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BACKGROUND: Atherosclerotic cardiovascular disease (heart attacks and strokes) is the major cause of death globally and is caused by the buildup of a plaque in the arterial wall. Genomic data showed that the B cell-activating factor (BAFF) receptor pathway, which is specifically essential for the survival of conventional B lymphocytes (B-2 cells), is a key driver of coronary heart disease. Deletion or antibody-mediated blockade of BAFF receptor ablates B-2 cells and decreases experimental atherosclerosis. Anti-BAFF immunotherapy is approved for treatment of autoimmune systemic lupus erythematosus, and can therefore be expected to limit their associated cardiovascular risk. However, direct effects of anti-BAFF immunotherapy on atherosclerosis remain unknown. METHODS: To investigate the effect of BAFF neutralization in atherosclerosis, the authors treated Apoe-/- and Ldlr-/- mice with a well-characterized blocking anti-BAFF antibody. Moreover, to investigate the mechanism by which BAFF impacts atherosclerosis, the authors studied atherosclerosis-prone mice that lack the alternative receptor for BAFF: transmembrane activator and calcium modulator and cyclophilin ligand interactor. RESULTS: The authors demonstrate here that anti-BAFF antibody treatment increased atherosclerosis in mice, despite efficient depletion of mature B-2 cells, suggesting a unique mechanism of action. Indeed, myeloid cell-specific deletion of transmembrane activator and calcium modulator and cyclophilin ligand interactor also results in increased atherosclerosis, while B cell-specific transmembrane activator and calcium modulator and cyclophilin ligand interactor deletion had no effect. Mechanistically, BAFF-transmembrane activator and calcium modulator and cyclophilin ligand interactor signaling represses macrophage IRF7-dependent (but not NF-κB-dependent) Toll-like receptor 9 responses including proatherogenic CXCL10 production. CONCLUSIONS: These data identify a novel B cell-independent anti-inflammatory role for BAFF in atherosclerosis and may have important clinical implications. ; This work was supported by grants of the Austrian Science Fund (SFB F54), the European Union (FP7 VIA), the British Heart Foundation, and the European Research Council (ERC). PS is supported by grants from the Swiss National Science Foundation.

The preparation of this review was funded by the Ministerio de Economia y Competitividad (now Ministerio de Ciencia e Innovacion) of the Government of Spain with number SAF2016-78631-P. G.G.H. is supported through this grant. ; Figure 1 was created with https://biorender.com/ on 29 April 2021. ; The B cell scaffold protein with ankyrin repeats (BANK1) is expressed primarily in B cells and with multiple but discrete roles in B cell signaling, including B cell receptor signaling, CD40-related signaling, and Toll-like receptor (TLR) signaling. The gene for BANK1, located in chromosome 4, has been found to contain genetic variants that are associated with several autoimmune diseases and also other complex phenotypes, in particular, with systemic lupus erythematosus. Common genetic variants are associated with changes in BANK1 expression in B cells, while rare variants modify their capacity to bind efferent effectors during signaling. A BANK1-deficient model has shown the importance of BANK1 during TLR7 and TLR9 signaling and has confirmed its role in the disease. Still, much needs to be done to fully understand the function of BANK1, but the main conclusion is that it may be the link between different signaling functions within the B cells and they may act to synergize the various pathways within a cell. With this review, we hope to enhance the interest in this molecule. ; Spanish Government SAF2016-78631-P

In recent years, a subgroup of B-cell precursor acute lymphoblastic leukemia (BCP ALL) without an established abnormality ("B-other") has been shown to be characterized by rearrangements of ABL1, ABL2, CSF1R, or PDGFRB (a.k.a. ABL-class genes). Using FISH with probes for these genes, we screened 55 pediatric and 50 adult B-other cases. Three (6%) of the adult but none of the childhood B-other cases were positive for ABL-class aberrations. RT-PCR and sequencing confirmed a rare SFPQ-ABL1 fusion in one adult B-other case with t(1;9)(p34;q34). Only six SFPQ-ABL1-positive BCP ALLs have been reported, present case included. A review of these shows that all harbored fusions between exon 9 of SFPQ and exon 4 of ABL1, that the fusion is typically found in adolescents/younger adults without hyperleukocytosis, and that IKZF1 deletions are recurrent. The few patients not treated with tyrosine kinase inhibitors (TKIs) and/or allogeneic stem cell transplantation relapsed, strengthening the notion that TKI should be added to the therapy of SFPQ-ABL1-positive BCP ALL. ; Funding Agencies|Swedish Childhood Cancer Foundation [PR2018-0004]; Swedish Cancer SocietySwedish Cancer Society [CAN 2017/291]; Swedish Research CouncilSwedish Research Council [2016-01084]; Governmental Funding of Clinical Research within the National Health Service; VetenskapsradetSwedish Research Council [2016-01084]

Activation-induced cytidine deaminase (AID) is essential for somatic hypermutation and class switch recombination in mature B-cells, while AID was also shown to play a role in developing pre-BCR/BCR-positive B-cells of the bone marrow. To further elucidate a potential function of Aid in the bone marrow prior to V(D) J-recombination, we utilized an in vivo model which exerts a B-cell developmental arrest at the pro-B cell stage with low frequencies of pro-B cell acute lymphoblastic leukemia (pro-B ALL) development. Therefore, p19ArfRag1 (AR) mice were crossed with Aid-deficient mice (ARA). Surprisingly, loss of Aid expression in pro-B cells accelerated pro-B ALL incidence from 30% (AR) to 98% (ARA). This effect was Aid dose dependent, since Aid animals of the same background displayed a significantly lower incidence (83%). Furthermore, B-cell-specific Aid up-regulation was observed in Aid-competent pro-B ALLs. Additional whole exome/sanger sequencing of murine pro-B ALLs revealed an accumulation of recurrent somatic Jak3 (p. R653H, p. V670A) and Dnm2 (p. G397R) mutations, which highlights the importance of active IL7R signaling in the pro-B ALL blast cells. These findings were further supported by an enhanced proliferative potential of ARA pro-B cells compared to Aid-competent cells from the same genetic background. In summary, we show that both Aid and Rag1 act as a negative regulators in pro-B cells, preventing pro-B ALL. ; J. Hauer has been supported by the German Cancer Foundation (110997), DJCLS02R/2016, KKS A2016/07 and from the "Forschungskommission" of the medical faculty of the Heinrich Heine University. A. Borkhardt has been supported by the German Children's Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. Research in I. Sánchez-García's group is partially supported by FEDER and by MINECO (SAF2012-32810, SAF2015-64420-R and Red de Excelencia Consolider OncoBIO SAF2014-57791-REDC), Instituto de Salud Carlos III (PIE14/00066), ISCIII- Plan de Ayudas IBSAL 2015 Proyectos Integrados (IBY15/00003), by Junta de Castilla y León (BIO/SA51/15, CSI001 U14, UIC-017, and CSI001U16), Fundacion Inocente Inocente and by the ARIMMORA project (European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 282891). I. Sánchez-García's lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. A. Borkhardt and I. Sánchez-García have been supported by the German Carreras Foundation (DJCLS R13/26). Research in C. Vicente-Dueñas' group is partially supported by a "Miguel Servet" Grant (CP14/00082 - AES 2013-2016 - FEDER) from the Instituto de Salud Carlos III (Ministerio de Economía y Competitividad) and by the Lady Tata International Award for Research in Leukaemia 2016-2017. A. Martín-Lorenzo was supported by FSE-Conserjería de Educación de la Junta de Castilla y León (CSI001-13). ; Peer Reviewed

This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License. ; B-cell precursor acute lymphoblastic leukemias (pB-ALLs) are the most frequent type of malignancies of the childhood, and also affect an important proportion of adult patients. In spite of their apparent homogeneity, pB-ALL comprises a group of diseases very different both clinically and pathologically, and with very diverse outcomes as a consequence of their biology, and underlying molecular alterations. Their understanding (as a prerequisite for their cure) will require a sustained multidisciplinary effort from professionals coming from many different fields. Among all the available tools for pB-ALL research, the use of animal models stands, as of today, as the most powerful approach, not only for the understanding of the origin and evolution of the disease, but also for the development of new therapies. In this review we go over the most relevant (historically, technically or biologically) genetically engineered mouse models (GEMMs) of human pB-ALLs that have been generated over the last 20 years. Our final aim is to outline the most relevant guidelines that should be followed to generate an "ideal" animal model that could become a standard for the study of human pB-ALL leukemia, and which could be shared among research groups and drug development companies in order to unify criteria for studies like drug testing, analysis of the influence of environmental risk factors, or studying the role of both low-penetrance mutations and cancer susceptibility alterations. ; This work was supported by the German "Bundesamt fur Strah-lenschutz (BfS)" pilot project on childhood leukemia no. 3612S70029. JH has been supported by the German Children's Cancer Foundation and from the "Forschungskommission" of the medical faculty of the Heinrich Heine University and the "Strategischer Forschungsfond" of the Heinrich-Heine-University. AB has been supported by the German Children's Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. Research in ISG group is partially supported by FEDER and by MICINN (SAF2012-32810), by NIH grant (R01 CA109335-04A1), by Junta de Castilla y León (BIO/SA06/13) and by the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program). ISG lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. Research at CC's lab was partially supported by FEDER, Fondo de Investigaciones Sanitarias (PI13/00160), CSIC P.I.E., Junta de Castilla y León, and from an institutional grant from the Fundación Ramón Areces. ; Peer Reviewed

Based on laboratory and clinical research findings and investments in immunotherapy by many institutions in academia, government funded laboratories, and industry, there is tremendous and deserved excitement in the field of cell and gene therapy. In particular, understanding of immune mediated control of cancer has created opportunities to develop new forms of therapies based on engineered T cells. Unlike conventional drugs or biologics, the source material for these new therapies is collected from the patient or donor. The next step is commonly either enrichment to deplete unwanted cells, or methods to positively select T cells prior to polyclonal expansion or antigen specific expansion. As the first generation of engineered T cell therapies have demonstrated proof of concept, the next stages of development will require the integration of automated technologies to enable more consistent manufacturing and the ability to produce therapies for more patients.

ETV6-RUNX1 is associated with the most common subtype of childhood leukemia. Pre-leukaemic clones carrying ETV6-RUNX1 oncogenic lesions are frequently found in neonatal cord blood, but only few ETV6-RUNX1 carriers develop pB-ALL. The highly demanding and pending challenge is to reveal the multistep natural history of ETV6-RUNX1 pB-ALL, because it can offer non-toxic prophylactic interventions to preleukemic carriers. However, the lack of a genetically engineered ETV6-RUNX1 mouse model mimicking the human pB-ALL has hampered our understanding of the pathogenesis of this disease. This rule has now been broken in a study of the effect of the ETV6-RUNX1 oncogene in cancer development in a mouse model in which oncogene expression is restricted to the stem cell compartment. In this article, we review the different attempts to model this disease, including the recent representative success stories and we discuss its potential application to both identify etiologic factors of childhood ETV6-RUNX1 pB-ALL and prevent the conversion of a preleukemic clone in an irreversible transformed state. ; J.H. has been supported by the German Children's Cancer Foundation, DJCLS 02R/2016, KKS A2016/07 and from the "Forschungskommission" of the medical faculty of the Heinrich Heine University. A.B. has been supported by the German Children's Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. Funding to S.N.C. from Salus Sanguinis, Fondation contre le cancer Belgium; Interuniversity Attraction Poles IAP and ARC 10/15-027 is acknowledged. Research in ISG group is partially supported by FEDER and by MINECO (SAF2012-32810, SAF2015-64420-R and Red de Excelencia Consolider OncoBIO SAF2014-57791-REDC), Instituto de Salud Carlos III (PIE14/00066), ISCIII- Plan de Ayudas IBSAL 2015 Proyectos Integrados (IBY15/00003), by Junta de Castilla y León (BIO/SA51/15, CSI001U14, UIC017, and CSI001U16), and by the Fundacion Inocente Inocente. ISG lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. A.B. and ISG have been supported by the German Carreras Foundation (DJCLS R13/26). Research in CVD group is partially supported by a "Miguel Servet" Grant (CP14/00082 - AES 2013-2016 - FEDER) from the Instituto de Salud Carlos III (Ministerio de Economía y Competitividad) and by the Lady Tata International Award for Research in Leukaemia 2016–2017. ; Peer Reviewed

Altres ajuts: this work was supported in part by Fundació La Marató de TV3 (201516-10, 201502-30). MM-T is sponsored by the PERIS (SLT002/16/00234) from the Generalitat de Catalunya; FB is a researcher from Fundació Institut de Recerca en Ciències de la Salut Germans Trias i Pujol, supported by the Health Department of the Catalan Government (Direcció General de Recerca i Innovació, Department Salut, Generalitat de Catalunya) and MF is funded by the Catalan Health Department (Generalitat de Catalunya) contract PERIS (SLT002/16/00069). ; Mesenchymal stem or stromal cells (MSC) have proven immunomodulatory properties toward B cell activation and induce regulatory B cells (Breg), through a dual mechanism of action that relies both on cell contact and secreted factors. One of them are MSC-derived extracellular vesicles (EVs), membrane nanovesicles that mediate cell communication and typically reflect the phenotype of the cell of origin. MSC-EVs could resemble MSC functions, and are being contemplated as an improved alternative to the MSC-based immunomodulatory therapy. In the present work, we focused on the factors secreted by MSC and aimed to elucidate the putative role of MSC-EVs in the immunomodulation of B cells. EVs and soluble protein-enriched fractions (PF) were isolated from MSC-conditioned medium (CM) using size-exclusion chromatography (SEC) and their capacity to modulate B cell activation, induction of Breg and B cell proliferation was compared to that of the whole MSCs. Co-culture with MSC or unfractionated CM induced naïve and CD24hiCD38hi, IL-10 producing (Breg) phenotypes on B cells while not affecting proliferation. MSC-PF had a comparable effect to MSCs, inducing a naïve phenotype, and even though they did not induce the shift toward a CD24hiCD38hi population, MSC-PF fostered IL-10 production by B cells. Conversely, MSC-EVs failed to promote naïve B cells and to reduce memory B cells. MSC-EVs induced CD24hiCD38hi B cells to a similar extent of that of MSC, but not bona fide Bregs since they did not produce IL-10. Our results show that B cell modulation by MSC is partially mediated by soluble factors other than EVs.

INTRODUCTION: Geographic access to novel oncology therapies, and the extent to which it may vary by potential sites of care, regions, and population characteristics, is poorly understood. We examined how expanding access to chimeric antigen receptor (CAR) T cell therapy administration sites impacts patient travel distances and time. METHODS: We used geographic information system techniques to calculate shortest travel distance and time between patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) and the nearest CAR T cell therapy administration site in three scenarios: academic hospitals; academic and community multispecialty hospitals; and academic and community multispecialty hospitals plus nonacademic specialty oncology network centers. Main outcome measures were differences in travel distance and time among the scenarios and the relationship between travel time and socioeconomic status, race, rural–urban areas, and non-Hodgkin lymphoma clusters. Non-Hodgkin lymphoma incidence, socioeconomic status, and administration centers were derived from governmental/publicly available data sources. RESULTS: Of 3922 patients eligible for CAR T cell therapy, more than 37% had to travel more than 1 h to the nearest academic hospital. Average travel time and distance were significantly reduced by 23% and 30% (P < 0.001), respectively, when access was expanded to include community hospitals plus a broader range of oncology specialty treatment centers. Compared to academic hospitals alone, increasing access to include community hospitals decreased time and distance by 7% and 8% (P < 0.01), respectively. In addition, there would be a lower proportion of sites operating as the only care provider within 25 miles if access was expanded outside of academic hospitals only. Longer travel time was associated with lower socioeconomic status. CONCLUSION: Many patients with DLBCL have long travel times to an academic hospital that administers CAR T cell therapy. Expanding access to care through site-of-care ...

Common variable immunodeficiency (CVID), the most prevalent symptomatic primary immunodeficiency, displays impaired terminal B-cell differentiation and defective antibody responses. Incomplete genetic penetrance and ample phenotypic expressivity in CVID suggest the participation of additional pathogenic mechanisms. Monozygotic (MZ) twins discordant for CVID are uniquely valuable for studying the contribution of epigenetics to the disease. Here, we generate a single-cell epigenomics and transcriptomics census of naïve-to-memory B cell differentiation in a CVID-discordant MZ twin pair. Our analysis identifies DNA methylation, chromatin accessibility and transcriptional defects in memory B-cells mirroring defective cell-cell communication upon activation. These findings are validated in a cohort of CVID patients and healthy donors. Our findings provide a comprehensive multi-omics map of alterations in naïve-to-memory B-cell transition in CVID and indicate links between the epigenome and immune cell cross-talk. Our resource, publicly available at the Human Cell Atlas, gives insight into future diagnosis and treatments of CVID patients. ; This study was funded by: Spanish Ministry of Science and Innovation (grant number PID2020-117212RB-I00/AEI/10.13038/501100011033) (E.B.), Instituto de Salud Carlos III (ISCIII), Ref. AC18/00057, associated with i-PAD project (ERARE European Union program) (E.B.), Wellcome Sanger core funding (grant no. WT206194) (R.V.-T.), the Chan Zuckerberg Initiative (grant 2020-216799) (R.V.-T. and E.B.), an EMBO short-term fellowship (J.R.U.), Fondo de Investigación Sanitaria Instituto de Salud Carlos III (FIS PI16/01605) (L.P.-M.), the Spanish Ministry of Science, Innovation and Universities (SAF2017-89109-P; AEI/FEDER, UE) (H.H.), Instituto de Salud Carlos III, Ministry of Health (PI16/00759) and European Regional Development Fund-European Social Fund—FEDER-FSE) (C.R-G.), Grupo DISA (OA18/017) (C.R.-G.), the UK Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0426) (G.K.) ...

This is an open-access paper. ; The B-cell compartment in which multiple myeloma stem cells reside remains unclear. We investigated the potential presence of mature, surface-membrane immunoglobulin-positive B lymphocytes clonally related to the tumor bone marrow plasma cells among different subsets of peripheral blood B cells from ten patients (7 with multiple myeloma and 3 with monoclonal gammopathies of undetermined significance). The presence of clonotypic immunoglobulin heavy chain gene rearrangements was determined in multiple highly-purified fractions of peripheral blood B-lymphocytes including surface-membrane IgM+ CD27- naïve B-lymphocytes, plus surface-membrane IgG+, IgA+ and IgM+ memory CD27+ B cells, and normal circulating plasma cells, in addition to (mono)clonal plasma cells, by a highly-specific and sensitive allele-specific oligonucleotide polymerase chain reaction directed to the CDR3 sequence of the rearranged IGH gene of tumor plasma cells from individual patients. Our results showed systematic absence of clonotypic rearrangements in all the different B-cell subsets analyzed, including M-compo-nent isotype-matched memory B-lymphocytes, at frequencies <0.03 cells/mL (range: 0.0003-0.08 cells/mL); the only exception were the myeloma plasma cells detected and purified from the peripheral blood of four of the seven myeloma patients. These results indicate that circulating B cells from patients with multiple myeloma and monoclonal gammopathies of undetermined significance are usually devoid of clonotypic B cells while the presence of immunophenotypically aberrant myeloma plasma cells in peripheral blood of myeloma patients is a relatively frequent finding. ; This work was supported by grants from European Union FP6 STREP MSCNet (N. E06005FF), Cooperative Research Thematic Network on Cancer (RTICs; RTICC RD06/0020/0035-FEDER, RD06/0020/0006, RD12/0036/0048, RD12/0036/0069 and G03/136), Instituto de Salud Carlos III/Subdirección General de Investigación Sanitaria Ministerio de Sanidad y Consumo (FIS: PI060339; 02/0905; 01/0089/01-02;PS09/01897, and PI06/0824-FEDER), Asociacion Española Contra el Cancer AECC (GCB120981SAN) and Gerencia Regional de Salud de Castilla y León; Ayuda de Excelencia de Castilla y León, Consejería de Educación (EDU/894/2009, GR37) Junta de Castilla y León, Valladolid, Spain. LST received a CAPES/Ministério da Educação scholarship from the Brazilian Government. ; Peer Reviewed

Self-tolerance by clonal anergy of B cells is marked by an increase in IgD and decrease in IgM antigen receptor surface expression, yet the function of IgD on anergic cells is obscure. Here we define the RNA landscape of the in vivo anergy response, comprising 220 induced sequences including a core set of 97. Failure to co-express IgD with IgM decreases overall expression of receptors for self-antigen, but paradoxically increases the core anergy response, exemplified by increased Sdc1 encoding the cell surface marker syndecan-1. IgD expressed on its own is nevertheless competent to induce calcium signalling and the core anergy mRNA response. Syndecan-1 induction correlates with reduction of surface IgM and is exaggerated without surface IgD in many transitional and mature B cells. These results show that IgD attenuates the response to self-antigen in anergic cells and promotes their accumulation. In this way, IgD minimizes tolerance-induced holes in the pre-immune antibody repertoire. ; This work was supported by NIH grant U19 AI100627 and NHMRC grants 585490, 1016953 and 1081858 to C.C.G., NHMRC CJ Martin Fellowship 595989 to J.H.R., an Endeavour Award from the Australian Government to Z.S. and the National Collaborative Research Infrastructure Scheme Australian Phenomics Facility