Abstract Background: Epidemiologic and other studies have identified environmental, occupational, and genetic risk factors for lymphoid and myeloid malignancies, but most studies have been conducted in Western populations. Investigations in populations with differing exposure patterns, distributions of disease subtypes, and genetic architecture are needed to fully understand hematopoietic tumor etiology. Methods: We conducted a large, multicenter, hospital-based case-control study of lymphoid and myeloid neoplasms in East Asia (AsiaLymph), including 5,671 lymphoid cases, 1,879 myeloid cases, and 3,858 controls. Participants completed a computer-assisted personal interview and provided biospecimens. Cases underwent central pathology review and were coded into the WHO Classification. Herein, we describe the study methods in detail and report association results for education, body mass index, and family history. Results: Greater BMI at age 20 but not at age 40 was associated with odds of total lymphoid neoplasm (per 5 kg/m2 increase: OR [95% CI]: 1.18 [1.09-1.27]), total myeloid neoplasm (OR [95% CI]: 1.17 [1.05-1.29]), and several subtypes. Greater educational attainment was associated with increased odds of total lymphoid neoplasm (for college vs. less than primary education: OR [95% CI]: 1.41 [1.21-1.65]) but not myeloid neoplasm (OR [95% CI]: 1.17 [0.95-1.45]; p-heterogeneity=0.02). There were also positive associations between family history of hematologic cancer in first degree relatives and odds of lymphoid neoplasm (OR [95% CI]: 1.53 [1.15-2.03]) and myeloid neoplasm (OR [95% CI]: 1.65 [1.11-2.44]) and specific subtypes. None of the evaluated risk factors were associated with NK/T-cell lymphoma, which supports a distinct etiology for this subtype. Conclusion: The AsiaLymph Study is one of the largest molecular epidemiology studies of both lymphoid and myeloid neoplasms with standardized World Health Organization classification of histopathologic subtypes and will serve as a valuable resource for etiologic investigations into risk factors for these malignancies. Citation Format: Qing Lan, Lauren M. Hurwitz, John K. Chan, Tai Hing Lam, Kexin Chen, Yok Lam Kwong, Xu Caigang, Brian CH Chiu, Raymond Liang, Ip Dennis, Wei Hu, Bryan Bassig, Mark Purdue, Jun Xu, Sarah Locke, Sophia S. Wang, James R. Cerhan, Sonja Berndt, Jonathan N. Hofmann, Jianxin Shi, Kai Yu, Shahinaz Gadalla, Lisa J. McReynolds, Rena Jones, Hongji Dai, Zhangyan Lyu, Lugui Qiu, Wei Liu, Huilai Zhang, Xianhuo Wang, Lindsay M. Morton, Stephen Chanock, Martha Linet, Melissa C. Friesen, Roel Vermeulen, Nathaniel Rothman. A multi-center hospital-based case-control study of lymphoid and myeloid neoplasms (AsiaLymph): Study design and initial findings for education, body mass index, and family history [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5051.

The tumor suppressor gene TP53 is the most frequently mutated gene in human cancers and has been a popular area of research in the field of oncology. The p53 protein, encoded by the TP53 gene, not only binds to many targeted genes but also regulates apoptosis, autophagy, cell cycle arrest, metabolism, senescence and the tumor immune microenvironment to suppress tumorigenesis. In recent years, an increasing number of new functions of p53 have been discovered, and p53-mediated tumor suppressor functions have been greatly expanded. Mutations in TP53 not only abolish its ability to suppress tumorigenesis but also confer carcinogenic properties to p53-mutant cells. Because of the prevalence of p53 dysfunction in various disease types, p53 has long been considered an attractive target for new anticancer drugs. However, drugs targeting p53 are still under investigation in early clinical trials and have not been approved for clinical use. This finding is consistent with the speculation that p53 is widely regarded as “undruggable.” Surprisingly, several novel therapeutic approaches targeting p53, including MDM2/4 antagonists, compounds that target specific p53 mutants or restore the wild-type function of the mutated p53 protein, p53-based genetic therapies and p53-based tumor immunotherapy, have been developed in recent years. Here, we present a review of the structure, inactivation, and roles of p53 in diseases. In addition, this review discusses the efforts to target diseases associated with p53 dysfunction and the challenges encountered in the clinical development of these approaches.

Introduction:Peripheral T-cell lymphoma (PTCL) is a heterogeneous and highly aggressive subtype of non-Hodgkin lymphoma. Approximately 30% of patients develop relapsed or refractory PTCL (R/R PTCL) due to disease recurrence or failure to achieve complete remission after first-line therapy. Despite therapeutic advances, the molecular and cellular mechanisms underlying treatment resistance in R/R PTCL remain unclear. Methods:Single-cell RNA sequencing and single-cell T-cell receptor sequencing were performed on seven tumor samples from six patients with R/R PTCL. These approaches were used to systematically characterize the transcriptional profiles of malignant T-cell clones and reactive T lymphocytes, define the transcriptomic landscape of R/R PTCL, and identify potential epigenetic biomarkers associated with drug response. Results:We observed significant upregulation of genes associated with cell proliferation, oncogenic signaling, and immune modulation in R/R PTCL. Within the tumor microenvironment, specific protumorigenic ligand-receptor interactions were identified, including CXCL13-CXCR5, CCL5-CCR5, and CD74-MIF interactions, which may facilitate immune evasion by malignant T cells. Longitudinal analysis of a patient who progressed following dual epigenetic therapy revealed marked downregulation of immune response-related genes, including HLA-DRA/DPA1/DRB5, CD74, C1QC, and LYZ, as well as functional reprogramming of tumor-associated macrophages. Enhanced LGALS9-HAVCR2 and CSF1-CSF1R interactions were also observed following combination treatment with chidamide and azacitidine. Discussion:This study delineates the transcriptional heterogeneity of malignant T-cell clones in R/R PTCL and suggests that this heterogeneity may contribute to resistance to epigenetic therapies. These findings provide novel insights into the molecular mechanisms underlying treatment resistance and highlight potential avenues for therapeutic intervention in R/R PTCL.

e19058 Background: Primary mediastinal large B-cell lymphoma (PMBCL) is a rare, aggressive and clinically heterogeneous lymphoma with unique clinical, pathological, and molecular features. More than 80% of PMBCL express CD30, combination regimens based on brentuximab vedotin (BV) may be a potential therapeutic option. There are few studies evaluating real-world treatment patterns and clinical outcomes of BV-based regimens for PMBCL in China, and our study aims to provide evidence of this regimen. Methods: This real-world study collected data from adults patients diagnosed with PMBCL at our center between May 2021 and April 2024. We retrospectively analyzed the treatment patterns, efficacy including ORR, CR rate, and safety in patients who received BV-based regimens. Results: A total of 12 adult patients diagnosed with PMBCL who received first-line therapy with BV-based regimen were enrolled in this study. The median age was 36 years (range, 21–55 years), and 41.7% were male. The ECOG performance score ranged from 0–1. The percentage of patients with IPI ≥2 was 58.3% (7/12), and 50% (6/12) of patients were clinically staged as stage III-IV. 2 patients had B symptoms. The median diameter of the largest mass was 10.0 cm (range, 4.9–13.2 cm), and 75% (9/12) of patients had a maximum mass over 7 cm. All patients were CD30 positive. 12 patients received first-line treatment with BV in combination with R-CHOP-like regimen. The median number of cycles for first-line therapy of BV (1.2mg/kg, 21 days/cycle) was 5.5 (range, 4–6 cycles). 2 patients were still receiving BV first-line therapy by July 3, 2024. During a median follow-up of 511 days (since the start of BV treatment), the best of ORR was 100% (12/12), the CR rate was 58.3% (7/12). The 10 patients who have finished first-line treatment had an ORR of 100% and a CR rate of 70% (7/10). Consolidation radiotherapy was performed in 50% (6/12) patients, of whom 3 had postradiotherapy evaluation results and no patients deepened response. By the date of follow-up, no patients progressed or died and 7 patients who achieved CR maintained in CR status. The most common hematologic adverse event (AE) was leukopenia (66.7%, 8/12), followed by neutropenia in (33.3%, 4/12). Grade≥3 hematologic AEs occurred in 16.7% (2/12). The most common nonhematologic AE was hepatic injury, with a prevalence of 58.3% (7/12), all of which are grade 1. No patients experienced grade≥ 3 peripheral neuropathy and other nonhematologic AEs. Conclusions: This real-world study explored the patterns and clinical efficacy of BV-based regimens for PMBCL in China. Our results show that BV-based regimens for patients with CD30-positive PMBCL demonstrate good efficacy and safety in real-world settings. This result needs to be confirmed in a larger cohort.

Primary large B-cell lymphoma of immune-privileged sites (IP-LBCL), a recently defined entity in WHO-HAEM5, includes primary diffuse large B-cell lymphoma (DLBCL) occurring in immune-privileged areas like the central nervous system (PCNS-LBCL), vitreoretinal system (PVR-LBCL), and testis (PT-LBCL) in immunocompetent patients. This study aimed to identify prognostic factors and create a predictive model for IP-LBCL. We analyzed 213 newly diagnosed IP-LBCL patients from April 2006 to April 2023. A nomogram and prognostic index, IPLBCL-PI, were developed based on elevated LDH, ECOG ≥ 2, and PCNS-LBCL subtype as independent risk factors for poorer PFS. IPLBCL-PI categorized patients into four risk groups: low, low-intermediate, intermediate-high, and high. The model effectively predicted both PFS and OS in the training cohort and was validated in two external centers. Subgroup analyses showed that IPLBCL-PI outperformed the Nottingham/Barcelona (NB) and Memorial Sloan Kettering Cancer Center (MSKCC) models in PCNS-LBCL and was comparable to the International Prognostic Index (IPI) in PT-LBCL. IPLBCL-PI is the first prognostic model for IP-LBCL, offering risk stratification and aiding clinical decision-making for this rare entity.

7057 Background: Recurrent abnormalities of immune surveillance-related genes play a crucial role in DLBCL progression. Prior studies have shown that CD58, a key adhesion molecule that acts as a ligand for the T-cell costimulatory molecule CD2, is frequently mutated or deleted in certain hematological malignancies. Downregulation or loss of CD58 is linked to resistance to ICB therapy in melanoma and CAR-T therapy in B-cell malignancies. Nevertheless, the role of CD58 in cancer is not yet well understood. Methods: Comprehensive analysis of the genetic characteristics of CD58 were performed through targeted deep sequencing (n=176), whole exome sequencing (n=38), and RNA-sequencing (n=162) in patients with de novo DLBCL. To investigate the mechanistic impacts of CD58 alterations on co-inhibitory molecules expression and immune cell function, we performed bulk and single-cell RNA-sequencing analysis of tumor samples and conducted co-IP, flow cytometry and co-culture assays in vitro. Results: We identified that CD58 mutation rate was 9.1%, and the copy number loss rate was 44.7% among all enrolled DLBCL patients. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free and overall survival. Single-cell RNA sequencing revealed that CD58 expression in tumor cells was negatively correlated with CD8 + T cell exhaustion/dysfunction status. CD58 inhibited the activity of the JAK2/STAT1 pathway by activating the Lyn/CD22/SHP1 axis, thereby limiting PD-L1 and IDO expression. Elevated PD-L1 and IDO expression in CD58 deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to CAR T-cell therapy. Direct activation of CD58-CD2 costimulatory signaling in combination with anti-PD-L1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to CAR T-cell therapy. Conclusions: Our study comprehensively characterized CD58 genetic alterations in DLBCL. We demonstrated that CD58 downregulation or mutation led to upregulation of PD-L1 and IDO expression mainly by regulating the LYN/CD22/SHP1 axis. Our findings provide novel insights for individualized therapy for DLBCL patients with CD58 mutation or deletion.

Diffuse large B-cell lymphoma (DLBCL) is one of the most common and lethal B-cell malignancies worldwide, with high relapse rate after standard treatment, and the relapsed cases are often difficult to treat. Ubiquitination has a pivotal role in cellular protein homeostasis and tumorigenic deubiquitinases (DUBs) stabilize oncoproteins during carcinogenesis. In this study, we have identified USP13 as one of the abnormally-overexpressed and stage-related DUBs in DLBCL critical to disease pathogenesis. Employing LC-MS/MS, Ran GTPase was characterized as potential substrate of USP13, with the interaction between Ran and USP13 modeled by Alphafold3. USP13 co-overexpressed, co-localized and correlated with Ran at protein level in DLBCL patient samples and cell lines. Pharmacological inhibition and genetic manipulation of USP13 modulated Ran protein stability and K11-linked ubiquitination level of Ran. By RNA-seq, pharmacological inhibition of USP13 via Spautin-1 treatment in DLBCL revealed downstream targets in NF-κB and Notch pathways. Suggested by the DRESIS Database, NF-κB and Notch signaling cascades are key to the resistance of Doxorubicin (Dox) and cyclophosphamide (CTX) within the standard R-CHOP regimen of DLBCL hinting benefits of combining Spautin-1 with Dox or CTX. Further in-vitro and in-vivo experiments confirmed Spautin-1 synergized with Dox or CTX to initiate ferroptosis in DLBCL with few toxicities to main organs by mediating ROS, GSH, MDA and ultimately LPO. Altogether, these results demonstrate USP13 deubiquitinates Ran in DLBCL, and Spautin-1 well synergizes with Dox or CTX to initiate ferroptosis. Combinational treatment with Spautin-1 and Dox or CTX may represent an effective approach and therapeutic hope to combat with DLBCL.

Background: Primary cutaneous peripheral T-cell lymphoma, not otherwise specified (pcPTCL-NOS), is a rare and aggressive form of lymphoma. Its characteristics and treatment outcomes remain poorly understood. Methods: We identified 15 patients who were diagnosed with pcPTCL-NOS between January 2014 and August 2024 at Tianjin Medical University Cancer Institute and Hospital (TMUCIH) in this retrospective study. The clinical and immunophenotypic features, treatment regimens, and outcomes of these patients were investigated. Results: All patients (4 men, 11 women; median age 54 years) presented with skin lesions, including five stage T1, four stage T2 and six stage T3 lesions. pcPTCL-NOS manifests clinically either with solitary or disseminated rapidly growing nodules/tumors and papules and, less often, ulcers. The lesion sites in patients presenting with solitary/localized tumors (stage T1 and T2) were the head and limbs, and those in patients presenting with disseminated lesions (stage T3) were the trunk, head, and limbs. The CD4/CD8 immunophenotypic characteristics were as follows: CD4+/CD8- 53.33%; CD4+/CD8+ 26.67%; CD4-/CD8- 13.33%; and CD4-/CD8+ 6.67%. One patient had a T follicular helper (TFH) phenotype. Five patients had aberrant expression of the B-cell marker CD20 by tumor cells. All patients received CHOP or CHOP-like regimens as the initial treatment, with three patients undergoing complete lesion resection before chemotherapy, seven patients receiving treatment combined with chidamide (tucidinostat), two patients receiving treatment combined with brentuximab vedotin, two patients receiving treatment combined with mitoxantrone liposomes (Lipo-Mit), three patients receiving treatment combined with radiotherapy, and two patients receiving ASCT after the first-line treatment. The OS rates at 1 year, 2 years, and 3 years were 80%, 77.8%, and 77.8%, respectively; the PFS rates were 60%, 44.4%, and 33.3%, respectively. With a median follow-up of 40 months, the median PFS was 21 months, and the median OS was not reached. Univariate analyses revealed that patients with B symptoms and the CD4-/CD8- phenotype had inferior outcomes (p < 0.05). Age, sex, tumor stage, PIT score, Ki-67 index, elevated β2-MG levels, expression of CD20 or PD1, and treatment selection were not associated with the prognosis. A trend of a survival benefit in patients with solitary (T1) tumors compared with patients with disseminated (T2, T3) tumors was observed, suggesting that it is possible to reduce the intensity of treatment in patients with T1 tumors in the future. Conclusions: pcPTCL-NOS is an aggressive but poorly characterized lymphoma that may require early and active systemic treatment. However, for patients with T1 tumors, reducing the intensity of treatment with CHOP should be appropriately considered.

Background:Hepatitis B virus (HBV) infection (surface antigen positive, HBsAg+) has been related to the increased risk in follicular lymphoma (FL). The further understanding of features in HBV-associated FL remains lacking. Methods:We explored clinical risk factors in HBsAg-positive patients from multicentric clinical investigation retrospectively (n = 276) and integrated HBV-related factors into Follicular Lymphoma International Prognostic Index (FLIPI) scoring system for risk prediction. The methylation profiles in pre- and paired HBsAg+FL occurring progression of disease within 2 years (POD24) were determined using the Human Methylation 850K BeadChip platform. Bulk RNA sequencing was performed for gene expression in samples from the same patient and confirmed using MycCd19Cre C57BL/6J chimera mice. Results:We found that HBsAg+ FL with a higher incidence of POD24. The high HBV-DNA load (>105 copies/mL) was identified as a pivotal risk factor. HBsAg+ FL with the rapidly decreasing viral load showed lower incidence of POD24 than those without viral control (P = 0.026). Integrated risk stratification incorporating HBV-related clinical parameters based on FLIPI scoring systems had potential predictive value for high-risk patients (AUC = 0.616, P = 0.002). The methylation profiles in pre-POD24-HBsAg+FL and paired POD24-HBsAg+FL showed distinguished signatures of methylated KMT2A, EP300-AS1, ARID1B, MHC I class molecular genes related to tumor cells, and TNFRSF1A, LTA, IQCE genes related to immune cells. Of note, we confirmed that the crucial CXCR5 mRNA expression with specific methylated regions was inversely correlated to featured MYC mRNA expression as "trans" regulation in both POD24-HBsAg+FL and MycCd19Cre lymphoma model. Conclusion:Integrated clinicopathological features into prediction system may provide precise risk stratification for HBV-positive FL. Modifiable DNA methylation acts as the potential targets for the combined treatment strategy to delay POD24 occurrence.

Little is known about the survival benefit of relmacabtagene autoleucel (relma-cel) in the current therapeutic landscape of relapsed/refractory (r/r) follicular lymphoma (FL). The current study compared the survival outcomes of Chinese FL patients administered relma-cel in RELIANCE (NCT04089215) and usual care in a retrospective, observational, large-scale real-world study (RWS). An indirect treatment comparison was carried out for 27 patients from RELIANCE and 53 patients from the RWS in China. Additionally, a direct comparison was made with the SCHOLAR-5 study, which assessed available treatment options abroad. After propensity score matching, disease status (FLIPI2 score, histological grade, relapse status, POD24) in the relma-cel group appeared to indicate more severe disease versus the usual care group. Nevertheless, median progression-free survival (PFS) was not reached (95% CI 8.97-NR) for relma-cel versus 19.98 months (95% CI 16.03-28.98) for usual care, indicating a hazard ratio (HR) of 0.40 (95% CI 0.13-1.23). Besides, a comparative analysis of RELIANCE and SCHOLAR-5, applying available treatment options abroad, revealed an HR for PFS of 0.20 (95% CI 0.07-0.58). At 24 months, 100% of patients survived after relma-cel infusion, versus 38.2% after usual care in China and 62.7% after usual care treatment in SCHOLAR-5, respectively. Relma-cel exhibits superior survival benefits versus current conventional therapies in r/r FL patients after ≥ 2 treatment lines.

Follicular lymphoma (FL) patients with low tumor burden at diagnosis frequently undergo the watch‐and‐wait (W&W) strategy. The study aimed to facilitate risk assessment in predicting the time to lymphoma treatment (TLT) for W&W patients through an integrated analysis of clinical factors and genetic mutations. A retrospective study was conducted on 214 FL patients managed with W&W between 2016 and 2023. Among them, 184 patients underwent targeted sequencing. The median follow‐up was 30.4 months (IQR 21.4–41.9, range 6.4–95.8). A clinico‐genetic model m3‐PRIMA‐PI was developed using the multivariate Cox proportional hazards method, incorporating two clinical parameters (bone marrow involvement and elevated β2‐MG) and three gene mutations ( KMT2D , EP300 , and TP53 ). Patients were categorized into low (69.0%), intermediate (21.7%), and high (9.2%) risk groups. Probabilities of treatment initiation at one year were 11.0% (95% CI, 5.2%–16.5%), 26.0% (95% CI, 10.7%–38.7%), and 54.3% (95% CI, 22.3%–73.1%); and at 2 years were 29.4% (95% CI, 20.2%–37.5%), 49.8% (95% CI, 31.1%–63.4%), and 93.5% (95% CI, 56.7%–99.0%), respectively. The predictive performance for TLT was superior with m3‐PRIMA‐PI, achieving a C‐index of 0.66 (95% CI, 0.63–0.69), compared to established indexes like FLIPI (C‐index 0.59, 95% CI, 0.56–0.62) and FLIPI2 (C‐index 0.59, 95% CI, 0.55–0.61). The above results were further validated in an independent external cohort. The m3‐PRIMA‐PI may provide a promising tool for risk stratification in W&W FL patients.

7060 Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and has an overall cure rate of approximately 60%. Previously, we observed high PIM1 mutation rates in DLBCL patients with poor outcome. However, the mechanism whether they lead to enhanced PIM1 kinase activity and contribute to lymphomagenesis is currently unknown. Methods: In this study, a multifaceted approach was employed to elucidate the functional consequences of PIM1 gene mutations and their implications in DLBCL. Recurrent PIM1 gene mutations that exhibited high frequencies across various lymphoma cohorts from public databases were screened and patient outcomes were stratified by PIM1 genen mutational sites. Liquid chromatography-mass spectrometry (LC-MS/MS) analysis combined with Co-IP was used to identify proteins interacting with PIM1. Transcriptomics analysis was utilized to identify proteins involved in critical cellular pathways relevant to PIM1 mutation. A high-throughput drug screening platform was leveraged to find potential therapeutic vulnerabilities unique to PIM1 mutant cells. The antiproliferative effects of PIM1 and PI3K inhibitor were evaluated in DLBCL cell lines and further validated in NSG mouse xenograft models. Results: We have identified PIM1 mutations, specifically P81S, E135K, L184F, and S97N, as frequently occurring variants, with the former three significantly associated with poor outcome. In particular, the PIM1 L184F mutation promoted cell proliferation and inhibited cell apoptosis in vitro and showed faster tumor growth in vivo. Mechanistically, the PIM1 L184F mutation was found to interact with the annexin A2 (ANXA2) gene, activating it through phosphorylation of serine 26. The activated ANXA2 gene then translocated from the cytoplasm to the cell membrane, binding with the Toll-like receptor 4 (TLR4) gene and recruiting BCAP to the cell membrane to interact with p85α further activating the PI3K/AKT/mTOR signaling pathway. Additionally, the high-throughput drug screening demonstrated that the PIM1 L184F mutated cells were more sensitive to the PI3K inhibitor YY20394. PIM1 inhibitor SMI-4a combined with YY20394 showed synergistic antitumor effects both in vitro and in vivo. Conclusions: Taken together, these findings not only shed light on an innovative regulatory mechanism for how PIM1 L184F mutation contributes to the pathogenesis of DLBCL but also provide a potential therapeutic strategy for effectively managing DLBCL patients harboring PIM1 L184F mutation.

The 2022 World Health Organization Classification of Haematolymphoid tumours classifies follicular lymphoma grades 1-2 (FL1-2) and grade 3A (FL3A) as classic follicular lymphoma (cFL) and reclassifies grade 3B (FL3B) as follicular large B-cell lymphoma (FLBL), without addressing cases of patients with concurrent FL and diffuse large B-cell lymphoma (FL/DLBCL). However, genetic information on FL histologic grading remains limited, and the latest classification lacks sufficient evidence to resolve whether these subgroups represent single or multiple distinct biological entities. This study analyzed clinical data from 831 patients, whole-exome sequencing (WES) from 149 patients, and transcriptome sequencing from 63 patients to explore differences among FL1-2, FL3A, FL3B, and FL/DLBCL. Clinical analyses revealed two distinct groups: an indolent group (FL1-2 and FL3A) with favorable prognosis and an aggressive group (FL3B and FL/DLBCL) characterized by poor prognosis. Genomics revealed that FL1-2 and FL3A share a common genetic background, whereas FL3B and FL/DLBCL lack mutations in epigenetic regulators CREBBP and KMT2D but exhibit additional copy number variations (CNVs), such as 1p36.32 losses and 3p21.1 gains, which are linked to poor prognosis. Transcriptomics revealed that with increasing histologic grade, immune-related pathway activity decreases, while the activity of metabolic and cell cycle pathways increases, which may be associated with the upregulation of MYC, IRF4, and BATF expression. Together, these findings define FL3B and FL/DLBCL as biologically and clinically distinct B-cell lymphomas, differing from traditional FL. FL1-2 and FL3A differ in their tumor microenvironments rather than genetic profiles.

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous malignancy. Advances in transcriptomic and genetic profiling have significantly enhanced our understanding of the disease's intrinsic pathogenesis, uncovering numerous potential therapeutic targets. However, the impact of tumor-infiltrating Regulatory T cells (Tregs) on the prognosis of DLBCL remains controversial. Here, we developed a Treg-associated gene signature by integrating single-cell and bulk transcriptome data to predict the prognosis of DLBCL patients receiving standard immunochemotherapy. In total, 227 Tregs feature genes were identified, six of which were selected for constructing a prognostic signature. DLBCL patients possessing high-risk scores had significantly poorer survival outcomes than those who possess low-risk scores in NCICCR and validation cohorts. Mutations in PIM1, MYD88, DTX1, CARD11, CD79B, ETV6, BCL6, and CDKN2A were predominantly observed in the high-risk group, whereas alterations in TNFRSF14 and DNMT3A were more frequently detected in the low-risk group. Immune infiltration analysis revealed that the high-risk group exhibited an immunosuppressive microenvironment, whereas the low-risk group showed a higher abundance of non-cellular components in the tumor microenvironment (TME). Finally, the Treg features TNFRSF25 and SELL can effectively predict long-term responses to Axicabtagene Ciloleucel (Axi-cel) treatment. In summary, our study developed a prognostic signature consisting of six Treg feature genes by integrating single-cell and bulk transcriptomics to predict clinical outcomes in DLBCL patients. The risk signature was significantly associated with immunological characteristics.

Our study aimed to assess the prognostic significance of the interim National Comprehensive Cancer Network International Prognostic Index and PET-CT-related parameters for predicting patient outcomes and achieving precise risk stratification for diffuse large B-cell lymphoma (DLBCL) patients. We retrospectively analyzed the clinicopathological and PET-CT data of 498 patients diagnosed with DLBCL across three medical centers in China. 418 patients were eligible for subsequent analysis after excluding those with incomplete data and 70% of which were randomly selected as the discovery cohort, whereas the remaining 30% constituted the validation cohort. The impact of candidate factors on survival was assessed via univariate and multivariate Cox proportional hazards models. The area under the curve AUC and C-index were calculated to assess the predictive performance of models. Univariate and multivariate Cox regression analyses identified changes in total lesion glycolysis (ΔTLG), iNCCN-IPI, interim abdominal residual disease (iARD) status, and changes in the maximum standardized uptake value (ΔSUVmax) as independent prognostic factors. Leveraging the outcomes of the multivariate analysis, we constructed the iPET-NCCN-IPI prognostic model and categorized DLBCL patients into two separate prognostic risk groups based on their computed Risk Scores (RS = 0.90×iNCCN-IPI + 1.41×ΔTLG + 0.79×ΔSUVmax + 0.83×iARD). The predictive performance of the model was validated by calculating the area under the receiver operating characteristic curve and the C-index. Notably, compared with other models, the iPET-NCCN-IPI demonstrated superior prognostic capability. In conclusion, our study indicates that the iPET-NCCN-IPI stratifies DLBCL patients into two distinct prognostic risk groups and surpasses other models in prognostic predictive ability.