Research publications

Found 92 publicacions matching the indicated search criteria.
McGraw KL, Cheng CH, Chen YA, Hou HA, Nilsson B, Genovese G, Cluzeau T, Pellagatti A, Przychodzen BP, Mallo M, Arenillas L, Mohamedali A, Adès L, Sallman DA, Padron E, Sokol L, Moreilhon C, Raynaud S, Tien HF, Boultwood J, Ebert BL, Sole F, Fenaux P, Mufti GJ, Maciejewski JP, Kanetsky PA, List AF

Non-del(5q) myelodysplastic syndromes-associated loci detected by SNP-array genome-wide association meta-analysis.

Blood Adv 26 Nov 2019, 3 (22) 3579-3589.
Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies. Known predisposing factors to adult MDS include rare germline mutations, cytotoxic therapy, age-related clonal hematopoiesis, and autoimmune or chronic inflammatory disorders. To date, no published studies characterizing MDS-associated germline susceptibility polymorphisms exist. We performed a genome-wide association study of 2 sample sets (555 MDS cases vs 2964 control subjects; 352 MDS cases vs 2640 control subjects) in non-del(5q) MDS cases of European genomic ancestry. Meta-analysis identified 8 MDS-associated loci at 1q31.1 (PLA2G4A), 3p14.1 (FAM19A4), 5q21.3 (EFNA5), 6p21.33, 10q23.1 (GRID1), 12q24.32, 15q26.1, and 20q13.12 (EYA2) that approached genome-wide significance. Gene expression for 5 loci that mapped within or near genes was significantly upregulated in MDS bone marrow cells compared with those of control subjects (P < .01). Higher PLA2G4A expression and lower EYA2 expression were associated with poorer overall survival (P = .039 and P = .037, respectively). Higher PLA2G4A expression is associated with mutations in NRAS (P < .001), RUNX1 (P = .012), ASXL1 (P = .007), and EZH2 (P = .038), all of which are known to contribute to MDS development. EYA2 expression was an independently favorable risk factor irrespective of age, sex, and Revised International Scoring System score (relative risk, 0.67; P = .048). Notably, these genes have regulatory roles in innate immunity, a critical driver of MDS pathogenesis. EYA2 overexpression induced innate immune activation, whereas EYA2 inhibition restored colony-forming potential in primary MDS cells indicative of hematopoietic restoration and possible clinical relevance. In conclusion, among 8 suggestive MDS-associated loci, 5 map to genes upregulated in MDS with functional roles in innate immunity and potential biological relevance to MDS.
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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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Baptista MJ, Sole F, Polliack A, Matutes E

Report of the International Splenic Lymphoma Study Group meeting held in 2019 in Barcelona, Spain.

Leuk. Lymphoma 15 Oct 2019, 1-3. Epub 15 Oct 2019More information
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
Ganster C, Müller-Thomas C, Haferlach C, Strupp C, Ogata K, Germing U, Hildebrandt B, Mallo M, Lübbert M, Müller C, Solé F, Götze KS, Vandenberghe P, Göhring G, Steinmetz T, Kröger N, Platzbecker U, Söling U, Raynaud S, Shirneshan K, Schanz J, Haase D

Comprehensive analysis of isolated der(1;7)(q10;p10) in a large international homogenous cohort of patients with myelodysplastic syndromes.

Genes Chromosomes Cancer 17 Apr 2019, . Epub 17 Apr 2019
The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the new comprehensive cytogenetic scoring system for MDS, chromosome 7 anomalies are no longer generally assigned to poor risk features but are thoroughly separated. However, der(1;7)(q10;p10), hereinafter der(1;7), is merged into the group labeled "any other single" and belongs to the intermediate risk group, just by definition due to lack of adequate clinical data. The aim of our international collaborative was to clarify the "real" prognostic impact of der(1;7) on a homogenous and well-documented data base. We performed detailed analysis of 63 MDS patients with isolated der(1;7) constituting the largest cohort hitherto reported. Furthermore, clinical data are compared with those of patients with isolated del(7q) and isolated monosomy 7. Median overall survival (OS) of patients with der(1;7) is 26 months (hazard ratio (HR) 0.91 for del(7q) vs der(1;7) and 2.53 for monosomy 7 vs der(1;7)). The der(1;7) is associated with profound thrombocytopenia most probably causing the reduced OS which is in striking contrast to the low risk for AML transformation (HR 3.89 for del(7q) vs der(1;7) and 5.88 for monosomy 7 vs der(1;7)). Molecular karyotyping indicates that der(1;7) is generated in a single step during mitosis and that a chromosomal imbalance rather than a single disrupted gene accounts for malignancy. Thus, the current cytogenetic scoring system assigning isolated der(1;7) to the intermediate risk group is now confirmed by a sufficient data set.
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Ribera J, Granada I, Morgades M, Vives S, Genescà E, González C, Nomdedeu J, Escoda L, Montesinos P, Mercadal S, Coll R, González-Campos J, Abella E, Barba P, Bermúdez A, Gil C, Tormo M, Pedreño M, Martínez-Carballeira D, Hernández-Rivas JM, Orfao A, Martínez-López J, Esteve J, Bravo P, Garcia-Guiñon A, Debén G, Moraleda JM, Queizán JA, Ortín X, Moreno MJ, Feliu E, Solé F, Ribera JM

The poor prognosis of low hypodiploidy in adults with B-cell precursor acute lymphoblastic leukaemia is restricted to older adults and elderly patients.

Br. J. Haematol. 27 Mar 2019, . Epub 27 Mar 2019
The prognostic significance of low-hypodiploidy has not been extensively evaluated in minimal residual disease (MRD)-oriented protocols for adult acute lymphoblastic leukaemia (ALL). We analysed the outcome of hypodiploid adult ALL patients treated within Programa Español de Tratamientos en Hematología (PETHEMA) protocols. The 5-year cumulative incidence of relapse (CIR) of low-hypodiploid B-cell precursor (BCP)-ALL was significantly higher than that of high-hypodiploids (52% vs. 12%, P = 0.013). Low-hypodiploid BCP-ALL patients aged ≤35 years showed superior survival (71% vs. 21%, P = 0.026) and lower 5-year CIR (17% vs. 66%, P = 0.090) than low-hypodiploids aged >35 years. Older adults and elderly low-hypodiploid BCP-ALL patients show dismal prognosis although achieving an end-induction good MRD response.
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Nagata Y, Narumi S, Guan Y, Przychodzen BP, Hirsch CM, Makishima H, Shima H, Aly M, Pastor V, Kuzmanovic T, Radivoyevitch T, Adema V, Awada H, Yoshida K, Li S, Sole F, Hanna R, Jha BK, LaFramboise T, Ogawa S, Sekeres MA, Wlodarski MW, Cammenga J, Maciejewski JP

Germline loss of function SAMD9 and SAMD9L alterations in adult myelodysplastic syndromes

Blood 15 Oct 2018, . Epub 15 Oct 2018More information
Miyazaki Y, Tuechler H, Sanz G, Schanz J, Garcia-Manero G, Solé F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Santini V, Lübbert M, Maciejewski J, Machherndl-Spandl S, Magalhaes SMM, Pfeilstöcker M, Sekeres MA, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D, Greenberg PL

Differing clinical features between Japanese and Caucasian patients with myelodysplastic syndromes: Analysis from the International Working Group for Prognosis of MDS.

Leuk. Res. Oct 2018, 73 51-57. Epub 6 Sep 2018
Clinical features of myelodysplastic syndromes (MDS) could be influenced by many factors, such as disease intrinsic factors (e.g., morphologic, cytogenetic, molecular), extrinsic factors (e.g, management, environment), and ethnicity. Several previous studies have suggested such differences between Asian and European/USA countries. In this study, to elucidate potential differences in primary untreated MDS between Japanese (JPN) and Caucasians (CAUC), we analyzed the data from a large international database collected by the International Working Group for Prognosis of MDS (300 and 5838 patients, respectively). JPN MDS were significantly younger with more severe cytopenias, and cytogenetic differences: less del(5q) and more +1/+1q, -1/del(1p), der(1;7), -9/del(9q), del(16q), and del(20q). Although differences in time to acute myeloid leukemia transformation did not occur, a significantly better survival in JPN was demonstrated, even after the adjustment for age and FAB subtypes, especially in lower, but not in higher prognostic risk categories. Certain clinical factors (cytopenias, blast percentage, cytogenetic risk) had different impact on survival and time to transformation to leukemia between the two groups. Although possible confounding events (e.g., environment, diet, and access to care) could not be excluded, our results indicated the existence of clinically relevant ethnic differences regarding survival in MDS between JPN and CAUC patients. The good performance of the IPSS-R in both CAUC and JP patients underlines that its common risk model is adequate for CAUC and JP.
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Schanz J, Solé F, Mallo M, Luño E, Cervera J, Granada I, Hildebrandt B, Slovak ML, Ohyashiki K, Fonatsch C, Pfeilstöcker M, Nösslinger T, Valent P, Giagounidis A, Aul C, Lübbert M, Stauder R, Krieger O, Le Beau MM, Bennett JM, Greenberg P, Germing U, Haase D

Clonal architecture in patients with myelodysplastic syndromes and double or minor complex abnormalities: Detailed analysis of clonal composition, involved abnormalities, and prognostic significance.

Genes Chromosomes Cancer 24 Sep 2018, . Epub 24 Sep 2018
The study analyzes the clonal architecture and the abnormalities involved in a series of 191 patients with myelodysplastic syndromes (MDS) and 2-3 clonal abnormalities. All patients were extracted from an international database. The patients were classified into six clonal subtypes (2A-3C) based on the number of abnormalities and the presentation of unrelated clones (UC) and/or a clonal evolution. UC were detected in 23/191 patients (12%). The composition of UC showed great variability. The only recurrent combination of abnormalities was del(5q) and + 8 in 8 of 23 patients (35%). In patients with clonal evolution, the clone size of the primary and secondary clone varied: Patients with -7 and + 8 in the primary clone showed a larger primary and a smaller secondary clone (-7: median 74% vs 10%; +8 73% vs 18%) while patients with del(5q) in the primary clone showed a smaller primary and a larger secondary clone (33% vs 61%). Univariate and multivariate analyses showed no significant differences regarding overall or AML-free survival between the clonal subtypes. Only the subtype 3C (3 abnormalities and clonal evolution) was an independent risk factor for developing AML (Hazard Ratio 5.5 as compared to subtype 2A, P < .05). Finally, our study confirms that the number of abnormalities clearly defines a significant risk factor for overall- as well as AML-free survival. Importantly, in patients with more than one clone, the calculation of the number of abnormalities in the entire sample instead of the number of abnormalities per clone allows a higher prognostic accuracy.
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Banús-Mulet A, Etxabe A, Cornet-Masana JM, Torrente MÁ, Lara-Castillo MC, Palomo L, Nomdedeu M, Díaz-Beyá M, Solé F, Nomdedeu B, Esteve J, Risueño RM

Serotonin receptor type 1B constitutes a therapeutic target for MDS and CMML.

Sci Rep 17 Sep 2018, 8 (1) 13883. Epub 17 Sep 2018
Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are chronic myeloid clonal neoplasms. To date, the only potentially curative therapy for these disorders remains allogeneic hematopoietic progenitor cell transplantation (HCT), although patient eligibility is limited due to high morbimortality associated with this procedure coupled with advanced age of most patients. Dopamine receptors (DRs) and serotonin receptors type 1 (HTR1s) were identified as cancer stem cell therapeutic targets in acute myeloid leukemia. Given their close pathophysiologic relationship, expression of HTR1s and DRs was interrogated in MDS and CMML. Both receptors were differentially expressed in patient samples compared to healthy donors. Treatment with HTR1B antagonists reduced cell viability. HTR1 antagonists showed a synergistic cytotoxic effect with currently approved hypomethylating agents in AML cells. Our results suggest that HTR1B constitutes a novel therapeutic target for MDS and CMML. Due to its druggability, the clinical development of new regimens based on this target is promising.
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