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Primary mediastinal B-cell lymphoma (PMBCL) is a rare but aggressive mature B-cell lymphoma that arises from thymic B cells and most commonly affects adolescents and young adults. PMBCL is now recognized by the WHO as a distinct entity from diffuse large B-cell lymphoma (DLBCL), not otherwise specified, with a unique clinical presentation and distinct morphologic features and molecular alterations. Similar to classic Hodgkin lymphoma, PMBCL tumors are characterized by alterations in the nuclear factor-κB and JAK/STAT pathways. These tumors also exhibit an immune evasion phenotype marked by upregulation of PD-L1 and loss of B2M. Historic data indicates that outcomes for pediatric patients with PMBCL are inferior compared with pediatric patients with DLBCL treated on the same protocols, and there is no current standard approach to initial treatment. Common regimens used for children with PMBCL include multiagent chemotherapy regimens designed for Burkitt lymphoma, such as Lymphomes Malins B (LMB)-based or Berlin-Frankfurt-Münster (BFM)-based chemotherapy ± rituximab. Based on initial data in adults showing excellent outcomes with the use of DA-EPOCH-R regimens, these regimens have also been adopted in pediatrics, although with mixed results. Novel agents are currently being studied in PMBCL with the goal of improving outcomes and reducing reliance on radiation and/or high-dose chemotherapy. Immune checkpoint blockade with PD-1 inhibition is of particular interest given the upregulation of PD-L1 in PMBCL and the known efficacy of these agents in the relapsed setting. Future efforts in PMBCL will also seek to determine the role of FDG-PET in evaluating response to therapy and the role of biomarkers in risk stratification.

New insights from genomic studies have had an impact on the definition and the diagnosis of several lymphoid tumors including follicular B-cell lymphomas, aggressive diffuse large B-cell lymphomas, and lymphoproliferations associated with acquired and posttransplant immunodeficiencies. Follicular lymphoma (FL) includes tumors whose behavior varies widely from indolent/early lesions to aggressive/transformed lymphomas. Although some large B-cell lymphomas can be subclassified as specific entities, the majority lack the characteristics necessary for subclassification and, thus, are termed diffuse large B-cell lymphoma, NOS. There have been, however, some changes in the classification of specific subtypes of large B-cell lymphoma as well as the addition of new entities, a few of which are highlighted in this article. The immunodeficiency-related lymphoproliferative disorders are currently divided into four major categories based on the clinical setting in which they arose: primary immune deficiency, post-transplant, HIV infection, and iatrogenic immunosuppression. In the two upcoming classifications systems for hematolymphoid neoplasms, International Consensus Classification (ICC) and WHO-HAEM-5, there is a divergence in the approach to categorize these lesions. Furthermore, whereas the WHO-HAEM-5 confirms the ability to classify a spectrum of EBV+ lesions as EBV+ DLBCL, NOS, the ICC has separated out lesions that are composed of a heterogenous cellular infiltrate into a new separate category, “EBV-positive polymorphic B cell lymphoproliferative disorder, NOS”. Both WHO-HAEM-5 and ICC recognize a number of KSHV/HHV8-associated lymphoid lesions and acknowledge that there is significant overlap among the different lesions. In the future, translation of these innovations in general practice requires further validation.

The Cuvette Centrale swamp forest around the Congo river has the most extensive peatland complex in the tropics, but due to its remoteness the peat was only recently discovered. The international project CongoPeat, which includes scientists from the Republic of the Congo and the Democratic Republic of the Congo and works with the local people of the Cuvette Centrale, is studying the peatlands to determine how they formed and the possible threats since it is vital that the peat is preserved. While the peatlands are at least 20,000 years old the peat is thin compared to other tropical peatlands of similar age. The JULES land surface model has been used with a reconstruction of the past annual rainfall and a simulation of other climate variables with the HadCM3 model to simulate the development of the peatlands. The model results support the hypothesis that a long period of reduced rainfall a few thousand years ago lead to a large loss of peat and recreate the age-depth profiles of the peat in measured soil cores including the feature called a “ghost interval”. This confirms that a constant high water table is needed to keep decomposition of the peat to a minimum and hence preserve the peatlands. JULES was then run with future climate projections from five global climate models to simulate how the peatlands could change up to 2100. In most projections the increased temperatures lead to increased evapotranspiration, lower water tables and increased decomposition of peat. In most cases peat is lost overall, particularly when rainfall is also reduced further lowering the water tables, in-spite of increased CO2 concentration increasing the amount of vegetation and litterfall while reducing the amount of plant transpiration. The risk to the peatland Carbon is greater at higher levels of global warming.

Arctic permafrost is yet the largest non-seasonal component of Earth's cryosphere and has been proposed as a climate tipping element. Already today, permafrost thaw and ground ice loss have detrimental consequences for Arctic communities and are affecting the global climate via carbon-cycle–feedbacks. However, it is an open question whether climatic changes drive permafrost loss in a way that gives rise to a tipping point, crossing of which would imply abrupt acceleration of thaw and disproportional unfolding of its impacts.Here, we address this question by geospatial analyses and a comprehensive literature review of the mechanisms and feedbacks driving permafrost thaw across spatial scales. We find that neither observation-constrained nor model-based projections of permafrost loss provide evidence for the existence of a global-scale tipping point, and instead suggest a quasi-linear response to global warming. We identify a range of processes that drive rapid permafrost thaw and irreversible ground ice loss on a local scale, but these do not accumulate to a non-linear response beyond regional scales.We emphasize that it is precisely because of this overall linear response, that there is no „safe space“ for Arctic permafrost where its loss could be acceptable. Every additional amount of global warming will proportionally subject additional land areas underlain by permafrost to thaw, implying further local impacts and carbon emissions.

The response of soil carbon represents one of the key uncertainties in future climate change due to competing soil carbon driven feedbacks. The ability of Earth System Models (ESMs) to simulate both present day and future soil carbon is therefore vital for reliably estimating global carbon budgets required for Paris agreement targets. In this presentation, the simulation of both present day and future soil carbon is investigated within CMIP6 ESMs.The ability of CMIP6 ESMs to simulate present day soil carbon is evaluated against empirical datasets, where a lack of consistency in modelled soil carbon remains from the previous generation of models (CMIP5). This underestimation is particularly dominant in the northern high latitude soil carbon stocks. The results suggest much of the uncertainty associated with modelled soil carbon stocks can be attributed to the simulation of below ground processes, and greater emphasis is required on improving the representation of below ground soil processes in future developments of models.Projections of soil carbon during the 21st century are also evaluated to quantify future soil carbon changes in CMIP6 ESMs and to assess the uncertainty of the soil carbon induced feedback to climate change. The response of soil carbon is broken down into changes due to increases in Net Primary Productivity (NPP) and reductions in soil carbon turnover time (τs), with the aim of isolating the differing responses which influence changes in future soil carbon storage. A reduction in the spread of soil carbon projections is identified in CMIP6 compared to CMIP5. However, similar reductions are not seen in the components due respectively to changes in NPP and τs. The relationship between the induced soil carbon changes due to NPP and τs is investigated and their overall effect on the future soil carbon response is presented.

SETD2 is the sole histone methyltransferase responsible for H3K36me3, with roles in splicing, transcription initiation, and DNA damage response. Homozygous disruption of SETD2 yields a tumor suppressor effect in various cancers. However, SETD2 mutation is typically heterozygous in diffuse large B-cell lymphomas. Here we show that heterozygous Setd2 deficiency results in germinal center (GC) hyperplasia and increased competitive fitness, with reduced DNA damage checkpoint activity and apoptosis, resulting in accelerated lymphomagenesis. Impaired DNA damage sensing in Setd2-haploinsufficient germinal center B (GCB) and lymphoma cells associated with increased AICDA-induced somatic hypermutation, complex structural variants, and increased translocations including those activating MYC. DNA damage was selectively increased on the nontemplate strand, and H3K36me3 loss was associated with greater RNAPII processivity and mutational burden, suggesting that SETD2-mediated H3K36me3 is required for proper sensing of cytosine deamination. Hence, Setd2 haploinsufficiency delineates a novel GCB context–specific oncogenic pathway involving defective epigenetic surveillance of AICDA-mediated effects on transcribed genes.Significance:Our findings define a B cell–specific oncogenic effect of SETD2 heterozygous mutation, which unleashes AICDA mutagenesis of nontemplate strand DNA in the GC reaction, resulting in lymphomas with heavy mutational burden. GC-derived lymphomas did not tolerate SETD2 homozygous deletion, pointing to a novel context-specific therapeutic vulnerability.This article is highlighted in the In This Issue feature, p. 1599

Supplementary Figure from SETD2 Haploinsufficiency Enhances Germinal Center–Associated AICDA Somatic Hypermutation to Drive B-cell Lymphomagenesis

Supplementary Methods - PDF file 100K, Reagents, gene expression profiling, RT-PCR, mice studies, clinical trial, patient samples, ex vivo treatments, immunohistochemistry and statistical analysis

Table S2 - PDF file 62K, Genes hypermethylated and repressed in doxorubicin resistant cell lines

Table S3 - PDF file 138K, mRNA qPCR and SMAD1 massARRAY primer

Figure S5 - PDF file 224K, Toxicity studies in mice

Supplemental Figure Legends

Figure S6 - PDF file 110K, Daunorubicin uptake in DLBCL cell lines

Supplementary Table S1. Sanger validated variants. Supplementary Table S2. Mutations in HSTL driver genes. Supplementary Table S3. Other mutations identified by exome sequencing. Supplementary Table S4. Copy number of HSTL patients and cell lines. Supplementary Table S5. Clinical and pathological characteristics of HSTL patients. Supplementary Tables S6, S7. Comparison to HSTL clinical data in the literature. Supplementary Table S8. Mutational frequencies in other lymphomas. Supplementary Table S9. HSTL mutations in other lymphoma driver genes. Supplementary Table S10. Gene set enrichment analysis of DERL2 SETD2 shRNA.

PU-H71 suppresses tumor growth in a Ramos xenograft Model.

Figures S7, S8 and S9 - PDF file 206K, SMAD1 expression in patients and functional experiments

Figures S1, S2, S3 and S4 - PDF file 394K, Combinatorial effect of demethylating agents and chemotherapy in cell lines and primary samples

IPA analysis of Hps90 client protein networks

Hsp90 is a molecular chaperone that protects proteins, including oncogenic signaling complexes, from proteolytic degradation. PU-H71 is a next-generation Hsp90 inhibitor that preferentially targets the functionally distinct pool of Hsp90 present in tumor cells. Tumors that are driven by the MYC oncoprotein may be particularly sensitive to PU-H71 due to the essential role of Hsp90 in the epichaperome, which maintains the malignant phenotype in the setting of MYC. Burkitt lymphoma (BL) is an aggressive B-cell lymphoma characterized by MYC dysregulation. In this study, we evaluated Hsp90 as a potential therapeutic target in BL. We found that primary BL tumors overexpress Hsp90 and that Hsp90 inhibition has antitumor activity in vitro and in vivo, including potent activity in a patient-derived xenograft model of BL. To evaluate the targets of PU-H71 in BL, we performed high-affinity capture followed by proteomic analysis using mass spectrometry. We found that Hsp90 inhibition targets multiple components of PI3K/AKT/mTOR signaling, highlighting the importance of this pathway in BL. Finally, we found that the anti-lymphoma activity of PU-H71 is synergistic with dual PI3K/mTOR inhibition in vitro and in vivo. Overall, this work provides support for Hsp90 as a therapeutic target in BL and suggests the potential for combination therapy with PU-H71 and inhibitors of PI3K/mTOR. Mol Cancer Ther; 16(9); 1779–90. ©2017 AACR.

Hsp90 client proteins identified by PU-H71 high affinity capture

BL tumors undergo growth suppression without apoptosis upon treatment with PU-H71 in-vivo.

BL tumors overexpress Hsp90

Supplementary Figure S1. Sanger sequencing chromatograms. Supplementary Figure S2. Cancer cell fraction for driver genes. Supplementary Figure S3. Ideogram with chromosome 7 alterations. Supplementary Figure S4. Examples of Exome Copy Number. Supplementary Figure S5. Exploratory Kaplan-Meier plots for clinical covariates. Supplementary Figure S6. Exploratory Kaplan-Meier plots for molecular covariates. Supplementary Figure S7. Sanger and exome sequencing validation of SETD2 biallelic mutation in one HSTL case. Supplementary Figure S8. SETD2 expression in mutant vs. wildtype cases. Supplementary Figure S9. Mutual exclusivity of STAT5B, PIK3CD, and STAT3 mutations.

BL cells but not normal GC B-cells are sensitive to inhibition by PU-H71.

Chemical Structure of PU-H71 and BEZ-235

This file contains supplemental additional experimental procedures, relevant references and 7 supplementary figures, including: S1 "Expression of EBV in RS samples"; S2 "Schematic representation of the RS-PDX models"; S3 "Disease engraftment and distribution of RS1316 i.v. model"; S4 "Phenotypic analysis of primary and derived-RS-PDXs"; S5 "Schematic diagram of proteins and corresponding mutations"; S6 "Differentially expressed genes in primary and RS-PDX"; S7 "Schematic sketch of the main mutated genes in our RS models and core signaling pathways they belong to and play a critical role". Supplementary tables contain additional information on sequencing results performed on primary and PDX-RS models.

Richter syndrome represents the evolution of chronic lymphocytic leukemia into an aggressive tumor, most commonly diffuse large B-cell lymphoma. The lack of in vitro and in vivo models has severely hampered drug testing in a disease that is poorly responsive to common chemoimmunotherapeutic combinations as well as to novel kinase inhibitors. Here we report for the first time the establishment and genomic characterization of two patient-derived tumor xenograft (PDX) models of Richter syndrome, RS9737 and RS1316. Richter syndrome xenografts were genetically, morphologically, and phenotypically stable and similar to the corresponding primary tumor. RS9737 was characterized by biallelic inactivation of CDKN2A and TP53, monoallelic deletion of 11q23 (ATM), and mutations of BTK, KRAS, EGR2, and NOTCH1. RS1316 carried trisomy 12 and showed mutations in BTK, KRAS, MED12, and NOTCH2. RNA sequencing confirmed that in both cases >80% of the transcriptome was shared between primary tumor and PDX. In line with the mutational profile, pathway analyses revealed overactivation of the B-cell receptor, NFκB, and NOTCH pathways in both tumors, potentially providing novel tumor targets. In conclusion, these two novel models of Richter syndrome represent useful tools to study biology and response to therapies of this highly aggressive and still incurable tumor.Significance: Two patient-derived xenograft models of Richter syndrome represent the first ex vivo model to study biology of the disease and to test novel therapeutic strategies. Cancer Res; 78(13); 3413–20. ©2018 AACR.

Supplementary Methods from Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation

Supplementary Figure 6 from Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation

Supplementary Figure 7 from Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation

S1P2 sphingosine 1-phosphate receptor signaling can regulate proliferation, survival, morphology, and migration in many cell types in vitro. Here, we report that S1P2−/− mice develop clonal B-cell lymphomas with age, such that approximately half of the animals display this neoplasm by 1.5 to 2 years of age. Histologic, immunophenotypic, and molecular analyses revealed a uniform tumor phenotype with features of germinal center (GC)–derived diffuse large B-cell lymphoma (DLBCL). Tumor formation was preceded by increases in GC B cells and CD69+ T cells, as well as an increased formation of spontaneous GCs, suggesting that S1P2 loss may promote lymphomagenesis in part by disrupting GC B-cells homeostasis. With the sole exception of rare lung tumors, the effect of S1P2 gene disruption is remarkably restricted to DLBCL. In humans, 28 of 106 (26%) DLBCL samples were found to harbor multiple somatic mutations in the 5′ sequences of the S1P2 gene. Mutations displayed features resembling those generated by the IgV-associated somatic hypermutation mechanism, but were not detected at significant levels in normal GC B cells, indicating a tumor-associated aberrant function. Collectively, our data suggest that S1P2 signaling may play a critical role in suppressing DLBCL formation in vivo. The high incidence of DLBCL in S1P2−/− mice, its onset at old age, and the relative lack of other neoplasms identify these mice as a novel, and potentially valuable, model for this highly prevalent and aggressive human malignancy. [Cancer Res 2009;69(22):8686–92]

Supplementary Figure 3 from Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation

Supplementary Figure 5 from Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation

Supplementary Figure 1 from Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation

Supplementary Tables 1-3 from Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation

Supplementary Figure 2 from Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation

Supplementary Figure 4 from Targeted Disruption of the S1P2 Sphingosine 1-Phosphate Receptor Gene Leads to Diffuse Large B-Cell Lymphoma Formation

Reliable estimates of soil carbon change are required to determine the carbon budgets consistent with the Paris climate targets. This study evaluates projections of soil carbon during the 21st century in CMIP6 Earth System Models (ESMs) under a range of atmospheric composition scenarios. In general, we find a reduced spread of changes in global soil carbon (ΔCs) in CMIP6 compared to the previous CMIP5 model generation. However, similar reductions were not seen in the derived contributions to ΔCs due to both increases in plant Net Primary Productivity (NPP, named ΔCs,NPP) and reductions in the effective soil carbon turnover time (τs, named ΔCs,τ). Instead, we find a strong relationship across the CMIP6 models between these NPP and τs components of ΔCs, with more positive values of ΔCs,NPP being correlated with more negative values of ΔCs,τ. We show that this emergent relationship is the result of 'false priming', which leads to a decrease in the effective soil carbon turnover time as a direct result of NPP increase and occurs when the rate of increase of NPP is relatively fast compared to the slower timescales of a multipool soil carbon model. The inclusion of more soil carbon models with multiple pools in CMIP6 compared to CMIP5, therefore seems to have contributed towards the reduction in the overall model spread in future soil carbon projections.

This paper describes the rationale and the protocol of the first component of the third simulation round of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP3a, www.isimip.org) and the associated set of climate-related and direct human forcing data (CRF and DHF, respectively). The observation-based climate-related forcings for the first time include high-resolution observational climate forcings derived by orographic downscaling, monthly to hourly coastal water levels, and wind fields associated with historical tropical cyclones. The DHFs include land use patterns, population densities, information about water and agricultural management, and fishing intensities. The ISIMIP3a impact model simulations driven by these observation-based climate-related and direct human forcings are designed to test to what degree the impact models can explain observed changes in natural and human systems. In a second set of ISIMIP3a experiments the participating impact models are forced by the same DHFs but a counterfactual set of atmospheric forcings and coastal water levels where observed trends have been removed. These experiments are designed to allow for the attribution of observed changes in natural, human and managed systems to climate change, rising CH4 and CO2 concentrations, and sea level rise according to the definition of the Working Group II contribution to the IPCC AR6.

Peripheral T-cell lymphomas are a heterogeneous, and usually aggressive, group of mature T-cell neoplasms with overlapping clinical, morphologic and immunologic features. A large subset of these neoplasms remains unclassifiable with current diagnostic methods ("not otherwise specified"). Genetic profiling and other molecular tools have emerged as widely applied and transformative technologies for discerning the biology of lymphomas and other hematopoietic neoplasms. Although the application of these technologies to peripheral T-cell lymphomas has lagged behind B-cell lymphomas and other cancers, molecular profiling has provided novel prognostic and diagnostic markers as well as an opportunity to understand the biologic mechanisms involved in the pathogenesis of these neoplasms. Some biomarkers are more prevalent in specific T-cell lymphoma subsets and are being used currently in the diagnosis and/or risk stratification of patients with peripheral T-cell lymphomas. Other biomarkers, while promising, need to be validated in larger clinical studies. In this review, we present a summary of our current understanding of the molecular profiles of the major types of peripheral T-cell lymphoma. We particularly focus on the use of biomarkers, including those that can be detected by conventional immunohistochemical studies and those that contribute to the diagnosis, classification, or risk stratification of these neoplasms.

Peatlands have often been neglected in Earth system models (ESMs). Where they are included, they are usually represented via a separate, prescribed grid cell fraction that is given the physical characteristics of a peat (highly organic) soil. However, in reality soils vary on a spectrum between purely mineral soil (no organic material) and purely organic soil, typically with an organic layer of variable thickness overlying mineral soil below. They are also dynamic, with organic layer thickness and its properties changing over time. Neither the spectrum of soil types nor their dynamic nature can be captured by current ESMs. Here we present a new version of an ESM land surface scheme (Joint UK Land Environment Simulator, JULES) where soil organic matter accumulation – and thus peatland formation, degradation and stability – is integrated in the vertically resolved soil carbon scheme. We also introduce the capacity to track soil carbon age as a function of depth in JULES and compare this to measured peat age–depth profiles. The new scheme is tested and evaluated at northern and temperate sites. This scheme simulates dynamic feedbacks between the soil organic material and its thermal and hydraulic characteristics. We show that draining the peatlands can lead to significant carbon loss, soil compaction and changes in peat properties. However, negative feedbacks can lead to the potential for peatlands to rewet themselves following drainage. These ecohydrological feedbacks can also lead to peatlands maintaining themselves in climates where peat formation would not otherwise initiate in the model, i.e. displaying some degree of resilience. The new model produces similar results to the original model for mineral soils and realistic profiles of soil organic carbon for peatlands. We evaluate the model against typical peat profiles based on 216 northern and temperate sites from a global dataset of peat cores. The root-mean-squared error (RMSE) in the soil carbon profile is reduced by 35 %–80 % in the best-performing JULES-Peat simulations compared with the standard JULES configuration. The RMSE in these JULES-Peat simulations is 7.7–16.7 kg C m−3 depending on climate zone, which is considerably smaller than the soil carbon itself (around 30–60 kg C m−3). The RMSE at mineral soil sites is also reduced in JULES-Peat compared with the original JULES configuration (reduced by ∼ 30 %–50 %). Thus, JULES-Peat can be used as a complete scheme that simulates both organic and mineral soils. It does not require any additional input data and introduces minimal additional variables to the model. This provides a new approach for improving the simulation of organic and peatland soils and associated carbon-cycle feedbacks in ESMs.

The Kaposi sarcoma herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8), is the causal agent of Kaposi sarcoma (KS), but is also pathogenetically related to several lymphoproliferative disorders, including primary effusion lymphoma (PEL)/extra-cavitary (EC)-PEL, KSHV-associated multicentric Castleman disease (MCD), KSHV-positive diffuse large cell lymphoma (DLBCL) and germinotropic lymphoproliferative disorder (GLPD). These different KSHV-associated diseases may co-occur and can have overlapping features. KSHV, similar to the Epstein-Barr virus (EBV), is a lymphotropic gamma herpesvirus which is preferentially present in abnormal lymphoid proliferations occurring in immune compromised individuals. Notably, both KSHV and EBV can infect and transform the same B cell, which is frequently seen in the KSHV-positive, EBV-positive PEL/EC-PELs. The mechanisms by which KSHV leads to lymphoproliferative disorders is thought to be related to the expression of a few transforming viral genes that can affect cellular proliferation and survival. There are critical differences between KSHV-MCD and PEL/EC-PEL, the two most common KSHV-associated lymphoid proliferations, including the viral associations, the patterns of viral gene expression and the cellular differentiation stage reflected by the phenotype and genotype of the infected abnormal B cells. Advances in treatment have improved outcomes, but mortality rates remain high. Our deepening understanding KSHV biology, the clinical features of KSHV-associated diseases, and newer clinical interventions should lead to improved and increasingly targeted therapeutic interventions.

Mutations affecting enhancer chromatin regulatorsCREBBPandKMT2Dare highly co-occurrent in germinal center (GC)-derived lymphomas and other tumors, even though regulating similar pathways. Herein, we report that combined haploinsufficiency ofCrebbpandKmt2d(C+K) indeed accelerated lymphomagenesis. C+K haploinsufficiency induced GC hyperplasia by altering cell fate decisions, skewing B cells away from memory and plasma cell differentiation. C+K deficiency particularly impaired enhancer activation for immune synapse genes involved in exiting the GC reaction. This effect was especially severe at super-enhancers for immunoregulatory and differentiation genes. Mechanistically, CREBBP and KMT2D formed a complex, were highly co-localized on chromatin, and were required for each-other’s stable recruitment to enhancers. Notably, C+K lymphomas in mice and humans manifested significantly reduced CD8+T-cell abundance. Hence, deficiency of C+K cooperatively induced an immune evasive phenotype due at least in part to failure to activate key immune synapse super-enhancers, associated with altered immune cell fate decisions.SIGNIFICANCEAlthough CREBBP and KMT2D have similar enhancer regulatory functions, they are paradoxically co-mutated in lymphomas. We show that their combined loss causes specific disruption of super-enhancers driving immune synapse genes. Importantly, this leads to reduction of CD8 cells in lymphomas, linking super-enhancer function to immune surveillance, with implications for immunotherapy resistance.

Multicellular life requires altruistic cooperation between cells. The adaptive immune system is a notable exception, wherein germinal center B cells compete vigorously for limiting positive selection signals. Studying primary human lymphomas and developing new mouse models, we found that mutations affecting BTG1 disrupt a critical immune gatekeeper mechanism that strictly limits B cell fitness during antibody affinity maturation. This mechanism converted germinal center B cells into supercompetitors that rapidly outstrip their normal counterparts. This effect was conferred by a small shift in MYC protein induction kinetics but resulted in aggressive invasive lymphomas, which in humans are linked to dire clinical outcomes. Our findings reveal a delicate evolutionary trade-off between natural selection of B cells to provide immunity and potentially dangerous features that recall the more competitive nature of unicellular organisms.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses are contagious respiratory pathogens with similar symptoms but require different treatment and management strategies. This study investigated the differences in laboratory test result profiles between SARS-CoV-2 and influenza infected patients upon presentation to emergency department (ED).Laboratory test results and demographic information from 723 influenza positive (2018/1/1 to 2020/3/15) and 1,281 SARS-CoV-2 positive (2020/3/11 to 2020/6/30) ED patients were retrospectively analyzed. The dataset was randomly divided into a training/validation set (2/3) and a test set (1/3) with the same SARS-CoV-2/influenza ratio. Four machine learning models in differentiating the laboratory profiles of RT-PCR confirmed SARS-CoV-2 and influenza positive patients were evaluated. The Shapley Additive Explanations technique was employed to visualize the impact of laboratory tests on the overall differentiation. Furthermore, the model performance was also evaluated in a new test dataset including 519 SARS-CoV-2 ED patients (2020/12/1 to 2021/2/28) and the previous influenza positive patients (2018/1/1 to 2020/3/15).A laboratory test result profile consisting of 15 blood tests, together with patient age, gender, and race can discriminate the two types of viral infections using a random forest (RF) model. The RF model achieved an area under the receiver operating characteristic curve (AUC) of 0.90 in the test set. Among the profile of 15 laboratory tests, the serum total calcium level exhibited the greatest contribution to the overall differentiation. Furthermore, the model achieved an AUC of 0.81 in a new test set.We developed a laboratory tests-based RF model differentiating SARS-CoV-2 from influenza, which may be useful for the preparedness of overlapping COVID-19 resurgence and future seasonal influenza.

Northern peatland stores a large amount of organic soil carbon and is considered to be one of the most significant CH4 sources among wetlands. The default wetland CH4 emission scheme in JULES (land surface model of the UK Earth System model) only takes into account the CH4 emissions from inundated areas in a simple way. However, it is known that the processes for peatland CH4 emission are complex. In this work, we coupled the process-based peatland CH4 emission model HIMMELI (HelsinkI Model of MEthane buiLd-up and emIssion for peatlands) with JULES (JULES-HIMMELI) by taking the HIMMELI input data from JULES simulations. Firstly, the soil temperature, water table depth (WTD) and soil carbon simulated by JULES, as well as the prescribed maximum leaf area index (LAI) in JULES were evaluated against available datasets at the studied northern wetland sites. Then, the simulated CH4 emissions from JULES and JULES-HIMMELI simulations were compared against the observed CH4 emissions at these sites. Moreover, sensitivities of CH4 emissions to the rate of anoxic soil respiration (anoxic Rs), surface soil temperature and WTD were investigated. Results show that JULES can well represent the magnitude and seasonality of surface (5–10 cm) and relatively deep (34–50 cm) soil temperatures, whereas the simulated WTD and soil carbon density profiles show large deviations from the site observations. The prescribed maximum LAI in JULES was within one standard deviation of the maximum LAIs derived from the Sentinel-2 satellite data for Siikaneva, Kopytkowo and Degerö sites, but lower for the other three sites. The simulated CH4 emissions by JULES have much smaller inter-annual variability than the observations. However, no specific simulation setup of the coupled model can lead to consistent improvements in the simulated CH4 emissions for all the sites. When using observed WTD or modified soil decomposition rate, there were only improvements in simulated CH4 fluxes at certain sites or years. Both simulated and observed CH4 emissions at sites strongly depend on the rate of anoxic Rs, which is the basis of CH4 emission estimates in HIMMELI. By excluding the effect from the rate of anoxic Rs on CH4 emissions, it is found that the Rs-log-normalized CH4 emissions (log normalization of the ratio of CH4 emission to anoxic Rs rate) show similar increasing trends with increased surface soil temperature from both observations and simulations, but different trends with raised WTD which may due to the uncertainty in simulated O2 concentration in HIMMELI. In general, we consider the JULES-HIMMELI model is more appropriate in simulating the wetland CH4 emissions than the default wetland CH4 emission scheme in JULES. Nevertheless, in order to improve the accuracy of simulated wetland CH4 emissions with the JULES-HIMMELI model, it is still necessary to better represent the peat soil carbon and hydrologic processes in JULES and the CH4 production and transportation processes in HIMMELI, such as plant transportation of gases, seasonality of parameters controlling oxidation and production, and adding microbial activities.