Abstract Background Microsatellite instability‐high/deficient mismatch repair (MSI‐H/dMMR) colorectal cancer (CRC) is a biologically distinct subtype with important clinical implications. While tissue‐based assays remain the standard, accessible preoperative surrogate markers are of interest. Systemic inflammatory indices, including the systemic immune‐inflammation index (SII) and neutrophil‐to‐lymphocyte ratio (NLR), have been explored, but their relationship with MSI‐H/dMMR status remains unclear. Objective To evaluate the association between systemic inflammatory indices and MSI‐H/dMMR status using published evidence, local clinical data and pathological corroboration. Methods This study included three components: (1) evidence synthesis of published cohorts comparing inflammatory indices between MSI‐H/dMMR and MSS/pMMR CRC; (2) a retrospective cohort of 28 patients (20 MSS and eight MSI‐H) assessing peripheral blood profiles and exploratory associations; and (3) immunohistochemical quantification of CD8 and myeloperoxidase (MPO) using a Python/OpenCV workflow. Results Six studies (n = 1598) were included in the NLR synthesis. The pooled random‐effects standardised mean difference was 0.93 (95% confidence interval [CI] 0.016–1.852), suggesting higher NLR in MSI‐H/dMMR cases, although heterogeneity was high (I2 = 97.8%). Excluding one influential study reduced the effect to 0.34 (95% CI −0.00 to 0.68). One study of SII suggested a modest increase in MSI‐H/dMMR cases. In the local cohort, lymphocyte count was higher in MSI‐H cases (p = .009), whereas SII and NLR were lower but not significant. Receiver operating characteristic analysis showed modest discrimination (SII area under the curve [AUC] = 0.675; NLR AUC = 0.656). Pathological quantification showed increased CD8 and reduced MPO/CD8 ratio in MSI‐H tumours. Conclusions MSI‐H/dMMR CRC exhibits a distinct but context‐dependent immune‐inflammatory phenotype. Systemic indices show heterogeneous patterns, while tissue findings indicate a lymphocyte‐enriched microenvironment. These markers may provide supportive immune context, but further validation is required. Trial registration PROSPERO CRD420261323742 (https://www.crd.york.ac.uk/PROSPERO/view/CRD420261323742).

Background:Anti-tumor immunity is the front line of human response to malignancy, which may shed light on early diagnosis of diffuse large B cell lymphoma (DLBCL). We aim at the introduction of immune-related genes to bring new insight in the establishment of a predictive model to facilitate the diagnosis of DLBCL and guide its therapy. Methods:First, we identified immune-related genes in DLBCL via GeneCards. With these genes, we conducted least absolute shrinkage and selection operator (LASSO) regression to select the genes with significant contribution to DLBCL and established a validated risk model to generate risk score. Later, a nomogram combining risk score with other common clinical index (age, gender, stage) was established to comprehensively evaluate the survival probability of patients with DLBCL. To guide the treatment, we implemented drug sensitivity analysis. To further understand the modulation and explore potential biomarkers, we constructed a competing endogenous RNA (ceRNA) network. Results:Hence, we established an immune-related genes-based risk model to predict the survival and progression of DLBCL. Validation of this risk model in internal test dataset and additional external validation datasets confirmed the robust performance of this model. The risk score was also found to be correlated with advanced stages and age over 60 years. We also found four novel second-line chemotherapies that can be used to treat patients with different risk scores. Conclusions:Overall, we established a predictive risk model based on immune-related genes from transcription level. This risk model can be utilized in clinical practice to facilitate physicians in diagnosing patients with DLBCL at an early stage and guide the treatment of DLBCL.

Double-strand breaks (DSBs) are universally acknowledged as the most detrimental type of DNA damage, and their effective repair primarily depends on the non-homologous end joining (NHEJ) pathway. Such DSBs, which require NHEJ for resolution, can arise from intrinsic and extrinsic DNA-damaging factors or emerge naturally during essential biological processes like V(D)J recombination and antibody class switch recombination. Failure to properly repair DSBs may lead to genomic instability, disruption of cellular functions, and immunodeficiency, thereby promoting the development of hematologic malignancies. Conversely, overexpression of NHEJ-related genes can enhance resistance to DNA-damaging therapies in these cancers. Analyzing mutations in key classical NHEJ (cNHEJ) components and understanding their mechanisms could provide valuable biomarkers for predicting therapeutic outcomes and guiding treatment decisions. Consequently, defects in cNHEJ may offer insights into the development of novel drugs targeting DNA repair pathways. We focus on genetic changes and alterations in gene regulation, while also providing an overview of cNHEJ.

T cell exhaustion plays an immunosuppressive role in malignant tumors.Continuous tumor antigen stimulation,the presence of suppressive immune cells and cytokines in the tumor microenvironment,the up regulation of inhibitory receptor expression on the surface of T cells,changes in T cell related transcription factors,and metabolites in the tumor microenvironment may lead to T cell exhaustion.Reversing the exhaustion of T cells in tumor patients is a promising strategy for tumor immunotherapy.This article will review the latest research progress on T cell exhaustion status,pathogenesis,reversal methods,and clinical applications in hematological tumors.

BACKGROUND:Diffuse large B-cell lymphoma (DLBCL), an aggressive type of non-Hodgkin's lymphoma, has a high relapse/refractory rate. We previously identified sex-determining region Y (SRY)-box transcription factor (SOX9) as a transcription factor that serves as a prognostic biomarker, particularly in BCL2-overexpressing DLBCL, and plays a vital role in lymphomagenesis. However, the molecular mechanisms that modulate the aberrant expression of SOX9 in this DLBCL subset remain unknown. METHODS:Cell viability, apoptosis and cell cycle assays were performed to determine whether SOX9 contributes to DLBCL chemoresistance and rescues silencing IRF4-induced phenotypes. Protein‒protein interactions and protein ubiquitination were elucidated using immunoprecipitation, immunohistochemistry, immunofluorescence and immunoblotting. Chromatin immunoprecipitation sequencing (ChIP-seq), ChIP and dual-luciferase reporter assays were used to investigate IRF4 binding to the SOX9 promoter. The therapeutic potential of IRF4 inhibition was evaluated in vitro and in a mouse model of DLBCL xenografts. RESULTS:SOX9 enhanced the resistance of the BCL2-overexpressing DLBCL subset to chemotherapy or a BCL2 inhibitor. Moreover, BCL2 inhibition downregulated SOX9 in an immunoglobulin heavy chain/BCL2-positive DLBCL subset. We further identified IRF4 as a key regulator of BCL2-induced SOX9 expression, and ChIP-seq confirmed that IRF4 is a key transcription factor for SOX9 in DLBCL. In addition, BCL2 promotes IRF4 entry into the nucleus by enhancing protein stability and downregulating proteasomal ubiquitination, thereby enforcing SOX9-mediated phenotypes. Finally, in a DLBCL cell line and xenografted mouse model, in vivo inhibition of IRF4 with an hIRF4 antisense oligonucleotide repressed lymphomagenesis and DLBCL chemoresistance. CONCLUSIONS:Our data support the conclusion that IRF4 plays an essential role in BCL2-induced upregulation of SOX9 expression, and targeting IRF4 may represent a promising therapeutic strategy to cure relapsed and refractory DLBCL. KEYPOINTS/HIGHLIGHTS:BCL2 activated IRF4 by enhancing its nuclear activity to induce sex-determining region Y (SRY)-box 9 protein (SOX9) aberrant expression, which is a critical pathway for drug resistance in BCL2-overexpressing diffuse large B-cell lymphoma (DLBCL). Targeting IRF4 may be worth investigating further regarding its potential to overcome the chemoresistance of BCL2-overexpressing DLBCL to standard therapies.

Despite the dual roles of GALNT3 in various cellular processes in tumorigenesis of solid tumors, the clinical and biological significance of GALNT3 in lymphomagenesis remains largely unknown. Herein, our bioinformatics analysis uncovers that GALNT3 dependent glucose metabolism was significantly elevated in DLBCL. Our DLBCL cohort study revealed that GALNT3 positivity is significantly associated with worse prognosis and clinical outcomes in DLBCL pathogenesis. Biologically, GALNT3 overexpression were found to promote DLBCL cell proliferation and cell cycle progression, while silencing GALNT3 inhibited lymphomagenesis. RNA-seq uncovers that GALNT3 upregulated FGFR2-MAPK signaling pathway in DLBCL. Moreover, protein mass spectrometry identified two potential O-Glycosylation sites of FGFR2 (Thr319 and Ser299). Further point mutation of glycosylation sites, confirmed that GALNT3 O-Glycosylates FGFR2 through Thr319. Besides, in vitro and in vivo rescue experiments demonstrated that Thr319 is indispensable for GALNT3-FGFR2-MAPK induced lymphomagenesis. In vitro pharmacological inhibition of FGFR2 with a selective inhibitor Futibatinib further demonstrated that it inhibited DLBCL cell growth, cell proliferation, induced cell cycle arrest, promoted cell apoptosis. Further in vivo study found that combination of Futibatinib with chemotherapy displayed better anti-tumor activity relative to single drug therapy in DLBCL treatment. Collectively, our data highlight the importance of considering the GALNT3-FGFR2-MAPK signaling axis as an attractive therapeutic target for lymphomagenesis. Besides, in vitro and in vivo rescue experiments demonstrated that Thr319 is indispensable for GALNT3-FGFR2-MAPK induced lymphomagenesis. In vitro pharmacological inhibition of FGFR2 with a selective inhibitor Futibatinib further demonstrated that it inhibited DLBCL cell growth, cell proliferation, induced cell cycle arrest, promoted cell apoptosis. Further in vivo study found that combination of Futibatinib with chemotherapy displayed better anti-tumor activity relative to single drug therapy in DLBCL treatment.Collectively, our data highlight the importance of considering the GALNT3-FGFR2-MAPK signaling axis as an attractive therapeutic target for lymphomagenesis.

Although the cellular role of uncoupling protein 2 (UCP2) in tumorigenesis has been reported in various solid tumor models, its role in leukemogenesis remains elusive. Herein, we demonstrated that UCP2 was highly expressed in AML and significantly associated with poor prognosis and chemoresistance, suggesting that UCP2 can be used as a potential biomarker in acute myeloid leukemia. Mechanistically, in vitro and in vivo silencing of UCP2 significantly impairs acute myeloid leukemia cell growth and survival, accompanied by the disruption of mitochondrial homeostasis. Interestingly, RNA-sequencing analysis and metabolic mass spectrometry revealed that silencing UCP2 resulted in accumulated branched-chain amino acids (BCAAs), which induced oxidative stress through the PI3K/AKT/mTOR signaling pathway. Additionally, the lack of BCAAs restored leukemic cell growth and survival and decreased mitochondrial ROS production induced by inhibiting UCP2. More importantly, supplementation of BCAA enhanced the anti-tumor activity of genipin, a selective inhibitor that targets UCP2, resulting in significantly reduced acute myeloid leukemia blasts, increased mouse survival, and magnified oxidative stress. Taken together, our study elucidates the rationale of targeting the UCP2-BCAA-PI3K/AKT/mTOR signaling axis in leukemogenesis and provides a novel strategy for leveraging the metabolic dependencies of leukemic cells.

BackgroundDiffuse large B-cell lymphoma (DLBCL), an aggressive subtype of non-Hodgkin lymphoma, exhibits heterogeneous clinical outcomes. While rituximab, a CD20 inhibitor, combined with chemotherapy has improved survival in some patients, resistance remains prevalent, particularly in hypoxic tumor microenvironments. Understanding hypoxia-related genes (HRGs) and their role in rituximab resistance is critical to addressing therapeutic challenges in high-risk DLBCL.MethodsGene expression profiles from GEO datasets (GSE56315: DLBCL tumor vs. normal; GSE104212: hypoxia-treated DLBCL cell lines) were analyzed to identify overlapping genes between DLBCL-signature genes (DSGs) and HRGs. protein interaction network topology analysis and Lasso regression modeling of TCGA-DLBC dataset were employed to screen regulator and hub genes. Hub genes linked to rituximab response and survival were validated in DLBCL patients receiving rituximab therapy. Functional enrichment analysis was used to explore associated pathways. The expression of the identified regulator and hub genes was validated using reverse transcription quantitative polymerase chain reaction (RT-qPCR).Results58 overlapping genes were identified between DSGs and HRGs. PPI network and Lasso regression revealed 5 MS4A1 regulator genes and 10 hub genes. Among these, LGALS1 (HR = 0.588, p = 0.00085), TIMP1 (HR = 0.591, p = 0.00098), ANXA1 (HR = 0.614, p=0.0024) and STAP1 (HR = 0.633, p=0.0035) were significantly associated with overall survival and GPNMB (AUC = 0.869), CDCA7 (AUC = 0.686), and STAP1 (AUC = 0.663) associated with treatment response in rituximab-treated patients. Functional analysis implicated these genes in B-cell receptor (BCR) and PI3K-AKT signaling pathways, suggesting their mechanistic roles in therapeutic resistance.ConclusionsThis study identifies hypoxia-associated genes critical to rituximab resistance in DLBCL, highlighting potential therapeutic targets. Their involvement in BCR and PI3K-AKT pathways underscores novel vulnerabilities for overcoming refractory disease. Our findings provide a foundation for developing strategies to improve outcomes in high-risk DLBCL patients with hypoxic microenvironments.

Diffuse large B-cell lymphoma (DLBCL), known as the predominant type of aggressive B-cell lymphoma, is biologically and clinically heterogeneous. The prognosis of DLBCL is quite different among subtypes. Hypoxia is one of the key elements in tumor microenvironment, promoting tumor progression by means of various mechanisms, such as increased proliferation, altered metabolism, enhanced angiogenesis, and greater migratory capability, among others. The primary purpose of this research is to investigate the connection between hypoxia-featured genes (HFGs), prognosis in DLBCL, and their capacity association with the immune microenvironment. Various hypoxia-associated patterns for DLBCL patients from GEO and TCGA databases were identified by means of an unsupervised consensus clustering algorithm. CIBERSORT and IOBR package is used to identify different immune infiltration status. To develop a predictive model using hypoxia-related genes, we conducted univariate Cox regression, multivariate Cox regression, and LASSO regression assessment. Subsequently, we confirmed the predictive importance of these hypoxia-associated genes, highlighting hypoxia-associated characteristics, and explored the connection between the hypoxia model and the immune environment. Three hypoxia clusters were identified. We also observed that each pattern of hypoxia response was significantly related to different prognoses. It was found that the immune status among hypoxia clusters is different. After developing a prognostic risk model using 5 hypoxia-related genes, we discovered that the risk score is related to immune factors and how effective drugs are in treating DLBCL. In DLBCL patients, varying hypoxia patterns correlate with both prognostic outcomes and the immune microenvironment. Hypoxia-featured genes (HFGs) function as a standalone predictive element in these patients. It is also potentially a reliable indicator for predicting clinical responses to ICI therapy and traditional drugs.

Anti-tumor immunity is the front line of human response to malignancy, which may shad the light to early diagnosis of DLBCL. The introduction of immune related genes will bring new insight in the establishment of a predictive model to facilitate the diagnosis of DLBCL and guide its therapy. Hence, we established an immune related genes based risk model to predict the survival and progression of DLBCL. First, we identify immune related genes in DLBCL via GeneCards. With these genes, we conducted LASSO regression to select those genes with significant contribution to DLBCL and established a risk model to generate risk score. Validation of this risk model in internal test dataset and additional external validation datasets confirm the robust performance of this model. The risk score was also found to correlated with advanced stages and age over 60. Later, a nomogram combining risk score with other common clinical index (age, gender, stage) was established to comprehensively evaluate the survival probability of patients with DLBCL. To guide the treatment, we also found four novel second-line chemotherapies can be used to treat patients with different risk scores. Overall, this novel model can be utilized in clinical practices and guide the treatment.

The biosynthesis and maturation of proteins are primarily regulated by the endoplasmic reticulum in its physiological state.Thus,the disruption of physiological homeostasis initiates the buildup of unfolded and misfolded proteins in the endoplasmic reticulum,resulting in endoplasmic reticulum stress(ERS)and unfolded protein response(UPR).One of the important pathways by which UPR maintains intracellular homeostasis under ERS is activating protein kinase R-like endoplasmic reticulum kinase(PERK).The activation of the PERK pathway stimulates eukaryotic translation initiation factor 2 subunit-α(eIF2α)phosphorylation and the selective translation of active transcription factor 4(ATF4),and PERK induces cell apoptosis by directly binding to the promoter of pro-apoptotic transcription factor C/EBP homologous protein(CHOP).This signaling pathway is also one of the important mechanisms by which UPR participates in the regulation of hematological malignancies and immune cells in a tumor microenvironment.This article provides an overview of advancements in research into the PERK-eIF2α-ATF4-CHOP signaling pathway in hematological malignancies and the potential therapeutic benefits of targeting this signaling pathway.

Objective To retrospectively analyze the expression and significance of γδ T cells and lymphocyte subsets in peripheral blood on patients with multiple myeloma (MM). Methods Fifty-five patients with multiple myeloma admitted to Yangpu Hospital Affiliated to Tongji University from January 2022 to August 2023 were selected as the disease group, and were categorized into stage I group, stage II group and stage III group according to the International Staging System (ISS) of multiple myeloma. All included patients were consecutive visits. Another 30 cases of healthy people with physical examination were selected as the control group. Flow cytometry was used to detect the γδ T cells and lymphocyte subsets in the peripheral blood of the subjects. After clinical indicators of patients and healthy controls were collected, the statistical analysis was conducted. Results Compared with the control group, the percentage of γδ T cells and CD8+ T cells in the disease group were higher, while, the absolute numbers of total peripheral blood lymphocytes (LYMT) and CD19+ B cells, percentage of CD19+ B cells, CD3+ T cells, CD4+ T cells were lower (P​<​0.05). The percentage of γδ T cells (P​<​0.001), the percentage of CD19+ B cells (P​=​0.003), the absolute number of CD3+ T cells (P​=​0.010), the absolute number of CD8+ T cells (P​=​0.002) were the significant influential factors of MM. γδ T cells (P​=​0.004), neutrophils (P​<​0.001), neutrophil to lymphocyte ratio (P​=​0.003), and white blood cell count (P​<​0.001) were statistically different in different stages. ROC curve suggested that the area under the curve of the percentage of γδ T cells in predicting the MM were 0.973 (P​<​0.001) which had certain diagnostic value. Conclusions γδ T cells and lymphocyte subsets (CD8+ T cells, CD19+ B cells, CD3+ T cells, etc.) in patients with newly diagnosis of MM can reflect the immune function of the patient’s organism, which is a key factor of MM. γδ T cells influence the staging of MM patients, and also have certain diagnostic value.

PurposeChimeric antigen receptor (CAR)-T cells against CD19 have been proven to be effective in treating B-cell hematological malignancies. However, the efficacy of this promising therapy is limited by many factors.MethodsIn this study, the germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) cell line OCI-Ly1, and patient-derived xenografted (PDX) mice (CY-DLBCL) were used as the CAR-T cell-resistant model. Meanwhile, the activated B-cell-like (ABC) DLBCL cell line OCI-Ly3 and PDX mice (ZML-DLBCL) were defined as the CAR-T sensitive model. The enhancement of CAR-T cell function by lenalidomide (LEN) was examined in vitro and in vivo.ResultsLenalidomide effectively enhanced the function of third-generation CD19-CAR-T cells by polarizing CD8(+) CAR-T cells to CD8 early-differentiated stage and Th1 type, reducing CAR-T cell exhaustion and improving cell expansion. It was further demonstrated that CAR-T cells combined with LEN substantially reduce the tumor burden and prolong the survival time in various DLBCL mouse models. LEN was also found to promote the infiltration of CD19-CAR-T cells into the tumor site by modulating the tumor microenvironment.ConclusionIn summary, the results of the present study suggest that LEN can improve the function of CD19-CAR-T cells, providing a basis for clinical trials using this combination therapy against DLBCL.

目的 对疫情期间临床医学生实验诊断学线上课程进行教学成效的调查与分析,为实验诊断学在线课程的优化和实现线上教学与线下教学同质等效目标提供理论依据.方法 选择上海交通大学医学院 2020级临床医学专业学生 79 名作为研究对象,其中临床医学五年制(儿科班)学生 54 名,4+4(硕博班)学生 25 名.另选择接受线下教学的 2019 级临床医学五年制(儿科班)学生 56 名和 4+4(硕博班)学生 25 名作为对照.通过客观成绩对比分析、主观感受调查问卷两方面对学情、学习质量和教学满意度进行评估和反馈.结果 2020级儿科班学生实验诊断学成绩高于 2019 级,但差异无统计学意义(P>0.05);2020 级硕博班学生实验诊断学成绩较 2019 级有所下降,差异有统计学意义(P<0.05).44.4％的学生对实验诊断学线上教学表示非常满意,30.2％的学生表示比较满意.与线下教学比较,线上教学最重要的优势是能反复回放观看,有利于巩固知识点,但线上课程最大的缺点为缺少学习氛围,学生的学习积极性不高.结论 疫情期间实验诊断学线上课程取得了较好的效果.如何优化课程体系、提高学生线上学习积极性、促进线上线下教学的深度融合、提升线上教学质量是今后努力的方向.

Diffuse large B‐cell lymphoma (DLBCL) is the most common lymphoid malignancy with a high relapse rate. We previously found that C‐X‐C motif chemokine receptor 4 (CXCR4) was highly expressed in DLBCL and associated with poor prognosis. This study focused on the effect of hypoxia‐inducible factor‐1α (HIF‐1α) on CXCR4 expression and the DLBCL progression. Two activated B cell‐like DLBCL cell lines Ly‐3 and SUDHL2 were transfected with overexpression and knockdown plasmids or HIF‐1α. The viability and migration of DLBCL cells were significantly increased under hypoxic conditions, or upon HIF‐1α overexpression under normoxic conditions, but the HIF‐1α downregulation led to inverse trends. However, the promoting effects of HIF‐1α overexpression on DLBCL cells were suppressed by Plerixafor (a CXCR4 inhibitor). The luciferase and chromatin immunoprecipitation assays revealed that HIF‐1α bound to the functional site HRE1 on CXCR4 promoter to activate its transcription. HIF‐1α‐mediated CXCR4 activation further led to increased phosphorylation of AKT/mTOR under hypoxic conditions. Taken together, this work reports that HIF‐1α promotes viability and migration of activated B cell‐like cells under hypoxia, which might involve the transcription of CXCR4 and the activation of the AKT/mTOR pathway. The finding may provide novel lights in the management of DCBCL.

弥漫大B细胞淋巴瘤(DLBCL)是成年人常见的高度侵袭性恶性血液肿瘤.DLBCL为一种高度异质性淋巴瘤,患者在分子生物学特征、临床表现和预后方面均存在巨大差异.目前越来越多的证据表明,肿瘤微环境对DLBCL的发生、发展发挥着重要的作用.CD47分子是一种整合素相关蛋白,在DLBCL细胞中过度表达,并在淋巴瘤免疫逃逸中起关键作用.本文拟就CD47分子相关信号通路、在DLBCL肿瘤微环境中的作用和DLBCL中靶向CD47分子的治疗策略等方面的研究进展进行综述.

Abstract Background To investigate the effects of hypoxia-inducible factor-1α (HIF-1α) on the viability and migration of diffuse large B cell lymphoma (DLBCL) cells and the underlying mechanisms. Methods HIF-1α overexpression and knockdown plasmids were constructed and transfected into DLBCL cells. The efficacy of HIF-1α expression was detected via real time quantitative polymerase chain reaction (RT-qPCR). Whether overexpression and knockdown HIF-1α affect the expression of chemokine receptor type 4 (CXCR4) and promote cells proliferation and migration were detected via CCK8 assay and Transwell assay. How HIF-1α works on CXCR4 was measured by double fluorescent reporter assay and chromatin immunoprecipitation (ChIP) assay. The expression level of CXCR4 and AKT/mTOR pathway-related proteins were detected via Western blot assay. Results CCK8 assay and Transwell assay showed that both hypoxic conditions and HIF-1α overexpression under normoxia promoted the viability and migration of DLBCL cells while HIF-1α knockdown showed inhibitory effects. The effects of HIF-1α on DLBCL cells were suppressed when the expression of CXCR4 was inhibited. Double fluorescent reporter enzyme assay and ChIP assay showed that HIF-1α combined with the functional site HRE1 of CXCR4 promoter to promote the transcription of CXCR4. Western blot assay demonstrated that HIF-1α promoted the expression of CXCR4 to activate the phosphorylation of AKT/mTOR pathway under hypoxia. Conclusion HIF-1α regulated CXCR4 by binding to the functional site HRE1 of CXCR4 promoter and further activate AKT / mTOR signaling pathway, thereby promoting the viability and migration of DLBCL cells under hypoxia.

Introduction: The chemoresistance mechanism of diffuse large B-cell lymphoma (DLBCL) is still poorly understood, and patient prognosis remains unsatisfactory. This study aimed to investigate drug resistance mechanisms in non-germinal center B-cell-like (non-GCB) DLBCL. Methods: Doxorubicin (DOX)-resistant OCI-Ly3 cells were generated through long-term incubation of cells in a medium with gradually increasing DOX concentrations. The expression levels of genes related to drug metabolism were determined using a functional gene grouping polymerase chain reaction (PCR) array. Drug-resistant proteins were identified using bioinformatics, and molecular association networks were subsequently generated. The association and mechanism of key genes were determined using a dual-luciferase reporter assay System and chromatin immunoprecipitation (ChIP). The expression of drug-resistant genes and target genes was then measured using Western blotting and immunohistochemistry. The correlation between gene expressions was analyzed using Spearman’s rank correlation coefficient. Results: Using the PCR array, MDR1 was identified as the key gene that regulates DOX resistance in OCI-Ly3/DOX-A100, a non-GCB DLBCL cell line. The dual-luciferase reporter assay system demonstrated that MDR1 transcription could be inhibited by PRDM1. ChIP results showed that PRDM1 had the ability to bind to the promoter region (−1,132 to −996) of MDR1. In OCI-Ly3/DOX cells, NF-κB activity and PRDM1 expression decreased with an increase in drug-resistant index, whereas MDR1 expression increased with enhanced drug resistance. Immunohistochemical analysis revealed that relative MDR1 expression was higher than that of PRDM1 in human DLBCL tissue samples. A negative correlation was observed between MDR1 and PRDM1. Conclusion: In non-GCB DLBCL cells, NF-κB downregulates PRDM1 and thereby promotes MDR1 transcription by terminating PRDM1-induced transcriptional inhibition of MDR1. Such a mechanism may explain the reason for disease recurrence in non-GCB DLBCL after R-CHOP or combined CHOP with bortezomib treatment. Our findings may provide a potential therapeutic strategy for reducing drug resistance in patients with DLBCL.

Background: Diffuse large B-cell lymphoma (DLBCL), the most common type of Non-Hodgkin’s Lymphoma (NHL), has a lethal nature. Thus, the establishment of a novel model to predict the prognosis of DLBCL and guide its therapy is an urgency. Meanwhile, pyroptosis is engaged in the progression of DLBCL with further investigations required to reveal the underlying mechanism. Methods: LASSO regression was conducted to establish a risk model based on those PRGs. External datasets, RT-qPCR and IHC images from The Human Protein Alta (HPA) database were utilized to validate the model. ssGSEA was utilized to estimate the score of immune components in DLBCL. Results: A model based on 8 PRGs was established to generate a risk score. Validation of the model confirmed its robust performance. The risk score was associated with advanced clinical stages and shorter overall survivals. Two novel second-line chemotherapies were found to be potential treatments for high-risk patients. The risk score was also found to be correlated with immune components in DLBCL. Conclusion: This novel model can be utilized in clinical practices to predict the prognosis of DLBCL and guide the treatment of patients at high risk, providing an overview of immune regulatory program via pyroptosis in DLBCL.