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informe REDECAN 2021

REDECAN publica les últimes dades de la incidència de neoplàsies hematològiques a Espanya

El Dr. Rafael Marcos-Gragera, membre de l'Institut de Recerca contra la Leucèmia Josep Carreras i líder del grup de el Registre del Càncer de Girona, de l'Institut Català d'Oncologia / Pla director d'oncologia, ha coordinat l'informe publicat per la Xarxa Espanyola de Registres de el Càncer (REDECAN) sobre la incidència de neoplàsies hematològiques que pronostica el diagnòstic de 26.000 nous casos el 2021. 

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sanchez-céspedes group

Noves dades sobre el paper de la proteïna MAX en el càncer de pulmó

Un equip científic liderat per la Dra. Montse Sanchez-Cespedes, líder de grup de l'Institut de Recerca contra la Leucèmia Josep Carreras, prova les característiques i la funció supressora de tumors de MAX i el seu paper en el desenvolupament de el càncer de pulmó de cèl·lules petites, un tipus de càncer de pulmó molt agressiu. Els resultats mostren que les cèl·lules canceroses que no tenen MAX presenten característiques neuroendocrines (tipus ASLC1 o NEUROD1) i que la seva capacitat oncogènica, independent de l'oncogèn MYC, implica una funció anormal del complex repressiu ncPRC1.6. 

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sáncez-céspedes + Parra

Impuls a la valorització i transferència de coneixement i tecnologia dels projectes de l’Institut de Recerca contra la Leucèmia Josep Carreras

Dos projectes de l’Institut, dirigits per la Dra. Maribel Parra i la Dra. Montserrat Sanchez-Cespedes junt amb el Dr. Octavio Romero, accedeixen al programa IP Booster, de la Comissió Europea, i al Programa Gínjol, finançat per I-CERCA, per a escalar en el procés de valorització dels seus projectes i explorar la seva capacitat de transferència.

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sanchez-céspedes group

Investigadors de l'Institut Josep Carreras troben una debilitat que podria aprofitar-se per tractar càncers defectius per SMARCA4

La Dra. Montserrat Sánchez-Céspedes i el Dr. Octavio Romero, del grup de Genètica del Càncer de l'Institut de Recerca contra la Leucèmia Josep Carreras, han descobert recentment que els tumors amb una forma genèticament inactivada de la proteïna remodeladora de la cromatina SMARCA4 són molt sensibles als inhibidors de la família de desmetiladores d'histones KDM6.

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Últimes publicacions

Llabata P, Torres-Diz M, Gomez A, Tomas-Daza L, Romero OA, Grego-Bessa J, Llinas-Arias P, Valencia A, Esteller M, Javierre BM, Zhang X, Sanchez-Cespedes M

MAX mutant small-cell lung cancers exhibit impaired activities of MGA-dependent noncanonical polycomb repressive complex.

Proc Natl Acad Sci U S A 14 Set 2021, 118 (37) .
The MYC axis is disrupted in cancer, predominantly through activation of the MYC family oncogenes but also through inactivation of the MYC partner MAX or of the MAX partner MGA. MGA and MAX are also members of the polycomb repressive complex, ncPRC1.6. Here, we use genetically modified MAX-deficient small-cell lung cancer (SCLC) cells and carry out genome-wide and proteomics analyses to study the tumor suppressor function of MAX. We find that MAX mutant SCLCs have ASCL1 or NEUROD1 or combined ASCL1/NEUROD1 characteristics and lack MYC transcriptional activity. MAX restitution triggers prodifferentiation expression profiles that shift when MAX and oncogenic MYC are coexpressed. Although ncPRC1.6 can be formed, the lack of MAX restricts global MGA occupancy, selectively driving its recruitment toward E2F6-binding motifs. Conversely, MAX restitution enhances MGA occupancy to repress genes involved in different functions, including stem cell and DNA repair/replication. Collectively, these findings reveal that MAX mutant SCLCs have either ASCL1 or NEUROD1 or combined characteristics and are MYC independent and exhibit deficient ncPRC1.6-mediated gene repression.
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Diaz de la Guardia R, Velasco-Hernandez T, Gutierrez-Agüera F, Roca-Ho H, Molina O, Nombela-Arrieta C, Bataller A, Fuster JL, Anguita E, Vives S, Zamora L, Nomdedeu JF, Gomez-Casares MT, Ramírez-Orellana M, Lapillonne H, Ramos-Mejia V, Rodríguez-Manzaneque JC, Bueno C, Lopez-Millan B, Menendez P

Engraftment characterization of risk-stratified AML patients in NSGS mice.

Blood Adv 1 Set 2021, . Epub 1 Set 2021
Acute myeloid leukemia (AML) is the commonest acute leukemia in adults. Disease heterogeneity is well-documented and patient stratification determines treatment decisions. Patient-derived xenografts (PDXs) of risk-stratified AMLs are crucial for studying AML biology and testing novel therapeutics. Despite recent advances in PDX modeling of AML, reproducible engraftment of human AML is mainly limited to high-risk (HR) cases, with inconsistent or very protracted engraftment observed for favorable-risk (FR) and intermediate-risk (IR) patients. We have characterized the engraftment robustness/kinetics in NSGS mice of 28 AML patients grouped according to molecular/cytogenetic classification, and have assessed whether the orthotopic co-administration of patient-matched bone marrow mesenchymal stromal cells (BM-MSCs) improves AML engraftment. PDX event-free survival correlated well with the predictable prognosis of risk-stratified AML patients. The majority (85%-94%) of the mice were engrafted in BM independently of the risk group, although HR-AML patients showed engraftment levels significantly superior to those of FR- and IR-AML patients. Importantly, the engraftment levels observed in NSGS mice by week 6 remained stable overtime. Serial transplantation and long-term culture-initiating cell (LTC-IC) assays revealed long-term engraftment limited to HR-AML patients, fitter leukemia-initiating cells (LICs) in HR- than in FR- or IR-AML samples, and the presence of AML-LICs in the CD34- leukemic fraction, regardless the risk group. Finally, orthotopic co-administration of patient-matched BM-MSCs with AML cells resulted dispensable for BM engraftment levels but favored peripheralization of engrafted AML cells. This comprehensive characterization of human AML engraftment in NSGS mice offers a valuable platform for in vivo testing of targeted therapies in risk-stratified AML patient samples.
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Zanetti SR, Velasco-Hernandez T, Gutierrez-Agüera F, Díaz VM, Romecín PA, Roca-Ho H, Sánchez-Martínez D, Tirado N, Baroni ML, Petazzi P, Torres-Ruiz R, Molina O, Bataller A, Fuster JL, Ballerini P, Juan M, Jeremias I, Bueno C, Menéndez P

A novel and efficient tandem CD19- and CD22-directed CAR for B-cell ALL.

Mol Ther 31 Ago 2021, . Epub 31 Ago 2021
CD19-directed chimeric antigen receptor (CAR) T-cells have yielded impressive response rates in refractory/relapse B-cell acute lymphoblastic leukemia (B-ALL);however, most patients ultimately relapse due to poor CAR T-cell persistence or resistance of either CD19+ or CD19- B-ALL clones. CD22 is a pan-B marker whose expression is maintained in both CD19+ and CD19- relapses. Indeed, CD22-CAR T-cells have been clinically used in B-ALL patients, although relapse also occurs. Tcells engineered with a tandem CAR (Tan-CAR) containing in a single contruct both CD19 and CD22 scFvs, might be advantageus in achieving higher remission rates and/or preventing antigen loss. We have generated and functionally validated using cutting-edge assays a 4-1BB-based CD22/CD19 Tan-CAR using in-house-developed novel CD19 and CD22 scFvs. Tan-CAR-expressing T-cells showed similar in vitro expansion than CD19-CAR T-cells with no increased of tonic signaling. CRISPR/Cas9-edited B-ALL cells confirmed the bispecificity of the Tan-CAR. Tan-CAR was as efficient as CD19-CAR in vitro and in vivo using B-ALL cell lines, patient samples and patient-derived xenografts (PDXs). Strikingly, the robust anti-leukemic activity of the Tan-CAR was slightly more effective in controling the disease in long-term follow-up PDX models. This Tan-CAR construct warrants a clinical appraisal to test whether simultaneous targeting of CD19 and CD22 enhances leukemia eradication and reduces/delays relapse rates and antigen loss.
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Rosa Hernández, Cristina Jiménez-Luna, Raúl Ortiz, Fernando Setién, Miguel López, Gloria Perazzoli, Manel Esteller, María Berdasco, Jose Prados, Consolación Melguizo

Impact of the Epigenetically Regulated Hoxa-5 Gene in Neural Differentiation from Human Adipose-Derived Stem Cells

Biology 2021, 10(8), 802 19 Ago 2021, .
Human adipose-derived mesenchymal stem cells (hASCs) may be used in some nervous system pathologies, although obtaining an adequate degree of neuronal differentiation is an important barrier to their applicability. This requires a deep understanding of the expression and epigenetic changes of the most important genes involved in their differentiation. We used hASCs from human lipoaspirates to induce neuronal-like cells through three protocols (Neu1, 2, and 3), determined the degree of neuronal differentiation using specific biomarkers in culture cells and neurospheres, and analyzed epigenetic changes of genes involved in this differentiation. Furthermore, we selected the Hoxa-5 gene to determine its potential to improve neuronal differentiation. Our results showed that an excellent hASC neuronal differentiation process using Neu1 which efficiently modulated NES, CHAT, SNAP25, or SCN9A neuronal marker expression. In addition, epigenetic studies showed relevant changes in Hoxa-5, GRM4, FGFR1, RTEL1, METRN, and PAX9 genes. Functional studies of the Hoxa-5 gene using CRISPR/dCas9 and lentiviral systems showed that its overexpression induced hASCs neuronal differentiation that was accelerated with the exposure to Neu1. These results suggest that Hoxa-5 is an essential gene in hASCs neuronal differentiation and therefore, a potential candidate for the development of cell therapy strategies in neurological disorders.
Carini Picardi Morais de Castro, Maria Cadefau, Sergi Cuartero

The Mutational Landscape of Myeloid Leukaemia in Down Syndrome

Cancers 2021, 13(16), 4144 18 Ago 2021, .
Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators—such as cohesin, CTCF or EZH2—and in signalling mediators of the JAK/STAT and RAS pathways. Most of them are also found in non-DS myeloid malignancies, albeit at extremely different frequencies. Intriguingly, mutations in proteins involved in the three-dimensional organization of the genome are found in nearly 50% of cases. How the resulting mutant proteins cooperate with trisomy 21 and mutant GATA1 to promote ML-DS is not fully understood. In this review, we summarize and discuss current knowledge about the sequential acquisition of genomic alterations in ML-DS.

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