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CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19− (pre)-leukemic cells represent an “early progenitor origin-related” mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19−CD22+ cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19−CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34+CD19−CD22+ cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34+CD19−CD22+ progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19− relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged., The work in P.M. and C.B.’s Laboratory was supported by the European Research Council (CoG-2014-646903, PoC-2018-811220) and the Spanish Ministry of Economy and Competitiveness (SAF2016-80481R, PID2019-108160RB-I00) (P.M.); the ISCIII (ISCIII/FEDER, PI17/01028 and PI20/00822), the Spanish Association against Cancer (AECC), and the FERO Foundation (C.B.). P.M. and J.M.R. acknowledge the support of ISCIII-RICORS within the Next Generation EU program (Plan de Recuperación, Transformación y Resiliencia). N.E. is supported by Cancer Research UK and a Children and Young People’s Cancer Innovation Award (DRCPGM\100058). A.R. is supported by a Wellcome Trust Clinical Research Career Development Fellowship (216632/Z/19/Z). A.O. was supported by ISCIII (PI19/011183). F.S. was supported by AGAUR/Generalitat de Catalunya (SGR288). The single-cell transcriptomic analysis was supported by MRC Discovery award MRCDA 0816-11 and the MRC WIMM Single Cell Facility and MRC-funded Oxford Consortium for Single-Cell Biology (MR/M00919X/1) provided assistance.

Purpose: Glioblastoma is the most aggressive brain tumor in adults and has few therapeutic options. The study of molecular subtype classifications may lead to improved prognostic classification and identification of new therapeutic targets. The Cancer Genome Atlas (TCGA) subtype classification has mainly been applied in U.S. clinical trials, while the intrinsic glioma subtype (IGS) has mainly been applied in European trials. Experimental Design: From paraffin-embedded tumor samples of 432 patients with uniformly treated, newly diagnosed glioblastoma, we built tissue microarrays for IHC analysis and applied RNA sequencing to the best samples to classify them according to TCGA and IGS subtypes. Results: We obtained transcriptomic results from 124 patients. There was a lack of agreement among the three TCGA classificatory algorithms employed, which was not solely attributable to intratumoral heterogeneity. There was overlapping of TCGA mesenchymal subtype with IGS cluster 23 and of TCGA classical subtype with IGS cluster 18. Molecular subtypes were not associated with prognosis, but levels of expression of 13 novel genes were identified as independent prognostic markers in glioma-CpG island methylator phenotype-negative patients, independently of clinical factors and MGMT methylation. These findings were validated in at least one external database. Three of the 13 genes were selected for IHC validation. In particular, high ZNF7 RNA expression and low ZNF7 protein expression were strongly associated with longer survival, independently of molecular subtypes. Conclusions: TCGA and IGS molecular classifications of glioblastoma have no higher prognostic value than individual genes and should be refined before being applied to clinical trials.

Haematological neoplasms are characterised by the presence of recurrent chromosomal abnormalities, making cytogenetics essential for establishing the diagnosis and prognosis. Chromosome banding analysis is mandatory for chronic myeloid leukaemia, neoplasms with eosinophilia, myelodysplastic syndromes and acute leukaemias. In contrast, in other myeloid neoplasms, chronic lymphocytic leukaemia, non-Hodgkin lymphoma and multiple myeloma, the study must be complemented with fluorescence in situ hybridization and/or microarrays, which can overcome some of the shortcomings of banding analysis to identify potential cryptic alterations or reciprocal translocations. In the genomic era, novel technologies such as next generation sequencing are now being used in clinical routine analysis, since they offer the possibility of studying mutations and copy number alterations in a single study at a higher resolution and/or sensitivity. However, they require highly qualified staff and further standardisation, especially regarding data analysis, thereby limiting their current applicability.

Leukemia cell lines have been widely used in the hematology field to unravel mechanistic insights and to test new therapeutic strategies. Myelodysplastic syndromes (MDS) comprise a heterogeneous group of diseases that are characterized by ineffective hematopoiesis and frequent progress to acute myeloid leukemia (AML). A few cell lines have been established from MDS patients after progression to AML but their characterization is incomplete. Here we provide a detailed description of the immunophenotypic profile of the MDS-derived cell lines SKK-1, SKM-1, F-36P; and MOLM-13. Specifically, we analyzed a comprehensive panel of markers that are currently applied in the diagnostic routine for myeloid disorders. To provide high-resolution genetic data comprising copy number alterations and losses of heterozygosity we performed whole genome single nucleotide polymorphism-based arrays and included the cell line OHN-GM that harbors the frequent chromosome arm 5q deletion. Furthermore, we assessed the mutational status of 83 disease-relevant genes. Our results provide a resource to the MDS and AML field that allows researchers to choose the best-matching cell line for their functional studies. (C) 2016 Wiley Periodicals, Inc.

Whole genome amplification (WGA) has become an invaluable method for preserving limited samples of precious stock material and has been used during the past years as an alternative tool to increase the amount of DNA before library preparation for next-generation sequencing. Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders characterized by presenting somatic mutations in several myeloid-related genes. In this work, targeted deep sequencing has been performed on four paired fresh DNA and WGA DNA samples from bone marrow of MDS patients, to assess the feasibility of using WGA DNA for detecting somatic mutations. The results of this study highlighted that, in general, the sequencing and alignment statistics of fresh DNA and WGA DNA samples were similar. However, after variant calling and when considering variants detected at all frequencies, there was a high level of discordance between fresh DNA and WGA DNA (overall, a higher number of variants was detected in WGA DNA). After proper filtering, a total of three somatic mutations were detected in the cohort. All somatic mutations detected in fresh DNA were also identified in WGA DNA and validated by whole exome sequencing.

Background The evolution of animal segmentation is a major research focus within the field of evolutionary–developmental biology. Most studied segmented animals generate their segments in a repetitive, anterior-to-posterior fashion coordinated with the extension of the body axis from a posterior growth zone. In the current study we ask which selection pressures and ordering of evolutionary events may have contributed to the evolution of this specific segmentation mode. Results To answer this question we extend a previous in silico simulation model of the evolution of segmentation by allowing the tissue growth pattern to freely evolve. We then determine the likelihood of evolving oscillatory sequential segmentation combined with posterior growth under various conditions, such as the presence or absence of a posterior morphogen gradient or selection for determinate growth. We find that posterior growth with sequential segmentation is the predominant outcome of our simulations only if a posterior morphogen gradient is assumed to have already evolved and selection for determinate growth occurs secondarily. Otherwise, an alternative segmentation mechanism dominates, in which divisions occur in large bursts through the entire tissue and all segments are created simultaneously. Conclusions Our study suggests that the ancestry of a posterior signalling centre has played an important role in the evolution of sequential segmentation. In addition, it suggests that determinate growth evolved secondarily, after the evolution of posterior growth. More generally, we demonstrate the potential of evo-devo simulation models that allow us to vary conditions as well as the onset of selection pressures to infer a likely order of evolutionary innovations. Electronic supplementary material The online version of this article (doi:10.1186/s13227-016-0052-8) contains supplementary material, which is available to authorized users.

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 similar to 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. (C) 2015 Wiley Periodicals, Inc.

Through the study of one case in particular this article wishes to contribute to adding to the knowledge concerning the importation of printed music in Spain from 1868 to 1892. The case in point refers to the commercial relations that existed during the above period between the German Editorial, Peters, and certain Spanish editors then in business. The material in question consists of nineteen documents -sixteen letters, two order lists and a steamship dispatch certificate- addressed mostly to Peters by five editors and a Spanish musical association, all of which are currently conserved in a well known Leipzig Archive: the Sächsisches Staatsarchiv Leipzig. Reading and analyzing the said documents introduces us to subject matter which, although it has been studied before, enshrouds many unanswered questions: through what channels was foreign music introduced, what means of payment were employed and what manner of repertory was requested? The answer to these questions will give us an idea of the tastes prevalent during that period as well as the commercial outlets utilized, etc.Este artículo pretende ser una aportación al mejor conocimiento de la importación de música impresa en España entre 1868 y 1892 a través de un caso concreto: la relación comercial que existió durante el periodo mencionado entre la editorial alemana Peters y algunos de los editores españoles entonces activos. El material tomado como base está formado por diecinueve documentos —esto es, dieciséis cartas, dos listas de pedido y un resguardo de envío en barco de vapor—, dirigidos en su mayoría a Peters por cinco editores y una asociación musical españoles que se conservan, en la actualidad, en un conocido archivo de Leipzig: el Sächsisches Staatsarchiv Leipzig. A través de la lectura y análisis de dichos documentos nos acercamos a un fenómeno que, aunque conocido y estudiado, todavía encierra diversos interrogantes: cuáles eran las vías de suministro de música foránea, qué fórmulas de pago se empleaban, qué tipo de repertorio se importaba (pudiendo así aproximamos tanto a los gustos imperantes en la época como a la salida mercantil que a éstos se daba), etc.

Complex karyotype (CK) is the poorest risk factor in patients with myelodysplastic syndrome (MDS). It has recently been reported that monosomal karyotype (MK) worsens the prognosis of patients with CK. PATIENTS AND METHODS; We analyzed 1,054 adult patients with MDS with an abnormal karyotype from the Spanish Registry of MDS. The aim of the study was to describe the incidence, characteristics, and prognosis of MK; the main end points were overall survival (OS) and leukemia-free survival.

This workshop brought together developmental biologists and oncologists for three intense days of discussions about the recent progress that has been made on the roles of homeodomain proteins in development, haematopoiesis and leukaemogenesis.

Comunicación presentada en el Congreso Internacional "Miguel Querol y la música hispánica del Barroco", que se celebró en Barcelona y Tarragona entre los días 5 y 7 de febrero de 2004., Durante los primeros años de actividad del IEM (Instituto Español de Musicología) -esto es, entre 1943 y 1948-, los entonces responsables del mismo, Monseñor Higinio Anglés y el Dr. Miguel Querol, tuvieron noticia de la oportunidad de adquirir una biblioteca musical "de gran interés" para el recién creado Instituto. Tras valorar el contenido de dicha biblioteca a través de un catálogo de la misma, y una vez iniciada la negociación sobre el precio a pagar por ésta, el trámite de compra se vió interrumpido por la aparición de una segunda entidad interesada en su adquisición: la Biblioteca Nacional, de Madrid, la cual gozaba -según sabemos por los documentos conservados-, de preferencia de compra frente al Instituto Español de Musicología. Después de más de un año de negociaciones, que quedaron reflejadas en la correspondencia intercambiada por los responsables del IEM en Barcelonay la sede central del CSIC (organismo del que dependía el IEM) en Madrid, la diferencia se resolvió de manera favorable para el Instituto, que adquirió finalmente la biblioteca musical de Anselmo González del Valle el dieciocho de diciembre de 1947., Congreso organizado por el Instituto de Musicología "Josep Ricart y Matas" de la Real Academia Catalana de Bellas Artes de Sant Jordi, por el Departamento de Musicología (Institución "Mila i Fontanals") del CSIC, por el Departamento de Arte (Licenciatura en Historia y Ciencias de la Música) de la Universidad Autónoma de Barcelona y por la Universidad de Granada, con patrocinio de, además de las citadas instituciones, el entonces llamado Ministerio de Ciencia y Tecnología, la Generalitat de Cataluña y la Diputación de Tarragona.

Comunicación presentada en "Musik im Spiel (19. Studentisches Symposium des DVSM e.V.)", celebrado en Bonn del 29.09.2004 al 02.10.2004 y organizado por Musikwissenschaftliches Seminar der Uni Bonn. Actas del Congreso todavía no publicadas.