Research publications

Found 63 publicacions matching the indicated search criteria.
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 Sep 2021, . Epub 1 Sep 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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Pamela Acha, Laura Palomo, Francisco Fuster-Tormo, Bianca Xicoy, Mar Mallo, Ana Manzanares, Javier Grau, Silvia Marcé, Isabel Granada, Marta Rodríguez-Luaces, María Díez-Campelo, Lurdes Zamora, Francesc Solé

Analysis of Intratumoral Heterogeneity in Myelodysplastic Syndromes with Isolated del(5q) Using a Single Cell Approach

Cancers 2021, 13(4), 841 17 Feb 2021, .
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological diseases. Among them, the most well characterized subtype is MDS with isolated chromosome 5q deletion (MDS del(5q)), which is the only one defined by a cytogenetic abnormality that makes these patients candidates to be treated with lenalidomide. During the last decade, single cell (SC) analysis has emerged as a powerful tool to decipher clonal architecture and to further understand cancer and other diseases at higher resolution level compared to bulk sequencing techniques. In this study, a SC approach was used to analyze intratumoral heterogeneity in four patients with MDS del(5q). Single CD34+CD117+CD45+CD19- bone marrow hematopoietic stem progenitor cells were isolated using the C1 system (Fluidigm) from diagnosis or before receiving any treatment and from available follow-up samples. Selected somatic alterations were further analyzed in SC by high-throughput qPCR (Biomark HD, Fluidigm) using specific TaqMan assays. A median of 175 cells per sample were analyzed. Inferred clonal architectures were relatively simple and either linear or branching. Similar to previous studies based on bulk sequencing to infer clonal architecture, we were able to observe that an ancestral event in one patient can appear as a secondary hit in another one, thus reflecting the high intratumoral heterogeneity in MDS del(5q) and the importance of patient-specific molecular characterization.
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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Pamela Acha, Montserrat Hoyos, Marta Pratcorona, Francisco Fuster-Tormo, Laura Palomo, Esther Ortega, Lurdes Zamora, Susana Vives, Isabel Granada, Julia Montoro, Antoni Garcia, Montserrat Arnan, Marta Cervera, Marta Canet, David Gallardo, Leonor Arenillas, Jordi Esteve, Joan Baragay, Olga Salamero, Cristina Motlló, Xavier Ortín, Jordi Sierra, Francesc Solé

Genetic characterization of acute myeloid leukemia patients with mutations in IDH1/2 genes

Leuk Res . 2021 Jan 11;101:106492. 11 Jan 2021, .
Highlights • IDH1/2 cases account for 23% of the studied cohort. • Mutual exclusivity was confirmed for IDH1 and IDH2 mutations. • IDH1 (86%) and IDH2 (89%) mutations frequently constitute an ancestral event.
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Comes M, Batlle M, Ribera JM

Treatment adapted to pregnancy in a patient with Burkitt lymphoma.

Med Clin (Barc) 12 Jun 2020, 154 (11) 470-471. Epub 20 Jul 2019More information
Sánchez R, Ribera J, Morgades M, Ayala R, Onecha E, Ruiz-Heredia Y, Juárez-Rufián A, de Nicolás R, Sánchez-Pina J, Vives S, Zamora L, Mercadal S, Coll R, Cervera M, García O, Ribera JM, Martínez-López J

A novel targeted RNA-Seq panel identifies a subset of adult patients with acute lymphoblastic leukemia with BCR-ABL1-like characteristics.

Blood Cancer J 24 Apr 2020, 10 (4) 43. Epub 24 Apr 2020
BCR-ABL1-like B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains poorly characterized in adults. We sought to establish the frequency and outcome of adolescent and adult BCR-ABL1-like ALL using a novel RNA-Seq signature in a series of patients with BCP-ALL. To this end, we developed and tested an RNA-Seq custom panel of 42 genes related to a BCR-ABL1-like signature in a cohort of 100 patients with BCP-ALL and treated with risk-adapted ALL trials. Mutations related to BCR-ABL1-like ALL were studied in a panel of 33 genes by next-generation sequencing (NGS). Also, CRLF2 overexpression and IKZF1/CDKN2A/B deletions were analyzed. Twenty out of 79 patients (12-84 years) were classified as BCR-ABL1-like (25%) based on heatmap clustering, with significant overexpression of ENAM, IGJ, and CRLF2 (P ≤ 0.001). The BCR-ABL1-like subgroup accounted for 29% of 15-60-year-old patients, with the following molecular characteristics: CRLF2 overexpression (75% of cases), IKZF1 deletions (64%), CDKN2A/B deletions (57%), and JAK2 mutations (57%). Among patients with postinduction negative minimal residual disease, those with the BCR-ABL1-like ALL signature had a higher rate of relapse and lower complete response duration than non-BCR-ABL1-like patients (P = 0.007). Thus, we have identified a new molecular signature of BCR-ABL1-like ALL that correlates with adverse prognosis in adult patients with ALL.
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Ferreira MSV, Kirschner M, Halfmeyer I, Estrada N, Xicoy B, Isfort S, Vieri M, Zamora L, Abels A, Bouillon AS, Begemann M, Schemionek M, Maurer A, Koschmieder S, Wilop S, Panse J, Brümmendorf TH, Beier F

Comparison of flow-FISH and MM-qPCR telomere length assessment techniques for the screening of telomeropathies.

Ann. N. Y. Acad. Sci. Apr 2020, 1466 (1) 93-103. Epub 24 Oct 2019
Assessment of telomere length (TL) in peripheral blood leukocytes is part of the diagnostic algorithm applied to patients with acquired bone marrow failure syndromes (BMFSs) and dyskeratosis congenita (DKC). Monochrome multiplex-quantitative polymerase chain reaction (MM-qPCR) and fluorescence in situ hybridization (flow-FISH) are methodologies available for TL screening. Dependent on TL expressed in relation to percentiles of healthy controls, further genetic testing for inherited mutations in telomere maintenance genes is recommended. However, the correct threshold to trigger this genetic workup is still under debate. Here, we prospectively compared MM-qPCR and flow-FISH regarding their capacity for accurate identification of DKC patients. All patients (n = 105) underwent genetic testing by next-generation sequencing and in 16 patients, mutations in DKC-relevant genes were identified. Whole leukocyte TL of patients measured by MM-qPCR was found to be moderately correlated with lymphocyte TL measured by flow-FISH (r² = 0.34; P < 0.0001). The sensitivity of both methods was high, but the specificity of MM-qPCR (29%) was significantly lower compared with flow-FISH (58%). These results suggest that MM-qPCR of peripheral blood cells is inferior to flow-FISH for clinical routine screening for suspected DKC in adult patients with BMFS due to lower specificity and a higher rate of false-positive results.
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Espasa A, Zamora L, Ribera JM

Granulocytic sarcoma: Study of two cases by high throughput sequencing.

Med Clin (Barc) 18 Mar 2020, . Epub 18 Mar 2020More information
Palomo L, Ibáñez M, Abáigar M, Vázquez I, Álvarez S, Cabezón M, Tazón-Vega B, Rapado I, Fuster-Tormo F, Cervera J, Benito R, Larrayoz MJ, Cigudosa JC, Zamora L, Valcárcel D, Cedena MT, Acha P, Hernández-Sánchez JM, Fernández-Mercado M, Sanz G, Hernández-Rivas JM, Calasanz MJ, Solé F, Such E

Spanish Guidelines for the use of targeted deep sequencing in myelodysplastic syndromes and chronic myelomonocytic leukaemia.

Br. J. Haematol. 16 Oct 2019, . Epub 16 Oct 2019
The landscape of medical sequencing has rapidly changed with the evolution of next generation sequencing (NGS). These technologies have contributed to the molecular characterization of the myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML), through the identification of recurrent gene mutations, which are present in >80% of patients. These mutations contribute to a better classification and risk stratification of the patients. Currently, clinical laboratories include NGS genomic analyses in their routine clinical practice, in an effort to personalize the diagnosis, prognosis and treatment of MDS and CMML. NGS technologies have reduced the cost of large-scale sequencing, but there are additional challenges involving the clinical validation of these technologies, as continuous advances are constantly being made. In this context, it is of major importance to standardize the generation, analysis, clinical interpretation and reporting of NGS data. To that end, the Spanish MDS Group (GESMD) has expanded the present set of guidelines, aiming to establish common quality standards for the adequate implementation of NGS and clinical interpretation of the results, hoping that this effort will ultimately contribute to the benefit of patients with myeloid malignancies.
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Acha P, Xandri M, Fuster-Tormo F, Palomo L, Xicoy B, Cabezón M, Marcé S, Granada I, Vela D, Sagüés M, Boque C, Plensa E, Pineda A, Feliu E, Solé F, Zamora L

Diagnostic and prognostic contribution of targeted NGS in patients with triple-negative myeloproliferative neoplasms.

Am. J. Hematol. Oct 2019, 94 (10) E264-E267. Epub 6 Aug 2019More information