Publications by authors named "Esperanza Such"

68 Publications

Analysis of SNP Array Abnormalities in Patients with DE NOVO Acute Myeloid Leukemia with Normal Karyotype.

Sci Rep 2020 04 3;10(1):5904. Epub 2020 Apr 3.

Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Nearly 50% of patients with de novo acute myeloid leukemia (AML) harbor an apparently normal karyotype (NK) by conventional cytogenetic techniques showing a very heterogeneous prognosis. This could be related to the presence of cryptic cytogenetic abnormalities (CCA) not detectable by conventional methods. The study of copy number alterations (CNA) and loss of heterozygozity (LOH) in hematological malignancies is possible using a high resolution SNP-array. Recently, in clinical practice the karyotype study has been complemented with the identification of point mutations in an increasing number of genes. We analyzed 252 de novo NK-AML patients from Hospital La Fe (n = 44) and from previously reported cohorts (n = 208) to identify CCA by SNP-array, and to integrate the analysis of CCA with molecular alterations detected by Next-Generation-sequencing. CCA were detected in 58% of patients. In addition, 49% of them harbored CNA or LOH and point mutations, simultaneously. Patients were grouped in 3 sets by their abnormalities: patients carrying several CCA simultaneously, patients with mutations in FLT3, NPM1 and/or DNMT3A and patients with an amalgam of mutations. We found a negative correlation between the number of CCA and the outcome of the patients. This study outlines that CCA are present in up to 50% of NK-AML patients and have a negative impact on the outcome. CCA may contribute to the heterogeneous prognosis.
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http://dx.doi.org/10.1038/s41598-020-61589-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125150PMC
April 2020

Impact of somatic mutations in myelodysplastic patients with isolated partial or total loss of chromosome 7.

Leukemia 2020 09 17;34(9):2441-2450. Epub 2020 Feb 17.

Department of Haematological Medicine, King's College Hospital, NHS Foundation Trust, London, UK.

Monosomy 7 [-7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with -7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with -7). Patients with del(7q) or -7 had similar demographic and disease-related characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in -7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0-8). There was no difference in mutation frequency between the two groups. Patients harbouring ≥2 mutations had a worse outcome than patients with <2 or no mutations (leukaemic transformation at 24 months, 38% and 20%, respectively, p = 0.044). Untreated patients with del(7q) had better overall survival (OS) compared with -7 (median OS, 34 vs 17 months, p = 0.034). In multivariable analysis, blast count, TP53 mutations and number of mutations were independent predictors of OS, whereas the cytogenetic subgroups did not retain prognostic relevance. This study highlights the importance of mutational analysis in terms of prognosis in MDS patients with isolated -7 or del(7q).
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http://dx.doi.org/10.1038/s41375-020-0728-xDOI Listing
September 2020

Do next-generation sequencing results drive diagnostic and therapeutic decisions in MDS?

Blood Adv 2019 11;3(21):3454-3460

Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

This article has a companion Point by Thol and Platzbecker.
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http://dx.doi.org/10.1182/bloodadvances.2019000680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855105PMC
November 2019

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

Br J Haematol 2020 03 16;188(5):605-622. Epub 2019 Oct 16.

Department of Haematology, Hospital Universitari i Politècnic La Fe, València, Spain.

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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http://dx.doi.org/10.1111/bjh.16175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064979PMC
March 2020

Dexamethasone does not prevent malignant cell reintroduction in leukemia patients undergoing ovarian transplant: risk assessment of leukemic cell transmission by a xenograft model.

Hum Reprod 2019 08;34(8):1485-1493

Reproductive Medicine Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.

Study Question: Does dexamethasone (DXM) incubation avoid the reintroduction of leukemic malignant cells after ovarian tissue retransplantation in vivo?

Summary Answer: DXM incubation prior to retransplantation of ovarian tissue does not prevent reintroduction of leukemic cells.

What Is Known Already: Retransplantation of cryopreserved ovarian cortex from patients diagnosed with acute lymphoblastic leukemia (ALL) involves a risk of reintroducing malignant cells. DXM treatment is effective at inducing leukemic cell death in vitro.

Study Design, Size, Duration: This was an experimental study where ovarian cortex fragments from patients with ALL were randomly allocated to incubation with or without DXM (n = 11/group) and grafted to 22 immunodeficient mice for 6 months. In a parallel experiment, 22 immunodeficient mice were injected i.p. with varying amounts of RCH-ACV ALL cells (human leukemia cell line) and maintained for 4 months.

Participants/materials, Setting, Methods: Cryopreserved ovarian fragments from patients with ALL were exposed in vitro to 0.4 μM DXM or basal media (control) prior to xenograft into ovariectomized severe combined immunodeficiency (SCID) mice (experiment 1). After 6 months of monitoring, leukemia cell contamination was assessed in ovarian grafts and mouse organs by histology, PCR (presence of mouse mtDNA and absence of p53 were together considered a negative result for the presence of human cells) and detection of immunoglobulin monoclonality and specific ALL markers if present in the patient.In experiment 2, a series of 22 immunodeficient female mice was injected with specific doses of the leukemia cell line RCH-ACV (103 - 5 × 106, n = 4/group) to assess the engraftment competence of the SCID model.

Main Results And The Role Of Chance: ALL metastatic cells were detected, by PCR, in five DXM-treated and one control human ovarian tissue graft as well as in a control mouse liver, although malignant cell infiltration was not detected by histology in any sample after 6 months. In total, minimal residual disease was present in three DXM-treated and three control mice.RCH-ACV cells were detected in liver and spleen samples after the injection of as little as 103 cells, although only animals receiving 5 × 106 cells developed clinical signs of disease and metastases.

Limitations, Reasons For Caution: This is an experimental study where the malignant potential of leukemic cells contained in human ovarian tissues has been assessed in immunodeficient mice.

Wider Implications Of The Findings: These results indicate that DXM incubation prior to retransplantation of ovarian tissue does not prevent reintroduction of leukemic cells. Therefore, caution should be taken in retransplanting ovarian tissue from patients with leukemia until safer systems are developed, as leukemic cells present in ovarian grafts were able to survive, proliferate and migrate after cryopreservation and xenograft.

Study Funding/competing Interest(s): Funded by the Regional Valencian Ministry of Education (PROMETEO/2018/137) and by the Spanish Ministry of Economy and Competitiveness (PI16/FIS PI16/01664 and PTQ-16-08222 for S.H. participation). There are no competing interests.
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http://dx.doi.org/10.1093/humrep/dez115DOI Listing
August 2019

Chronic graft-versus-host disease could ameliorate the impact of adverse somatic mutations in patients with myelodysplastic syndromes and hematopoietic stem cell transplantation.

Ann Hematol 2019 Sep 16;98(9):2151-2162. Epub 2019 Jul 16.

Hematology Department, University Hospital of Salamanca, IBSAL Institute for Biomedical Research of Salamanca, Paseo de San Vicente, 139, 37007, Salamanca, Spain.

Somatic mutations in patients with myelodysplastic syndromes (MDS) undergoing allogeneic hematopoietic stem cell transplantation (HSTC) are associated with adverse outcome, but the role of chronic graft-versus-host disease (cGVHD) in this subset of patients remains unknown. We analyzed bone marrow samples from 115 patients with MDS collected prior to HSCT using next-generation sequencing. Seventy-one patients (61%) had at least one mutated gene. We found that patients with a higher number of mutated genes (more than 2) had a worse outcome (2 years overall survival [OS] 54.8% vs. 31.1%, p = 0.035). The only two significant variables in the multivariate analysis for OS were TET2 mutations (p = 0.046) and the development of cGVHD, considered as a time-dependent variable (p < 0.001), correlated with a worse and a better outcome, respectively. TP53 mutations also demonstrated impact on the cumulative incidence of relapse (CIR) (1 year CIR 47.1% vs. 9.8%, p = 0.006) and were related with complex karyotype (p = 0.003). cGVHD improved the outcome even among patients with more than 2 mutated genes (1-year OS 88.9% at 1 year vs. 31.3%, p = 0.02) and patients with TP53 mutations (1-year CIR 20% vs. 42.9%, p = 0.553). These results confirm that cGVHD could ameliorate the adverse impact of somatic mutations in patients with MDS with HSCT.
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http://dx.doi.org/10.1007/s00277-019-03751-6DOI Listing
September 2019

RNA Sequencing Analysis for the Identification of a PCM1/PDGFRB Fusion Gene Responsive to Imatinib.

Acta Haematol 2019 14;142(2):92-97. Epub 2019 May 14.

Hematology Department, University Hospital La Fe, Valencia, Spain.

The platelet-derived growth factor receptor β (PDGFRB) gene translocations lead to a spectrum of chronic myeloid neoplasms, frequently associated with eosinophilia. Clinical heterogeneity is associated with a molecular one. Here, we report a novel case of a patient harboring a t(5;8)(q33;p22) translocation, resulting in the PCM1/PDGFRB fusion. Conventional cytogenetics and RNA sequencing were performed to identify the chromosomes and the genes involved in the rearrangement, respectively. This study shows that the combination of different strategies is pivotal to fine-tune the diagnosis and the clinical management of the patient. After 1 year of treatment with imatinib, the patient achieves hematological and molecular remission. We present an attractive strategy to identify novel and/or cryptic fusions, which will be relevant for clinicians dealing with the diagnosis of the patients with myelodysplastic syndrome/myeloproliferative diseases with atypical manifestations.
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http://dx.doi.org/10.1159/000497348DOI Listing
February 2020

Clinical Utility of a Next-Generation Sequencing Panel for Acute Myeloid Leukemia Diagnostics.

J Mol Diagn 2019 03 19;21(2):228-240. Epub 2018 Dec 19.

Molecular Biology Unit, Clinical Pathology Service, La Fe University and Polytechnic Hospital, Valencia, Spain; La Fe Health Research Institute, Hematology Research Group, Valencia, Spain; CIBERONC, Carlos III Health Research Institute, Madrid, Spain. Electronic address:

Next-generation sequencing (NGS) has redefined the genetic landscape of acute myeloid leukemia (AML), providing new molecular markers for diagnostic and prognostic classifications. However, its application in the clinical setting is still challenging. We hypothesized that a 19-gene AML-targeted NGS panel could be a valid approach to obtain clinically relevant information. Thus, we assessed the ability of this panel to classify AML patients according to diagnostic and prognostic indexes in a cohort of 162 patients. The assay yielded a median read depth >2000×, with 88% of on-target reads and a mean uniformity >93% without significant global strand bias. The method was sensitive and specific, with a valid performance at the clinical variant allele frequency cutoff of 3% for point mutations and 5% for insertions or deletions (INDELs). Three-hundred thirty-nine variants were found (36% INDELs and 64% single nucleotide variants). Concordance between NGS and other conventional techniques was 100%, but the NGS approach was able to identify more clinically relevant mutations. Finally, all patients could be classified into one of the 2016 World Health Organization diagnostic categories and virtually all into the recently proposed prognostic indexes (2017 European LeukemiaNet and Genomic classification). To sum up, we validate a reliable and reproducible method for AML diagnosis and demonstrate that small, well-designed NGS panels are sufficient to guide clinical decisions according to the current standards.
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http://dx.doi.org/10.1016/j.jmoldx.2018.09.009DOI Listing
March 2019

The modular network structure of the mutational landscape of Acute Myeloid Leukemia.

PLoS One 2018 10;13(10):e0202926. Epub 2018 Oct 10.

Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202926PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179200PMC
March 2019

Hidden myelodysplastic syndrome (MDS): A prospective study to confirm or exclude MDS in patients with anemia of uncertain etiology.

Int J Lab Hematol 2019 Feb 5;41(1):109-117. Epub 2018 Oct 5.

Hematology, Hospital Universitario de Salamanca-IBSAL, Salamanca, Spain.

Introduction: Diagnosis of myelodysplastic syndromes (MDSs) when anemia is the only abnormality can be complicated. The aim of our study was to investigate the primary causes of anemia and/or macrocytosis of uncertain etiology.

Methods: We conducted a multicenter, prospective study over 4 months in three hematology laboratories. In step 1, we used an automated informatics system to screen 137 453 hemograms for cases of anemia and/or macrocytosis (n = 2702). In step 2, we excluded all patients whose anemia appeared to be due to a known cause. This left 290 patients had anemia of uncertain etiology. In step 3, we conducted further investigations, including a peripheral blood smear, and analysis of iron, vitamin B12, folate, and thyroid hormone levels.

Results: A differential diagnosis was obtained in 139 patients (48%). The primary causes of anemia were iron deficiency (n = 59) and megaloblastic anemia (n = 39). In total, 25 hematologic disorders were diagnosed, including 14 patients with MDS (56%). The median age of MDS patients was 80 years, 12 had anemia as an isolated cytopenia, and most (n = 10) had lower-risk disease (IPSS-R ≤ 3.5). SF3B1 mutations were most frequent (n = 6) and correlated with the presence of ring sideroblasts (100%) and associated with better prognosis (P = 0.001).

Conclusions: Our prospective, four-step approach is an efficient and logical strategy to facilitate the diagnosis of MDS on the basis of unexplained anemia and/or macrocytosis, and may allow the early diagnosis of the most serious causes of anemia. Molecular analysis of genes related to MDS could be a promising diagnostic and prognostic approach.
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http://dx.doi.org/10.1111/ijlh.12933DOI Listing
February 2019

Azacitidine improves outcome in higher-risk MDS patients with chromosome 7 abnormalities: a retrospective comparison of GESMD and GFM registries.

Br J Haematol 2018 05 2;181(3):350-359. Epub 2018 Apr 2.

Service d'Hematologie, St Louis, assistance publique hôpitaux de Paris and Paris Diderot University, Paris, France.

Treatment with azacitidine (AZA) has been suggested to be of benefit for higher-risk myelodysplastic syndrome (HR-MDS) patients with chromosome 7 abnormalities (Abn 7). This retrospective study of 235 HR-MDS patients with Abn 7 treated with AZA (n = 115) versus best supportive care (BSC; n = 120), assessed AZA treatment as a time-varying variable in multivariable analysis. A Cox Regression model with time-interaction terms of overall survival (OS) at different time points confirmed that, while chromosome 7 cytogenetic categories (complex karyotype [CK] versus non-CK) and International Prognostic Scoring System risk (high versus intermediate-2) retained poor prognosis over time, AZA treatment had a favourable impact on OS during the first 3 years of treatment compared to BSC (Hazard ratio [HR] 0·5 P < 0·001 at 1 year, 0·7 P = 0·019 at 2 years; 0·73 P = 0·029 at 3 years). This benefit was present in all chromosome 7 categories, but tended to be greater in patients with CK (risk reduction of 82%, 68% and 53% at 1, 3 and 6 months in CK patients; 79% at 1 month in non-CK patients, P < 0·05 for all). AZA also significantly improved progression-free survival (P < 0·01). This study confirms a time-dependent benefit of AZA on outcome in patients with HR-MDS and cytogenetic abnormalities involving chromosome 7, especially for those with CK.
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http://dx.doi.org/10.1111/bjh.15190DOI Listing
May 2018

Imiquimod inhibits growth and induces differentiation of myeloid leukemia cell lines.

Cancer Cell Int 2018 30;18:15. Epub 2018 Jan 30.

2Departamento de Microbiología y Ecología, Universitat de València, Burjasot, Spain.

Background: The antitumoral effects of different Toll-like receptor (TLRs) agonists is mediated by activating immune responses to suppress tumors growth, although TLR ligands may also have a direct effect on tumoral cells. Given that TLR signaling induces hematopoietic cell differentiations this may serve as a novel differentiation therapeutic approach for AML.

Methods: We investigated the effects of agonists for the ten human TLRs on the proliferation, apoptosis, cell cycle and differentiation of ten different types of myeloid leukemia cell lines (HL-60, U-937, KG-1, KG-1a, K-562, Kasumi-1, EOL-1, NB4, MOLM-13 and HEL). Proliferation was measured using the CellTiter 96 Aqueous One Solution Cell Proliferation Assay (Promega). Staining and analysis with a flow cytometer was used to identify cell cycle progression and apoptosis. Differentiation was measured by staining cells with the EuroFlow™ antibody panel for AML and analyzed by flow cytometry. FlowJo software was used to analyze the cytometric data. In all experiments, statistical significance was determined by a two-tailed test.

Results: The activation of particular TLRs on some cell lines can induce growth inhibition and Imiquimod (a TLR 7 agonist) was the most effective agonist in all leukemic cell lines examined. Imiquimod was able to induce apoptosis, as well as to induce cell cycle alteration and upregulation of myeloid differentiation markers on some of the cell lines tested.

Conclusions: Our results, together with the known efficacy of Imiquimod against many tumor entities, suggest that Imiquimod can be a potential alternative therapy to AML. This drug has a direct cytotoxic effect on leukemic cells, has the potential to induce differentiation, and can also stimulate the activation of cellular immune responses anti-AML.
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http://dx.doi.org/10.1186/s12935-018-0515-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791367PMC
January 2018

Mutations in the DNA methylation pathway and number of driver mutations predict response to azacitidine in myelodysplastic syndromes.

Oncotarget 2017 Dec 27;8(63):106948-106961. Epub 2017 Oct 27.

Hematology Department, Hospital Universitario 12 Octubre, CNIO, Universidad Complutense, Madrid, Spain.

We evaluated the association of mutations in 34 candidate genes and response to azacitidine in 84 patients with myelodysplastic syndrome (MDS), with 217 somatic mutations identified by next-generation sequencing. Most patients (93%) had ≥1 mutation (mean=2.6/patient). The overall response rate to azacitidine was 42%. No clinical characteristic was associated with response to azacitidine. However, total number of mutations/patient was negatively associated with overall drug response (odds ratio [OR]: 0.56, 95% confidence interval [CI]: 0.33-0.94; p=0.028), and a positive association was found for having ≥1 mutation in a DNA methylation-related gene: (OR: 4.76, 95%CI: 1.31-17.27; p=0.017). Mutations in (hazard ratio [HR]: 3.88; 95%CI: 1.94-7.75) and (HR: 2.50; 95%CI: 1.23-5.09) were associated with shorter overall survival. Meta-analysis of 6 studies plus present data (n=815 patients) allowed assessment of the association of drug response with mutations in 9 candidate genes: and mutations predicted a more favorable drug response compared with 'wild-type' peers (pooled OR: 1.67, 95%CI: 1.14-2.44; p=0.01). In conclusion, mutations in the DNA methylation pathway, especially mutations, and low number of total mutations are associated with a better response to azacitidine.
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http://dx.doi.org/10.18632/oncotarget.22157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5739787PMC
December 2017

A Rare Case of Pure Erythroid Sarcoma in a Pediatric Patient: Case Report and Literature Review.

Children (Basel) 2017 Dec 20;4(12). Epub 2017 Dec 20.

Department of Hematology, Hospital de Elda, 03600 Elda, Alicante, Spain.

We describe an exceptional case of erythroid sarcoma in a pediatric patient as a growing orbital mass with no evidence of morphologic bone marrow involvement, who was finally diagnosed of pure erythroid sarcoma based on histopathology and flow cytometry criteria. We discuss the contribution of standardized eight-color flow cytometry as a rapid and reliable diagnostic method. The use of normal bone marrow databases allowed us to identify small aberrant populations in bone marrow and later confirm the diagnosis in the neoplastic tissue.
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http://dx.doi.org/10.3390/children4120113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742758PMC
December 2017

Negative impact on clinical outcome of the mutational co-occurrence of SF3B1 and DNMT3A in refractory anemia with ring sideroblasts (RARS).

Leuk Lymphoma 2017 07 24;58(7):1686-1693. Epub 2016 Oct 24.

a Department of Hematology , University Hospital La Fe , Valencia , Spain.

The incidence of SF3B1 mutations in patients with RARS is high. Recently, it has been shown that SF3B1 and DNMT3A mutations overlap more often than expected, although it is not clear how this could affect the disease. We studied SF3B1 and DNMT3A in 123 RARS patients: 101 out of 123 samples (82%) had somatic mutations in SF3B1, and 13 of them (13%) showed a co-mutation (SF3B1DNMT3A). All co-mutated patients had a normal karyotype, and 12 of them (92%) were lower-risk patients (IPSS and IPSS-R). Despite their favorable profile, SF3B1DNMT3A patients showed a higher RBC transfusion dependency (92% versus 48%, p = .007), a shorter overall survival (OS) (median, 30 versus 97 months, p = .034), and a higher risk of progression to acute myeloid leukemia (AML) at 5 years (25% versus 2%, p = .023) than SF3B1DNMT3A patients. In conclusion, DNMT3A mutations are present in a significant proportion of SF3B1 patients with a negative clinical impact.
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http://dx.doi.org/10.1080/10428194.2016.1246725DOI Listing
July 2017

Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia.

Blood 2016 09 6;128(10):1408-17. Epub 2016 Jul 6.

Department of Molecular Medicine, University of Pavia, Pavia, Italy; Department of Hematology Oncology, Istituto di Ricovero e Cura a Carattere Scientifico Fondazione Policlinico San Matteo, Pavia, Italy;

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm with variable clinical course. To predict the clinical outcome, we previously developed a CMML-specific prognostic scoring system (CPSS) based on clinical parameters and cytogenetics. In this work, we tested the hypothesis that accounting for gene mutations would further improve risk stratification of CMML patients. We therefore sequenced 38 genes to explore the role of somatic mutations in disease phenotype and clinical outcome. Overall, 199 of 214 (93%) CMML patients carried at least 1 somatic mutation. Stepwise linear regression models showed that these mutations accounted for 15% to 24% of variability of clinical phenotype. Based on multivariable Cox regression analyses, cytogenetic abnormalities and mutations in RUNX1, NRAS, SETBP1, and ASXL1 were independently associated with overall survival (OS). Using these parameters, we defined a genetic score that identified 4 categories with significantly different OS and cumulative incidence of leukemic evolution. In multivariable analyses, genetic score, red blood cell transfusion dependency, white blood cell count, and marrow blasts retained independent prognostic value. These parameters were included into a clinical/molecular CPSS (CPSS-Mol) model that identified 4 risk groups with markedly different median OS (from >144 to 18 months, hazard ratio [HR] = 2.69) and cumulative incidence of leukemic evolution (from 0% to 48% at 4 years, HR = 3.84) (P < .001). The CPSS-Mol fully retained its ability to risk stratify in an independent validation cohort of 260 CMML patients. In conclusion, integrating conventional parameters and gene mutations significantly improves risk stratification of CMML patients, providing a robust basis for clinical decision-making and a reliable tool for clinical trials.
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http://dx.doi.org/10.1182/blood-2016-05-714030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036538PMC
September 2016

The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.

PLoS One 2016 17;11(2):e0148346. Epub 2016 Feb 17.

Hematology Service, Hospital Universitario y Politécnico La Fe, Valencia, Spain.

Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148346PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757557PMC
July 2016

Analysis of the Possible Persistent Genotoxic Damage in Workers Linked to the Ardystil Syndrome.

Genet Test Mol Biomarkers 2016 Feb 30;20(2):94-7. Epub 2015 Dec 30.

1 Servicio de Protección Radiológica, Hospital Universitario y Politécnico La Fe , Valencia, Spain .

Background: A combination of several factors including a change in the paint application system; a lack of proper hygiene; and inadequate safety measures caused a severe health impact in the workers of some textile painting factories. This outbreak, mainly characterized by respiratory disorders, caused the death of six people and it has been classified as Ardystil syndrome.

Materials And Methods: Fifty-two workers involved in the outbreak and 48 healthy subjects not known to have exposed to the potentially mutagenic agents participated in the study. The program evaluated possible genotoxic damage through the sister chromatid exchange (SCE) cytogenetic biomarker assay. We determined the frequency of SCE, high-frequency cells (HFCs), and a ratio, which can be considered as a new parameter, allowing for the study of the SCE distribution pattern among the chromosomes.

Results: There was no statistically significant difference in the SCE frequency and in the mean number of HFCs between the control and the Ardystil-affected groups. However, smoking increased the incidence of all parameters studied in both the case and control groups.

Conclusions: This study shows that workers involved in the Ardystil syndrome did not suffer genotoxic damage as measured by SCE and HFCs when compared with the control group.
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http://dx.doi.org/10.1089/gtmb.2015.0177DOI Listing
February 2016

Prognostic impact of chromosomal translocations in myelodysplastic syndromes and chronic myelomonocytic leukemia patients. A study by the spanish group of myelodysplastic syndromes.

Genes Chromosomes Cancer 2016 Apr 22;55(4):322-7. Epub 2015 Dec 22.

Hospital Clínic, Barcelona, Spain.

Chromosomal translocations are rare in the myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). With the exception of t(3q), translocations are not explicitly considered in the cytogenetic classification of the IPSS-R and their impact on disease progression and patient survival is unknown. The present study was aimed at determining the prognostic impact of translocations in the context of the cytogenetic classification of the IPSS-R. We evaluated 1,653 patients from the Spanish Registry of MDS diagnosed with MDS or CMML and an abnormal karyotype by conventional cytogenetic analysis. Translocations were identified in 168 patients (T group). Compared with the 1,485 patients with abnormal karyotype without translocations (non-T group), the T group had a larger proportion of patients with refractory anemia with excess of blasts and higher scores in both the cytogenetic and global IPSS-R. Translocations were associated with a significantly shorter survival and higher incidence of transformation into AML at univariate analysis but both features disappeared after multivariate adjustment for the IPSS-R cytogenetic category. Patients with single or double translocations other than t(3q) had an outcome similar to those in the non-T group in the intermediate cytogenetic risk category of the IPSS-R. In conclusion, the presence of translocations identifies a subgroup of MDS/CMML patients with a more aggressive clinical presentation that can be explained by a higher incidence of complex karyotypes. Single or double translocations other than t(3q) should be explicitly considered into the intermediate risk category of cytogenetic IPSS-R classification.
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http://dx.doi.org/10.1002/gcc.22333DOI Listing
April 2016

Impact of SNP array karyotyping on the diagnosis and the outcome of chronic myelomonocytic leukemia with low risk cytogenetic features or no metaphases.

Am J Hematol 2016 Feb 9;91(2):185-92. Epub 2015 Dec 9.

Hematology Service, ICO-Hospital Germans Trias I Pujol, Institut De Recerca Contra La Leucèmia Josep Carreras, Universitat Autònoma De Barcelona, Badalona, Spain.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder with heterogeneous clinical, morphological and genetic characteristics. Clonal cytogenetic abnormalities are found in 20-30% of patients with CMML. Patients with low risk cytogenetic features (normal karyotype and isolated loss of Y chromosome) account for ∼80% of CMML patients and often fall into the low risk categories of CMML prognostic scores. We hypothesized that single nucleotide polymorphism arrays (SNP-A) karyotyping could detect cryptic chromosomal alterations with prognostic impact in these subgroup of patients. SNP-A were performed at diagnosis in 128 CMML patients with low risk karyotypes or uninformative results for conventional G-banding cytogenetics (CC). Copy number alterations (CNAs) and regions of copy number neutral loss of heterozygosity (CNN-LOH) were detected in 67% of patients. Recurrent CNAs included gains in regions 8p12 and 21q22 as well as losses in 10q21.1 and 12p13.2. Interstitial CNN-LOHs were recurrently detected in the following regions: 4q24-4q35, 7q32.1-7q36.3, and 11q13.3-11q25. Statistical analysis showed that some of the alterations detected by SNP-A associated with the patients' outcome. A shortened overall survival (OS) and progression free survival (PFS) was observed in cases where the affected size of the genome (considering CNAs and CNN-LOHs) was >11 Mb. In addition, presence of interstitial CNN-LOH was predictive of poor OS. Presence of CNAs (≥1) associated with poorer OS and PFS in the patients with myeloproliferative CMML. Overall, SNP-A analysis increased the diagnostic yield in patients with low risk cytogenetic features or uninformative CC and added prognostic value to this subset of patients.
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http://dx.doi.org/10.1002/ajh.24227DOI Listing
February 2016

Study of the S427G polymorphism and of MYBL2 variants in patients with acute myeloid leukemia.

Leuk Lymphoma 2016 Feb 19;57(2):429-435. Epub 2015 Jun 19.

a Department of Medical Pathology , Hospital Universitario y Politécnico La Fe , Valencia , Spain.

Dysregulation of MYBL2 has been associated to tumorigenesis and the S427G polymorphism could induce partial inactivation of MYBL2, associating it with cancer risk. It has previously been shown that MYBL2 was over-expressed in some acute myeloid leukemias (AML), portending poor prognosis. However, to date no studies have investigated the S427G or other genetic variants of MYBL2 in AML. This study analyzed the S427G in 197 AML patients and 179 controls and screened the MYBL2 sequence in patients. In contrast to other studies in solid tumors, the S427G was not associated with the incidence of AML. This study detected four unannotated genetic alterations, of which the Q67X could be involved in MYBL2 dysfunction. Eight polymorphisms were identified, among which the rs73116571, located in a splicing region, was associated with higher incidence in AML and weaker MYBL2 expression, suggesting pre-disposition to AML. Additional functional studies should be performed to verify these genetic variations as possible targets in AML.
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http://dx.doi.org/10.3109/10428194.2015.1049167DOI Listing
February 2016

Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2): Clinical and biological features and comparison with other acute myeloid leukemias with cytogenetic aberrations involving long arm of chromosome 3.

Hematology 2015 Sep 13;20(8):435-441. Epub 2015 Feb 13.

a Department of Hematology Hospital Universitario de Canarias , Ofra s/n, 38320 La Laguna, Spain.

Objectives: To compare, from a biological and clinical perspective, a significant group of patients with AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) with another group of AML carrying different abnormalities of 3q at q21 or q26, the latter named as the AML abn(3q) group.

Methods: We developed a national survey with the participation of 13 Spanish hospitals, and retrospectively reviewed (from 1990 to 2010) these subtypes of AML. Fifty-five patients were collected: 35 with AML inv(3)/t(3;3) and 20 with AML abn(3q). A data collecting page that included main features at diagnosis, therapeutic approach and response, and survival variables, was distributed and completed.

Results: We did not find significant differences in sex, age, history of myelodysplastic syndrome or chemo-/radiotherapy, clinical presentation, WBC and platelet counts, hemoglobin level, blasts immunophenotype, serum lactatedehydrogenase, peripheral blood and bone marrow cellular dysplasia, and bone marrow biopsy findings. Although the association with monosomy 7 was significantly more frequent in AML inv(3)/t(3;3), this did not seem to influence outcome. The lack of response to the different modalities of treatment and the aggressive course of the disease were the standard in both cohorts of patients.

Discussion: Although not yet recognized by the World Health Organization classification, our results are in agreement with the findings of other authors, who include both subsets of AML together in the same group of adverse prognosis.

Conclusion: In an attempt to simplify and bound entities with similar genetic background and clinical behavior, it would be desirable to bring together both subgroups of AML in a single section.
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http://dx.doi.org/10.1179/1607845415Y.0000000003DOI Listing
September 2015