B Xicoy, S Marcé, J Bargay, A Garrido, M Tormo, L Arenillas, R Coll, J Borras, M Hoyos, D Valcárcel, L Escoda, F Vall-Llovera, A Garcia, L L Font, E Rámila, M J Jiménez, M Buschbeck, L Zamora, CETLAM group

Different methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival

2021 Jan 14;13(1):9 14 Jan 2021, .
Background: Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic. Results: Unsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress. Conclusions: Our findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival.
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Celia González-Gil, Jordi Ribera, Josep Maria Ribera, Eulàlia Genescà

The Yin and Yang-Like Clinical Implications of the CDKN2A/ARF/CDKN2B Gene Cluster in Acute Lymphoblastic Leukemia

Genes 2021, 12, 79. 9 Jan 2021, .
Acute lymphoblastic leukemia (ALL) is a malignant clonal expansion of lymphoid hematopoietic precursors that exhibit developmental arrest at varying stages of differentiation. Similar to what occurs in solid cancers, transformation of normal hematopoietic precursors is governed by a multistep oncogenic process that drives initiation, clonal expansion and metastasis. In this process, alterations in genes encoding proteins that govern processes such as cell proliferation, differentiation, and growth provide us with some of the clearest mechanistic insights into how and why cancer arises. In such a scenario, deletions in the 9p21.3 cluster involving CDKN2A/ARF/CDKN2B genes arise as one of the oncogenic hallmarks of ALL. Deletions in this region are the most frequent structural alteration in T-cell acute lymphoblastic leukemia (T-ALL) and account for roughly 30% of copy number alterations found in B-cell-precursor acute lymphoblastic leukemia (BCP-ALL). Here, we review the literature concerning the involvement of the CDKN2A/B genes as a prognosis marker of good or bad response in the two ALL subtypes (BCP-ALL and T-ALL). We compare frequencies observed in studies performed on several ALL cohorts (adult and child), which mainly consider genetic data produced by genomic techniques. We also summarize what we have learned from mouse models designed to evaluate the functional involvement of the gene cluster in ALL development and in relapse/resistance to treatment. Finally, we examine the range of possibilities for targeting the abnormal function of the protein-coding genes of this cluster and their potential to act as anti-leukemic agents in patients.
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Marc Armengol, Juliana Carvalho Santos, Miranda Fernández-Serrano, Núria Profitós-Pelejà, Marcelo Lima Ribeiro, Gaël Roué

Immune-Checkpoint Inhibitors in B-Cell Lymphoma

Cancers 2021, 13(2), 214 8 Jan 2021, .
For years, immunotherapy has been considered a viable and attractive treatment option for patients with cancer. Among the immunotherapy arsenal, the targeting of intratumoral immune cells by immune-checkpoint inhibitory agents has recently revolutionised the treatment of several subtypes of tumours. These approaches, aimed at restoring an effective antitumour immunity, rapidly reached the market thanks to the simultaneous identification of inhibitory signals that dampen an effective antitumor response in a large variety of neoplastic cells and the clinical development of monoclonal antibodies targeting checkpoint receptors. Leading therapies in solid tumours are mainly focused on the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) pathways. These approaches have found a promising testing ground in both Hodgkin lymphoma and non-Hodgkin lymphoma, mainly because, in these diseases, the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Although several trials have already demonstrated evidence of therapeutic activity with some checkpoint inhibitors in lymphoma, many of the immunologic lessons learned from solid tumours may not directly translate to lymphoid malignancies. In this sense, the mechanisms of effective antitumor responses are different between the different lymphoma subtypes, while the reasons for this substantial difference remain partially unknown. This review will discuss the current advances of immune-checkpoint blockade therapies in B-cell lymphoma and build a projection of how the field may evolve in the near future. In particular, we will analyse the current strategies being evaluated both preclinically and clinically, with the aim of fostering the use of immune-checkpoint inhibitors in lymphoma, including combination approaches with chemotherapeutics, biological agents and/or different immunologic therapies.
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Voltà-Durán E, Serna N, Sánchez-García L, Aviñó A, Sánchez JM, López-Laguna H, Cano-Garrido O, Casanova I, Mangues R, Eritja R, Vázquez E, Villaverde A, Unzueta U.

Design and engineering of tumor-targeted, dual-acting cytotoxic nanoparticles

Acta Biomater. 2021 Jan 1;119:312-322. 1 Jan 2021, .
The possibility to conjugate tumor-targeted cytotoxic nanoparticles and conventional antitumoral drugs in single pharmacological entities would open a wide spectrum of opportunities in nanomedical oncology. This principle has been explored here by using CXCR4-targeted self-assembling protein nanoparticles based on two potent microbial toxins, the exotoxin A from Pseudomonas aeruginosa and the diphtheria toxin from Corynebacterium diphtheriae, to which oligo-floxuridine and monomethyl auristatin E respectively have been chemically coupled. The resulting multifunctional hybrid nanoconjugates, with a hydrodynamic size of around 50 nm, are stable and internalize target cells with a biological impact. Although the chemical conjugation minimizes the cytotoxic activity of the protein partner in the complexes, the concept of drug combination proposed here is fully feasible and highly promising when considering multiple drug treatments aimed to higher effectiveness or when facing the therapy of cancers with acquired resistance to classical drugs.
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Events

5 March 2021 12:00 - 13:00
Online. Hans Clevers, Hubrecht Institute for Developmental Biology and Stem Cell Research and at the Princess Máxima Center for Pediatric Oncology, Nederland

Organoids to model human disease