Mutation status and immunoglobulin gene rearrangements in patients from northwest and central region of Spain with chronic lymphocytic leukemia

This is an open access article distributed under the Creative Commons Attribution License.-- et al.The aim of this study was to investigate the frequency and mutation status of the immunoglobulin heavy variable chain (IGHV) in a cohort of 224 patients from northwest and central region of Spain diagnosed with chronic lymphocytic leukemia (CLL), and to correlate it with cytogenetic abnormalities, overall survival (OS) and time to first treatment (TTFT). 125 patients had mutated IGHV, while 99 had unmutated IGHV. The most frequently used IGHV family was IGHV3, followed by IGHV1 and IGHV4. The regions IGHV3-30, IGHV1-69, IGHV3-23, and IGHV4-34 were the most commonly used. Only 3.1% of the patients belonged to the subfamily IGHV3-21 and we failed to demonstrate a worse clinical outcome in this subgroup. The IGHV4 family appeared more frequently with mutated pattern, similar to IGHV3-23 and IGHV3-74. By contrast, IGHV1-69 was expressed at a higher frequency in unmutated CLL patients. All the cases from IGHV3-11 and almost all from IGHV5-51 subfamily belonged to the group of unmutated CLL.The study was partially supported by grants from the Spanish Fondo de Investigaciones Sanitarias 02/1041, FIS 09/01382, FIS 09/01543, and PI12/00281; RD12/0036/0069 from Red Tematica de Investigación Cooperativa en Cáncer (RTICC), Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Economy and Competitiveness & European Regional Development Fund (ERDF) “Una manera de hacer Europa”; and Caja de Burgos-Banca Cívica. A. Rodrígues was fully supported by an Ayuda Predoctoral FIS de Formación en Investigacion by the Spanish Fondo de Investigaciones Sanitarias. M. Hernandez-Sanchez was partially supported by a grant from the “Fundacion Española de Hematología y Hemoterapia.” Partially supported by grants from “Proyectos de Investigacion Biomédica del SACYL” 106/A/06.Peer Reviewe

Allele and haplotype frequencies of HLA-A, -B, -C, -DRB1, -DQB1 and -DQA1 in Castile and Leon region from North West of Spain

HLA studies have been used to determine the admixture of different populations within the Iberian Peninsula including neighbouring regions with shared origins, such as Portugal and Castile and Leon. These studies certainly can be used to study human migration that could establish populations currently settled according to genetic distant analysis based on the HLA diversity and language variety.This work was supported by the “Gerencia Regional de Salud de Castilla y Leon” (GRS 2080/A/19, 2019) and (GRS COVID 70/A/20, 2020)

Building a network of TP53 and IGHV testing reference centers across Spain: the Red53 initiative

© The Author(s) 2021.Among the different biomarkers predicting response in chronic lymphocytic leukemia (CLL), the most influential parameters are the mutational status of the IGHV genes and the presence of TP53 gene disruptions. Nevertheless, these important assessments are not readily available in most centers dealing with CLL patients. To provide this molecular testing across the country, the Spanish Cooperative Group on CLL (GELLC) established a network of four analytical reference centers. A total of 2153 samples from 256 centers were analyzed over a period of 30 months. In 9% of the patients, we found pathological mutations in the TP53 gene, whereas 48.96% were classified as IGHV unmutated. Results of the satisfaction survey of the program showed a Net Promoter Score of 85.15. Building a national network for molecular testing in CLL allowed the CLL population a broad access to complex biomarkers analysis that should translate into a more accurate and informed therapeutic decision-making.This work was supported in part by Janssen Pharmaceutical Companies of Johnson & Johnson. MC holds a contract from Ministerio de Ciencia, Innovación y Universidades (RYC-2012-12018)

Host virus and pneumococcus-specific immune responses in high-count monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia: implications for disease progression

[EN]Patients diagnosed with chronic lymphocytic leukemia (CLL) display a high incidence of infections due to an associated immunodeficiency that includes hypogammaglobulinemia. A higher risk of infections has also been recently reported for high-count monoclonal B-cell lymphocytosis, while no information is available in low-count monoclonal B-cell lymphocytosis. Here, we evaluated the status of the humoral immune system in patients with chronic lymphocytic leukemia (n=58), as well as in low- (n=71) and high- (n=29) count monoclonal B-cell lymphocytosis versus healthy donors (n=91). Total free plasma immunoglobulin titers and specific levels of antibodies against cytomegalovirus, Epstein-Barr virus, influenza and S.pneumoniae were measured by nephelometry and ELISA-based techniques, respectively. Overall, our results show that both CLL and high-count monoclonal B-cell lymphocytosis patients, but not low-count monoclonal B-cell lymphocytosis subjects, present with relatively high levels of antibodies specific for the latent viruses investigated, associated with progressively lower levels of S.pneumoniae-specific immunoglobulins

Low-count monoclonal B-cell lymphocytosis persists after seven years of follow up and is associated with a poorer outcome

[EN]Low-count monoclonal B-cell lymphocytosis is defined by the presence of very low numbers of circulating clonal B cells, usually phenotypically similar to chronic lymphocytic leukemia cells, whose biological and clinical significance remains elusive. Herein, we re-evaluated 65/91 low-count monoclonal B-cell lymphocytosis cases (54 chronic lymphocytic leukemia-like and 11 non-chronic lymphocytic leukemialike) followed-up for a median of seven years, using high-sensitivity flow cytometry and interphase fluorescence in situ hybridization. Overall, the clone size significantly increased in 69% of low-count monoclonal B-cell lymphocytosis cases, but only one subject progressed to high-count monoclonal B-cell lymphocytosis. In parallel, the frequency of cytogenetic alterations increased over time (32% vs. 61% of cases, respectively). The absolute number of the major T-cell and natural killer cell populations also increased, but only among chronic lymphocytic leukemia-like cases with increased clone size vs. age- and sex-matched controls. Although progression to chronic lymphocytic leukemia was not observed, the overall survival of low-count monoclonal B-cell lymphocytosis individuals was significantly reduced vs. non-monoclonal Bcell lymphocytosis controls (P=0.03) plus the general population from the same region (P≤0.001), particularly among females (P=0.01); infection and cancer were the main causes of death in low-count monoclonal B-cell lymphocytosis. In summary, despite the fact that mid-term progression from low-count monoclonal B-cell lymphocytosis to high-count monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia appears to be unlikely, these clones persist at increased numbers, usually carrying more genetic alterations, and might thus be a marker of an impaired immune system indirectly associated with a poorer outcome, particularly among females

Cultura y Lengua aplicadas a las enseñanzas de la Información (II)

Se trata de un proyecto de integración cultural y lingüística dirigido a alumnos sinohablantes para ayudarles a desarrollar competencias culturales y lingüístico-pragmáticas en español en el ámbito de la comunicación y la información. Se exponen los objetivos alcanzados, la metodología y las actividades desarrolladas en la segunda edición del proyecto, la descripción de los seminarios "Aula sin fronteras: ¡comunícate!" y del "Cinefórum sin fronteras"

Genomic mutation profile in progressive chronic lymphocytic leukemia patients prior to first-line chemoimmunotherapy with FCR and rituximab maintenance (REM)

Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia in Western countries and is notable for its variable clinical course. This variability is partly reflected by the mutational status of IGHV genes. Many CLL samples have been studied in recent years by next-generation sequencing. These studies have identified recurrent somatic mutations in NOTCH1, SF3B1, ATM, TP53, BIRC3 and others genes that play roles in cell cycle, DNA repair, RNA metabolism and splicing. In this study, we have taken a deep-targeted massive sequencing approach to analyze the impact of mutations in the most frequently mutated genes in patients with CLL enrolled in the REM (rituximab en mantenimiento) clinical trial. The mutational status of our patients with CLL, except for the TP53 gene, does not seem to affect the good results obtained with maintenance therapy with rituximab after front-line FCR treatment

Poètiques de resistència/resiliència

La brutal realitat de la pandèmia i el que en deriva ens força –ens obliga– a replantejar els principis i fonaments de l’art en una societat que desapareix per moments: més que líquida, descobrim ara una societat volatilitzada, críptica, desesperada. La desigualtat que creix de manera desmesurada i el canvi climàtic, que ja es mesura en catàstrofes. Les violències, directes o estructurals, derivades de diferències mal enteses. Cada vegada més descosits, ens cal emparar-nos en valors positius i transformadors. Com a noves persones creadores, els i les artistes novells han de presentar percepcions del món que els hi ha tocat habitar –viure– amb llenguatges que adrecin aquestes problemàtiques. Amb propostes artístiques que deixin de banda prejudicis impostats, han de buscar el diàleg amb el públic per generar confluències i complicitats

Estudio de polimorfismos genéticos en la evolución clínica de pacientes sometidos a trasplante alogenico de progenitores hematopoyéticos

[EN]Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is a wellestablished treatment procedure that can potentially cure patients with hematologic malignancies and inherited or acquired non-malignant diseases. An interaction between recipient immunocompetent cells with the donor cells takes place, triggering a series of alloreactive phenomena which will determine the success or failure of the transplant. The most important events are the immune recognition, resulting in graftversus- host disease (GvHD) and graft-versus-tumor (GvT) effect, the graft rejection and relapse. These phenomena are related to the chimerism establishment and posttransplant tolerance, conditioned by genetic and clinical factors [i.e. stem cell source or myeloablative vs. non-myeloablative regimen]. Contributions like the development of conditioning regimens with lower toxicity, the better management of GvHD, the development of more effective tools for monitoring the engraftment and the better knowledge of GvHD and GvT effects are leading to improvement in the allo-HSCT outcome, with an increased survival reducing allo-HSCT derived complications. Therefore, there is a remarkable increase in the number of indications and patients that could be beneficed by this procedure. However, despite the increasing knowledge in this area, about 20-30% of patients undergoing allo-HSCT die due to procedure-derived complications, mainly GvHD and disease relapse, the major complications of allogeneic HSCT. The HLA system is the most important genetic factor in that processes due to its antigen presentation ability. However, even in the setting of identical HLA allo-HSCT in which disease relapse rate is relatively low (about 20%), up to 40% of the patients present acute and/or chronic GvHD4. This GvHD is a major cause of morbidity and mortality, thereby limiting the use of the procedure. Thus, in these processes there are other factors implicated, such us genetic differences out of HLA loci, the minor histocompatibility antigens (mHLA), cytokine gene polymorphisms implicated in the cytokine storm of the GvHD8 or polymorphisms in proteins related to innate immune response. Finally, a better knowledge of the immunogenetics together with the clinical risk factors will allow a more accurate assessment of the risk of transplant-related complications. This fact could lead to the generation of a clinicprognostic index that would help to select the most appropiate donor, to modify the conditioning regimen and to develope individualized immunosuppressive therapy, GvHD prophylaxis and the graft and post-transplant immunotherapy manipulation11. Moreover, a more exhaustive knowledge on the role of donor and recipient genotypes in GvHD triggering or maintainance, could help to include new clinical assays using new drugs. On the other side, HLA system, as antigen presenting system, could have a role in the development and/or control of some neoplasias. With this premise, its role will be analyzed in multiple myeloma patients, a representative disease from our center. In this thesis, we aim to analyze the influence of three groups of genetic polymorphisms in the allo-HSCT setting (HLA, microsatellites and two adhesion molecules). The obtained results will be discussed below.[ES]En el presente trabajo de tesis doctoral se ha analizado el valor de algunos sistemas polimórficos (sistema HLA, regiones microsatélite y polimorfismos en dos genes codificantes de moléculas de adhesión) en un grupo de pacientes receptores de un trasplante alogénico de progenitores hematopoyéticos de sangre periférica de un donante emparentado HLA idéntico. Igualmente se analiza la influencia del sistema HLA en el desarrollo y evolución clínica de pacientes con mieloma múltiple sometido a diferentes esquemas terapéuticos incluido el trasplante alogénico

The novel HLA-DQB1*06:03:27 allele characterised by sequence-based typing in a European bone marrow donor

A single nucleotide substitution in exon 3 of HLA-DQB1*06:03:01 results in a new allele, HLA-DQB1*06:03:27.Gerencia Regional de Salud de Castilla y Leon, Grant/Award Number: GRS 2080/A/19, 201