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PubMed2026

Diversified cell origin of Helicobacter pylori eradication-responsive gastric diffuse large B-cell lymphomas.

A significant proportion of gastric diffuse large B-cell lymphoma with mucosa-associated lymphoid tissue [DLBCL(MALT)] and without MALT ('pure' DLBCL) can be resolved by Helicobacter pylori eradication (HPE). Gastric MALT lymphoma is an indolent lymphoma derived from memory B cells in the marginal zone. In the present study, we aimed to explore the origin of large cells in HPE-responsive gastric DLBCLs (complete remission after HPE). We investigated gastric lymphoma biopsies from 31 patients with HPE-responsive DLBCLs [15 'pure' DLBCLs, 16 DLBCL(MALT)s]. We used the Hans algorithm (CD10, BCL-6, and MUM1) to define the origins of germinal center B cell (GCB) and non-GCB. To further ascertain the cellular origin, 11 'pure' DLBCLs were examined using an Agilent whole-human genome microarray. Eleven DLBCLs [eight with 'pure' DLBCL and three with DLBCL(MALT)] were also assessed using Lymph2Cx. Specific GCB markers, including BACH2, AID, and BCL2 rearrangement and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) codon 641 mutations, were evaluated in 31 patients with HPE-responsive gastric DLBCLs. According to the Hans algorithm, 53% (8/15) of gastric 'pure' DLBCLs and 50% (8/16) of DLBCL(MALT)s were of the GCB phenotype. Gene expression assays revealed that five of six patients with 'Hans' GCB had GCB genetic signatures, whereas four of five patients with 'Hans' non-GCB had activated B-cell genetic signatures. The Lymph2Cx assay revealed the GCB subtype in seven of eight patients with 'Hans' GCB. The expression patterns of BACH2 (p = 0.005) and AID (p = 0.038) closely correlated with the 'Hans' GCB phenotype. BCL2 rearrangements and EZH2 codon 641 mutations were detected in 44% (7/16) and 13% (2/16) of patients with 'Hans' GCB, respectively. In another cohort of 29 HPE-unresponsive gastric DLBCLs [19 'pure' DLBCLs and 10 DLBCL(MALT)s], we found a close association between the 'Hans' GCB subtype and the GCB subtype as determined by the Agilent whole-human genome microarray and Lymph2Cx in lymphoma cells of these patients. In conclusion, more than half of HPE-responsive large cell lymphoma cases in the stomach were of GCB origin. © 2026 The Pathological Society of Great Britain and Ireland.

Humans↗

PubMed2026

Oncogenic Mutations and Tumor Microenvironment Alterations in Diffuse Large B-Cell Lymphoma With Bulky Disease.

BACKGROUND: Bulky disease represents a clinically aggressive subset of diffuse large B-cell lymphoma (DLBCL) associated with adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on bulky disease in DLBCL. METHODS: We analyzed a cohort of 939 patients with newly diagnosed DLBCL. Using DNA (n = 934) and RNA (n = 524) sequencing, we compared oncogenic mutations and tumor microenvironment (TME) alterations based on tumor diameter, with cutoff values at 5.0 cm and 10.0 cm. Further stratification by mutations in key genes (CD58, STAT6, EBF1) correlated with tumor diameter revealed distinct transcriptomic and immunologic profiles. Subsequent single-cell RNA sequencing, guided by these mutational signatures, resolved the cellular heterogeneity within the TME. RESULTS: Integrative analysis revealed that tumor diameter correlated with increased incidence of mutations in CD58, STAT6, and EBF1; adverse genetic subtypes such as EZB-like MYC+ and TP53Mut; activation of oncogenic pathways (JAK/STAT, BCR, PI3K, and MYC); and an immunosuppressive tumor microenvironment. Notably, immune checkpoint molecules varied across the bulky stages, with CTLA-4, TIGIT, ICOS, and CD28 expression inversely correlated with tumor diameter, while CD70 and 4-1BBL expression positively correlated. Single-cell RNA sequencing further revealed mutation-specific tumor microenvironment insights. CD58-mutated tumor exhibited a profoundly immune-deserted microenvironment dominated by malignant B cells with minimal immune infiltration, whereas STAT6-mutated tumor was associated with increased fibroblasts and CD4 + T cells, particularly regulatory T cells (Treg) and Th1-like cells; EBF1-mutated tumor was characterized by increased proportions of malignant B cells. CONCLUSIONS: Collectively, our findings highlight the biological complexity of bulky disease, identifying candidate molecular targets and providing a biological framework for future therapeutic hypothesis generation in this clinically aggressive subset of DLBCL.

Humans↗

PubMed2026

Tumor-Infiltrating Clonal Hematopoiesis Is Associated with Adverse Clinical Outcomes in Diffuse Large B-cell Lymphoma.

UNLABELLED: Tumor-infiltrating clonal hematopoiesis (TI-CH) contributes to the progression of nonhematologic cancers. CH is prevalent in the peripheral blood of patients with diffuse large B-cell lymphoma (DLBCL), but TI-CH prevalence and clinical relevance remain largely unexplored. In this study, through genome- and exome-wide sequencing of DLBCL biopsies and blood samples from 304 treatment-naïve patients, we identified TI-CH in 13.5% of cases, which emerged as an independent risk indicator for disease progression and death. TI-CH cases had an enrichment of inflammatory myeloid signatures revealed by gene expression profiling of tumor biopsies. In addition, we developed a TI-CH-associated prognostic signature (CAPS) based on 24 differentially expressed genes. A high CAPS score correlated with poor survival across four patient cohorts and remained significant in three cohorts after adjustment for patient age, sex, International Prognostic Index score, and cell-of-origin classification. Collectively, these findings establish a link between TI-CH and clinical outcomes and implicate the inflammatory signature as the potential underlying basis. SIGNIFICANCE: TI-CH correlates with disease progression and death in patients and with the inflammatory modeling of the DLBCL tumor microenvironment. Our results underscore the clinical and biological relevance of TI-CH and suggest its potential as a biomarker for risk stratification and as a target for therapeutic intervention in DLBCL.

Humans↗

PubMed2026

SLC1A5 and NUMA1 are potential regulators and therapeutic targets of ferroptosis in diffuse large B-cell lymphoma.

BACKGROUND: Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has emerged as a potential therapeutic target in various cancers, including diffuse large B-cell lymphoma (DLBCL). This study aimed to identify and characterize ferroptosis-related panel genes with prognostic value in DLBCL. METHODS: Transcriptomic data from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were analyzed to identify differentially expressed genes (DEGs) in DLBCL samples. Gene set variation analysis (GSVA) and network topology analysis were performed to identify key ferroptosis-related genes. Lasso regression was utilized to construct a prognostic model based on the identified panel genes. In vitro experiments, including gene silencing, overexpression, and ferroptosis induction, were conducted to evaluate the functional roles of the identified genes, NUMA1 and SLC1A5, in DLBCL cells. RESULTS: A panel of ferroptosis-related genes with prognostic value, including NUMA1 and SLC1A5, was identified in DLBCL samples. Silencing SLC1A5 or overexpressing NUMA1 in DLBCL cells enhanced sensitivity to ferroptosis inducers, increased intracellular labile iron and lipid peroxidation levels, promoted mitochondrial damage, and modulated the expression of key ferroptosis markers. Furthermore, SLC1A5 silencing or NUMA1 overexpression augmented radiation-induced ferroptosis in DLBCL cells. CONCLUSION: NUMA1 and SLC1A5 are potential ferroptosis regulators and therapeutic targets in DLBCL. Silencing the ferroptosis-suppressive transporter SLC1A5 or restoring NUMA1 expression promotes lipid peroxidation and ferroptotic cell death, thereby sensitizing DLBCL cells to ferroptosis and enhancing radiosensitivity-providing a rationale for novel ferroptosis-based therapeutic strategies.

Humans↗

PubMed2026

LymphGen-Sig: Integrating Genetic and Transcriptional States to Predict Therapeutic Response in Diffuse Large B-Cell Lymphoma.

PURPOSE: Genetic classification may advance precision medicine in diffuse large B-cell lymphoma (DLBCL), but existing tools like LymphGen (LG) are limited by complexity and incomplete classification and do not incorporate nongenetic features that affect disease biology and therapeutic outcomes. To address these limitations, we developed LG-sig (LGsig), a gene expression-based platform that classifies all DLBCLs and harmonizes both genetic and nongenetic dimensions of the disease. METHODS: LGsig was built on the distinct subtype-specific gene expression signature of each LG class using paired genomic and transcriptomic data (National Cancer Institute/British Columbia Cancer Agency; N = 764). Model development was restricted to DLBCLs classified into MYD88L265P and CD79B mutations (MCD), BCL6 translocation and NOTCH2 mutations (BN2), EZH2 mutations and BCL2 translocation (EZB), or SGK1 and TET2 mutations (ST2). Gene features were selected by differential gene expression, with 294 genes being optimal for classification using a nearest shrunken centroid classifier. LGsig classifications were designated as MCDsig, BN2sig, ST2sig, and EZBsig. The final model was applied to RNAseq from archival samples from the POLARIX trial (N = 678) to assess outcomes after polatuzumab vedotin-R-CHP (pola-R-CHP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for each LGsig subtype. RESULTS: LGsig accurately identified LG subtypes using transcriptional data alone and extended assignments to all previously LG-unclassified cases. Importantly, LG-unclassified DLBCLs reassigned by LGsig mirrored the transcriptional and clinical features of their corresponding LG counterparts, supporting their reclassification. In addition, LGsig reassigned LG A53 DLBCLs, characterized by aneuploidy and TP53 alterations, into more biologically and therapeutically relevant LGsig clusters. Finally, LGsig improved the performance of LG as a biomarker in the POLARIX study, by identifying distinct DLBCL subtypes exhibiting a survival benefit with pola-R-CHP over R-CHOP in both LG-classified and LG-unclassified cases. CONCLUSION: LGsig expands molecular classification beyond current genetic classifiers in DLBCL by integrating both genetic and transcriptional dimensions of the disease to better inform subtype-specific therapeutic strategies.

Journal Article↗

PubMed2026

Efficacy of R-GDP therapy as salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma.

R-GDP has been established as an effective salvage treatment for Rel/Ref DLBCL. We aimed to clarify the efficacy of R-GDP therapy. We included 41 consecutive patients with Rel/Ref DLBCL, who received R-GDP therapy as salvage chemotherapy at our hospital between January 2014 and August 2024. Thirty-three patients received R-GDP therapy as a 2nd-line regimen, whereas 8 received R-GDP as a 3rd or later-line regimen. The ORR was 70.7%. 23 out of 25 relapsed patients (92%) responded to R-GDP therapy, whereas only 6 out of 16 refractory patients responded (37.5%). With regard to the duration of response, the response rates in 19 patients with late relapse (at least 12 months) and 6 with early relapse (less than 12 months) were 94.7% and 83.3% (p = 0.43). Overall, the 2-year PFS and OS rates were 48.8% and 74.2%, respectively. 18 responders underwent ASCT with a 2-year PFS after ASCT of 61.2%. Although CAR-T is recommended in patients with Rel/Ref DLBCL, R-GDP is a realistic option given the limited availability of immediate CAR-T therapy. Further studies including genomic profiles are warranted to identify factors that can predict a response to R-GDP in Rel/Ref DLBCL.

Humans↗

PubMed2026

RPLP0 drives diffuse large B-cell lymphoma cell proliferation through reactive oxygen species-dependent AKT/mTOR activation and inhibition of stress-induced autophagy.

Diffuse large B-cell lymphoma (DLBCL) is a common, aggressive subtype of non-Hodgkin lymphoma with poor outcomes. Identifying the primary molecular causes of DLBCL remains key. The present study examined the function of ribosomal protein lateral stalk subunit P0 (RPLP0) in DLBCL pathogenesis. The Cancer Genome Atlas-DLBCL and GSE12453 datasets overlapping differentially expressed genes were identified. Hub genes were identified via protein-protein interaction network analysis. DLBCL cells were subjected to functional tests following RPLP0 overexpression or knockdown. Reverse transcription-quantitative PCR, western blotting, flow cytometry, transmission electron microscopy, colony formation assay and biochemical analysis were among the tests performed. N-acetylcysteine (NAC), rapamycin (RAPA) and 3-MA were among the medication therapies. In the DLBCL datasets, six ribosome-associated genes were differentially expressed. RPLP0 knockdown inhibited the proliferation of DLBCL cells and caused G2-phase arrest, without impacting apoptosis. Thioredoxin, heat shock protein family A member 1A and heat shock protein family B member 1 expression was downregulated by RPLP0 knockdown, which also increased the NAD+/NADH ratio, promoted reactive oxygen species (ROS) accumulation and caused mitochondrial membrane potential depolarization. Meanwhile, 3-MA reversed the effects of RPLP0 knockdown, which encouraged LC3-II accumulation, autophagy-related gene 5 (ATG5) overexpression and an increase in autophagic vesicles. Autophagy-related indicators were decreased, and AKT/mTOR phosphorylation was increased by RPLP0 overexpression, which RAPA inhibited. NAC therapy preserved the viability of RPLP0-silenced cells, restored p-AKT/p-mTOR levels and restored normal LC3 and ATG5 expression. These findings suggest that RPLP0 regulates stress-induced autophagy through ROS-dependent AKT/mTOR signaling and may represent a potential therapeutic target for DLBCL.

AKT/mTOR signaling pathway↗

PubMed2026

An immune exhaustion signature predicts prognosis and identifies patients with diffuse large B-cell lymphoma (DLBCL) who derive preferential benefit from chimeric antigen receptor (CAR)-T cell therapy.

BACKGROUND: The tumor microenvironment (TME) is a key determinant of prognosis in diffuse large B-cell lymphoma (DLBCL). While T-cell exhaustion is implicated in therapeutic failure, its precise molecular hallmarks and utility for predicting response to modern immunotherapies, such as chimeric antigen receptor (CAR)-T cell therapy, remain unclear. METHODS: We performed an integrative analysis of transcriptomic and clinical data from multiple DLBCL cohorts (The Cancer Genome Atlas [TCGA], GSE181063, GSE10846, GSE248835, GSE182434). We used unsupervised clustering, exploratory analysis of single-cell RNA sequencing data, and the least absolute shrinkage and selection operator for variable selection (LASSO-Cox) regression to characterize the exhausted TME, construct a prognostic model, and evaluate its predictive value for CAR-T cell therapy. The model's dynamic behavior was assessed in a proof-of-concept longitudinal cohort of patients treated with the T-cell-engaging bispecific antibody glofitamab. RESULTS: We identified a "high-exhaustion" subtype associated with significantly poorer overall survival (OS; log-rank P = 0.016). Based on this, we developed a five-gene immune exhaustion-Related Prognostic Score (IERPS) that served as a robust independent predictor of poor OS across multiple cohorts. Critically, in a cohort of 256 relapsed/refractory patients, the IERPS was strongly prognostic for event-free survival (EFS) in the standard-of-care (SOC) arm (HR = 2.02, 95% confidence interval [95% CI]: 1.07-3.81, P = 0.029) but lost prognostic significance in the CAR-T arm (HR = 0.70, 95 % CI: 0.35-1.40, P = 0.314). This significant interaction suggests that CAR-T cell therapy may abrogate the poor prognosis associated with a high IERPS. Biologically, exploratory single-cell analysis (n = 4 samples) defined the high-IERPS state by hallmarks of classical T-cell exhaustion, and a descriptive case study showed the score dynamically tracked clinical response to glofitamab. CONCLUSIONS: A state of active T-cell exhaustion and a suppressive TME drive the adverse immune phenotype in DLBCL. Our IERPS model captures this dysfunctional state, acting as a powerful prognostic tool and, more importantly, as a potential predictive biomarker to identify high-risk patients who appear to overcome their inherently poor prognosis through CAR-T cell therapy.

Biomarkers↗

PubMed2026

Hypothalamic-Pituitary Axis Involvement in Primary Central Nervous System Lymphoma.

CONTEXT: Primary central nervous system lymphoma (PCNSL) is a rare malignancy that may involve the hypothalamic-pituitary axis (HPA), leading to underrecognized but clinically significant endocrine dysfunction. OBJECTIVE: This work aims to characterize the spectrum and patterns of HPA-related endocrine disturbances in patients with PCNSL. DATA SOURCES: A systematic search was conducted in PubMed, EMBASE, Scopus, and Web of Science, supplemented by gray literature. The search concluded in February 2025. STUDY SELECTION: We included studies reporting adult PCNSL cases with documented dysfunction of at least one hormonal axis. Exclusion criteria were preexisting hypopituitarism or lack of endocrine data. DATA EXTRACTION: Data on demographics, tumor localization, hormonal axes affected, radiological findings, treatment, and outcomes were extracted. Risk of bias was assessed using JBI tools. RESULTS: Ninety-nine cases met the inclusion criteria. Diffuse large B-cell lymphoma accounted for 84% of cases. Endocrine dysfunction included isolated adenohypophyseal involvement (46%), neurohypophyseal (8%), and combined (45%). The most affected pituitary axes were the gonadal and thyroid axes, with 89.7% and 89.2% involvement, respectively. Hypothalamic tumors were strongly associated with combined dysfunction (odds ratio = 9.47; 95% CI, 3.76-23.86; P < .001). Persistent endocrinopathy was more frequent in progressive disease. No direct association was found between endocrine dysfunction and mortality. CONCLUSION: HPA dysfunction in PCNSL is frequent and often underdiagnosed. Hypothalamic involvement is associated broader hormonal impairment. Routine hormonal screening and multidisciplinary management should be standard in PCNSL care to minimize complications and improve outcomes.

Humans↗

PubMed2026

[Aggressive B-cell lymphomas with MYC gene cluster amplification: a clinicopathological analysis of eight cases].

Objective: To investigate the clinicopathological characteristics, molecular genetics, treatments and prognosis of aggressive B-cell lymphomas (ABCL) with MYC gene cluster amplification. Methods: Eight cases of ABCL with MYC gene cluster amplification were collected, including 6 cases from the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China and 2 consultation cases from outside hospitals. The histomorphology, immunohistochemical profiles, and molecular genetic characteristics were analyzed. Clinical follow-up and literature review were also conducted. Results: Among the eight patients, six were male and two were female, with an age 71.5 (61.7, 74.2) years. All six in-house patients presented with abdominal pain at onset, without B symptoms. Most cases were classified as Ann Arbor stage Ⅲ-Ⅳ. Extranodal involvement occurred in 5 of the 6 in-house cases, primarily affecting the gastrointestinal tract (4/5). All initial bone marrow biopsies showed no evidence of lymphoma. One patient had a history of immunosuppression following renal transplantation. Two cases exhibited diffuse large B-cell lymphoma (DLBCL) morphology. The other six showed high-grade features, while three of them showed Burkitt lymphoma-like morphology. Except for one case of blastoid variant mantle cell lymphoma, the remaining six cases (6/7) displayed a germinal center B-cell phenotype. None of the in-house cases harbored bcl-2 or bcl-6 rearrangements as shown by fluorescence in situ hybridization. 11q alterations were identified in all but one consultation case, including gain/loss type in five cases and 11q gain in two. 11q telomere loss of heterozygosity by chromosomal microarray analysis was not detected in one of the two cases with 11q gain that was subject to the test. The duration of follow-up ranged from 5.9 to 55.5 months, with 5 patients alive at the end of the study. Conclusions: ABCL with MYC gene cluster amplification often presents high-grade morphology and gastrointestinal involvement, which strongly suggests the alteration of 11q. It seems to have a favorable prognosis.

Humans↗

PubMed2026

Mast cell leukemia with complex genomic alterations in an elderly patient with prior hematologic and solid malignancies: a case report.

INTRODUCTION: Mast cell leukemia (MCL) is the rarest and most aggressive variant of systemic mastocytosis (approximately 1% of cases), with a median survival of under 2 years. Diagnosis requires ≥20% atypical mast cells in the marrow aspirate, and the disease frequently overlaps with myeloid neoplasms. CASE PRESENTATION: An 86-year-old man with paranasal sinus diffuse large B-cell lymphoma in remission since 2017 after R-CHOP and methotrexate, and prostate adenocarcinoma treated in 2019, presented with acute pancytopenia, presumed to represent lymphoma relapse. Serum tryptase exceeded 11 999 ng/mL; the aspirate showed 20% pleomorphic mast cells (CD117+, weak CD25, CD2-), confirming aleukemic MCL. Formal CMML criteria could not be confirmed due to the unavailability of monocyte differential data; however, the findings raised suspicion for an associated myeloid neoplasm, with SM with an associated hematological neoplasm remaining an alternative classification. Karyotyping was normal; next-generation sequencing revealed pathogenic variants in TP53, RB1, DAXX, ASXL1, TET2, and SRSF2, and a rare extracellular-domain KIT p.D419del. He declined inpatient midostaurin, deteriorated rapidly, and died 2 weeks later. CLINICAL DISCUSSION: This case illustrates a therapy-related MCL (plausible but unconfirmed given the non-leukemogenic profile of methotrexate and the focal nature of prostate stereotactic body radiation therapy) with a suspected associated myeloid neoplasm and complex pathogenic mutations. The KIT p.D419del extracellular domain variant is a rare non-D816V mutation; the canonical D816V was not detected on NGS, though the presence of a low-variant allele fraction D816V cannot be fully excluded due to assay sensitivity. Despite midostaurin, the disease remained aggressive. CONCLUSION: Persistent unexplained cytopenias warrant heightened suspicion of MCL, and comprehensive genomic profiling clarifies diagnosis, distinguishes overlapping myeloid disease, and informs prognosis in this aggressive, refractory neoplasm.

case report↗

PubMed2025

Exploring the Genetic Landscape of Primary Marginal Zone Lymphoma of the Urinary Bladder.

Extranodal marginal zone B-cell lymphoma (MZL) of mucosa-associated lymphoid tissue is the most frequent primary lymphoma of the urinary bladder. Although MZLs from various anatomical sites are often associated with autoimmune disorders, infections, and site-characteristic genetic alterations, the molecular foundations and potential infectious triggers of urinary bladder MZL remain poorly understood. To elucidate the disease etiology and correlation with MZLs arising in other locations, we examined a cohort of 17 cases (11 women and 6 men) diagnosed with primary bladder MZL between 2005 and 2025. Immunohistochemical analysis confirmed the literature, with all samples testing positive for the pan B-cell markers CD20 and CD79a and negative for CD5 (except 1), cyclin D1, and SOX11. Thirteen samples exhibited secretory differentiation and displayed immunoglobulin light chain restriction (9 κ and 4 λ). No gene rearrangements in BCL2, BCL6, BCL10, IRF4, MALT1, and MYC were detected. High-throughput sequencing identified 31 pathogenic/likely pathogenic somatic mutations across 18 genes, with TBL1XR1 (n = 8), MAP2K1 (n = 4), and TNFAIP3 (n = 2) being the most frequently mutated ones. Additionally, all cases included variants of unknown significance. The sample of 1 patient tested positive for Chlamydia trachomatis, human betaherpesvirus 6B, and Epstein-Barr virus. Escherichia coli was detected in 5 samples. We provide compelling evidence that urinary bladder MZL is a point mutation-driven disease rather than gene fusion-driven disease and that E coli is present in approximately one-third of tumor biopsies. These tumors frequently harbor pathogenic mutations in genes encoding components regulating plasma cell differentiation and the pleiotropic MAPK/ERK signaling pathway. TBL1XR1, which was unexpectedly frequently mutated, is generally linked to more aggressive variants of MZL and diffuse large B-cell lymphoma; however, its prognostic significance in urinary bladder MZL remains to be determined. Comparative analysis highlighted partial overlap of urinary bladder MZL mutational profiles with those found in salivary gland MZL.

Humans↗

PubMed2026

Clinical outcomes of Epstein-Barr virus infection/reactivation following CAR-T cell therapy: A systematic review.

BACKGROUND: Epstein-Barr virus (EBV) infection or reactivation is an emerging but underrecognized complication following chimeric antigen receptor T-cell (CAR-T) therapy and is likely associated with treatment-induced immune dysregulation. Data regarding its clinical impact remain limited. OBJECTIVE: To evaluate the reported occurrence, clinical manifestations, and outcomes of EBV infection or reactivation in adults undergoing CAR-T therapy. METHODS: A systematic review was conducted in accordance with the PRISMA 2020 guidelines. PubMed, Embase, and Cochrane CENTRAL were searched from inception to March 2025 for studies reporting EBV infection or reactivation after CAR-T therapy in adults. Due to limited and heterogeneous data, results were synthesized descriptively. RESULTS: Five studies comprising 80 patients were included (median age, 55 years; 52.6% male among patients with reported sex data [10/19]). Across the included studies, 11 EBV infection/reactivation events were identified among 80 described CAR-T recipients, representing 13.8% of the reported sample rather than a true incidence estimate. Among events with usable individualized timing data, the median interval from CAR-T infusion to EBV detection/reactivation was 9.8 months (approximate range, 1-44 months). Because EBV surveillance strategies and definitions were inconsistently reported across studies, this proportion should not be interpreted as a true incidence estimate. Four patients (36.4%) developed EBV-associated disease, including three cases of EBV-related lymphoproliferative disorder and one case of EBV-associated diffuse large B-cell lymphoma. Among seven patients with reported post-CAR-T treatment response, four achieved Complete Remission/ Continuous Complete Remission; treatment response should be interpreted separately from final survival status. Confirmed EBV-related mortality occurred in 2/11 patients with reported EBV infection/reactivation and in 2/4 patients with EBV-associated disease; all-cause mortality could not be reliably estimated because patient-level vital status could not be fully attributed to the EBV-reactivated subgroup. Reported toxicities predominantly consisted of low-grade cytokine-release syndrome; however, toxicity data were limited. CONCLUSION: Although infrequently reported, EBV infection or reactivation after CAR-T therapy may be associated with substantial morbidity and mortality among affected patients. However, the available evidence is limited by the small sample size, heterogeneous study designs, and inconsistent EBV surveillance practices.

Humans↗

PubMed2026

Identification of immune cell type-specific susceptibility genes in multiple cancers using transcriptome-wide association studies.

BACKGROUND: Transcriptome-wide association studies (TWAS) integrate gene expression and genome-wide association studies (GWAS) to identify disease susceptibility genes. Because gene expression varies substantially across cell types within tissues, cell type-specific prediction models may enhance the power of TWAS. METHODS: We conducted cell type-specific TWAS leveraging single-cell RNA sequencing data from the OneK1K cohort (14 immune cell types, 1.27 million cells) and GWAS summary statistics for 7 cancers (>290 000 cases in total). To improve prediction accuracy, we developed a modeling framework that incorporates shared gene expression effects across cell types. RESULTS: At a false discovery rate of 5%, we identified 106 (Bonferroni 5%: 13) previously unreported loci for breast cancer, 51 (4) loci for prostate cancer, 11 (4) loci for lung cancer, 39 (5) loci for melanoma, 9 (1) loci for ovarian cancer, and 2 (1) loci for diffuse large B-cell lymphoma, with most genes exhibiting cell type specificity. Gene set analyses confirmed joint associations of unreported genes with breast and prostate cancer risk in UK Biobank data. Additional lung tissue single-cell RNA sequencing data with 113 individuals validated 18 of 32 (56.3%) statistically significant genes for lung cancer. Across cancers, 139 statistically significant genes were shared by at least 2 cancer types and were primarily enriched in specific immune cell types. CONCLUSION: Cell type-specific TWAS improve the identification of novel cancer susceptibility loci and provide insights into the immune landscape of cancer etiology.

Humans↗

PubMed2026

A Knowledge-Enhanced Multimodal Framework with Genomic Reconstruction for DLBCL Drug Response Prediction.

Diffuse large B-cell lymphoma (DLBCL) exhibits substantial biological heterogeneity, leading to pronounced variability in patient response to therapy. Accurate drug response prediction is therefore critical for precision treatment but remains challenging in clinical settings where genomic sequencing, a highly informative modality, is frequently incomplete. Existing methods, often developed from cell-line pharmacogenomic datasets or single-modality data, typically assume fully observed molecular profiles and thus show limited robustness under missing genomic data. To address this limitation, a knowledge-enhanced multimodal framework with genomic reconstruction (KeM-DRP) is proposed for individualized drug response prediction in DLBCL. The framework models the central role of genomics by integrating biological prior knowledge through a gene-pathway-biological process hierarchy, enabling robust representation learning from sparse observations. To compensate for missing genomic measurements, a cross-modal genomic compensation module reconstructs genomically informed latent features from routinely available clinical modalities. Furthermore, a genomics-guided adaptive fusion strategy dynamically integrates heterogeneous modalities conditioned on observed or reconstructed genomic representation. Experiments on a real-world DLBCL cohort demonstrate that KeM-DRP consistently outperforms competitive baselines. The reconstructed genomic representation represents most predictive utility, highlighting the robustness and practical value of the framework under incomplete genomic data.

Journal Article↗

PubMed2026

A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death.

Developing cancer therapies that induce specific death of malignant cells is critical for preventing relapse. Highly effective strategies, such as immunotherapy, exemplify this principle. Here, we provide the mechanistic basis for a small-molecule approach that leverages chemically induced proximity (CIP) to kill diffuse large B cell lymphoma, the most common non-Hodgkin lymphoma. We developed lysine acetyltransferase (KAT)-based TCIPs (transcriptional/epigenetic chemical inducers of proximity), or KAT-TCIPs, which redirect p300/CREB-binding protein (CBP) to activate cell-death networks repressed by the oncogenic driver BCL6. Our lead KAT-TCIP reprograms the epigenome to initiate apoptosis. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance protein-protein interactions may be exploited to confer the potency and selectivity of KAT-TCIPs. Thus, oncogenic drivers can be co-opted to activate robust cell death. Consistent with their gain-of-function mechanism, TCIPs recruiting different transcriptional activators-p300, BRD4, or CDK9-produce distinct genomic responses, suggesting specialized therapeutic uses.

Humans↗

PubMed2026

Cell-free DNA genomic and fragmentomic features for early outcome prediction in large B cell lymphoma.

Curative-intent immunochemotherapy fails in ∼30% of patients with large B cell lymphoma (LBCL), yet no validated molecular tool enables early identification of high-risk individuals to guide treatment intensification. Using shallow whole-genome sequencing (sWGS) of plasma cell-free DNA from 190 LBCL patients, we develop and validate the ACT score (aberrations, composition of fragments, and terminal motif analyses), a composite classifier integrating genomic and fragmentomic features from a single post-cycle-1 sample. ACT-positive patients have worse 2-year outcomes versus ACT-negative patients: time-to-progression 29% vs. 83% (hazard ratio [HR]: 4.4, 95% confidence interval [CI]: 1.9-10.0; p = 1.5 × 10-4) and overall survival 47% vs. 93% (HR: 8.7, 95% CI: 3.0-25.4; p = 1.8 × 10-6). The ACT score is independently prognostic of the International Prognostic Index, and their combination identifies the highest risk patients. Unlike mutation-based approaches, this assay requires neither tumor tissue, germline control, nor a baseline plasma sample. Built on open-source tools and sWGS, the ACT score offers a feasible, scalable strategy for early risk stratification in aggressive LBCL.

Humans↗

PubMed2026

A Patient-Derived Xenograft Repository Capturing Clinical and Molecular Heterogeneity of Large B-cell Lymphoma.

UNLABELLED: Large B-cell lymphomas (LBCL) are a clinically and molecularly diverse group of malignancies with a rapidly evolving therapeutic landscape that has introduced new areas of clinical need, such as post-CD19 chimeric antigen receptor T (CART19) progression. Patient-derived xenograft (PDX) models are an important tool for mechanistic studies and preclinical evaluation of new therapies and can be generated from a variety of clinical contexts that capture tumor-intrinsic resistance mechanisms. We therefore undertook a comprehensive effort to generate PDX models that encompass the molecular landscape of LBCLs and include important clinical scenarios for new drug development. Here, we describe the first 48 models within this publicly available repository, capturing the transcriptional and genetic subsets of LBCL. These models also include 23 generated from post-CART19 progression patient biopsies, which reproduce patterns of progression driven by CD19 mutation or expression loss, as well as tumor cell-intrinsic CART19 resistance that we validated in vivo. SIGNIFICANCE: Here, we describe X-LYMPH (Xenografts of Lymphoma), a publicly available and molecularly annotated PDX repository that captures the heterogeneity of LBCL. X-LYMPH includes models of CAR T-cell resistance, providing a shared foundation for mechanistic research and therapeutic development for lymphomas. See related commentary by Evgin and Steidl, p. 655.

Humans↗