Targeting regulated cell death (RCD) in hematological malignancies: Recent advances and therapeutic potential.

Regulated cell death (RCD) is a form of cell death that can be regulated by numerous biomacromolecules. Accumulating evidence suggests that dysregulated expression and altered localization of related proteins in RCD promote the development of cancer. Targeting subroutines of RCD with pharmacological small-molecule compounds is becoming a promising therapeutic avenue for anti-tumor treatment, especially in hematological malignancies. Herein, we summarize the aberrant mechanisms of apoptosis, necroptosis, pyroptosis, PANoptosis, and ferroptosis in hematological malignancies. In particular, we focus on the relationship between cell death and tumorigenesis, anti-tumor immunotherapy, and drug resistance in hematological malignancies. Furthermore, we discuss the emerging therapeutic strategies targeting different RCD subroutines. This review aims to summarize the significance and potential mechanisms of RCD in hematological malignancies, along with the development and utilization of pertinent therapeutic strategies.

Targeted protein degradation in hematologic malignancies: latest updates from the 2023 ASH annual meeting.

Protein degraders, emerging as a novel class of therapeutic agents, have gained widespread attention due to their advantages. They have several advantages over traditional small molecule inhibitors, including high target selectivity and ability to target "undruggable" targets and overcome inhibitor drug resistance. Tremendous research and development efforts and massive investment have resulted in rapid advancement of protein degrader drug discovery in recent years. Here, we overview the latest clinical and preclinical updates on protein degraders presented at the 2023 ASH Annual Meeting.

NCAPD3 promotes diffuse large B-cell lymphoma progression through modulating SIRT1 expression in an H3K9 monomethylation-dependent manner.

INTRODUCTION: Condensin, a family of structural maintenance of chromosome complexes, has been shown to regulate chromosome compaction and segregation during mitosis. NCAPD3, a HEAT-repeat subunit of condensin II, plays a dominant role in condensin-mediated chromosome dynamics but remains unexplored in lymphoma. OBJECTIVES: The study aims to unravel the molecular function and mechanism of NCAPD3 in diffuse large B-cell lymphoma (DLBCL). METHODS: The expression and clinical significance of NCAPD3 were assessed in public database and clinical specimens. Chromosome spreads, co-immunoprecipitation (co-IP), mass spectrometry (MS), and chromatin immunoprecipitation (ChIP) assays were conducted to untangle the role and mechanism of NCAPD3 in DLBCL. RESULTS: NCAPD3 was highly expressed in DLBCL, correlated with poor prognosis. NCAPD3 deficiency impeded cell proliferation, induced apoptosis and increased the chemosensitivity. Instead, NCAPD3 overexpression facilitated cell proliferation. In vivo experiments further indicated targeting NCAPD3 suppressed tumor growth. Noteworthily, NCAPD3 deficiency disturbed the mitosis, triggering the formation of aneuploids. To reveal the function of NCAPD3 in DLBCL, chromosome spreads were conducted, presenting that chromosomes became compact upon NCAPD3 overexpression, instead, loose, twisted and lacking axial rigidity upon NCAPD3 absence. Meanwhile, the classical transcription-activated marker, H3K4 trimethylation, was found globally upregulated after NCAPD3 knockout, suggesting that NCAPD3 might participate in chromatin remodeling and transcription regulation. MS revealed NCAPD3 could interact with transcription factor, TFII I. Further co-IP and ChIP assays verified NCAPD3 could be anchored at the promoter of SIRT1 by TFII I and then supported the transcription of SIRT1 via recognizing H3K9 monomethylation (H3K9me1) on SIRT1 promoter. Function reversion assay verified the oncogenic role of NCAPD3 in DLBCL was partially mediated by SIRT1. CONCLUSION: This study demonstrated that dysregulation of NCAPD3 could disturb chromosome compaction and segregation and regulate the transcription activity of SIRT1 in an H3K9me1-dependent manner, which provided novel insights into targeted strategy for DLBCL.

Serum indicators in functional high-risk multiple myeloma patients undertaking proteasome inhibitors therapy: a retrospective study.

OBJECTIVES: Multiple myeloma (MM) is a class of malignant plasma cell diseases. An increasing application of autologous stem cell transplantation (ASCT) and anti-myeloma agents represented by proteasome inhibitors (PIs) has improved the response rates and survival of MM patients. Patients progressing within 12 months were recently categorized with functional high-risk (FHR), which could not be clarified by existing genetic risk factors, with poor outcomes. Our study aimed to investigate clinical indices related to FHR and seek prognostic roles in transplant-eligible MM patients. METHODS: Demographic and individual baseline clinical characteristics were compared by using the Pearson's chi-square and Mann-Whitney U test. Progression-free survival (PFS) and overall survival (OS) were described by Kaplan-Meier estimates and compared using the log-rank test. Logistic regression analysis was used to assess the association of baseline characteristics at MM diagnosis with FHR status. RESULTS: From 18th January 2010 to 1st December 2022, 216 patients were included and divided into two groups according to the FHR status. There was no difference in baseline data between the two groups. Renal impairment (RI, Scr > 2 mg/dL) was common in MM patients and made sense in FHR status. AST levels were validated as independent predictors for FHR status (p = 0.019). DISCUSSION: Patients with RI or higher AST levels (AST > 40 U/L) tended to have worse outcomes. However, transplants had apparently improved prognoses. CONCLUSION: Therefore, in the PIs era, transplantations are still effective therapies for transplant-eligible MM patients.

Maintenance and consolidation strategies for patients with untreated advanced follicular lymphoma: A systematic review and network meta-analysis of randomized trials.

BACKGROUND: The emergence of novel and efficient antibody maintenance approaches has provided more options for post-induction treatment of advanced follicular lymphoma (FL), and further comparisons are required to determine the most clinically beneficial regimen. The authors conducted a systematic review and meta-analysis to evaluate the maintenance or consolidation strategy. METHODS: The authors performed two independent searches in PubMed, Web of Science, the Cochrane library databases, Scopus, and Embase for randomized controlled trials (RCTs) evaluating maintenance or consolidation therapy in untreated FL patients. Extracted data included the clinical characteristics, treatment regimen, progression-free survival (PFS), overall survival (OS), and adverse effects. They then pooled the data and used a Bayesian random-effects model to combine direct comparisons with indirect evidence. RESULTS: The authors screened 1515 records and identified 13 eligible RCTs that assessed nine different regimens in 5681 advanced FL patients. Reconstructed individual survival data presented that obinutuzumab had the highest effect sizes and certainty of the evidence for PFS (hazard ratio, 0.43; 95% confidence interval, 0.22-0.79) and tolerability compared with observation. However, no benefit was observed in patients according to the OS, regardless of which regimen was taken. Considering other regimens, although an extended course of rituximab maintenance and consolidation therapies presented PFS benefits compared with standard rituximab maintenance, they were also associated with higher toxicity. CONCLUSIONS: Although obinutuzumab and rituximab maintenance treatment improved PFS significantly, its clinical benefit requires further validation in larger populations. Furthermore, because few trials informed each treatment comparison, research is needed to refine the understanding of this complex and rapidly evolving treatment landscape.

Incidence and mortality of second primary malignancies after lymphoma: a population-based analysis.

BACKGROUND: Second primary malignancies (SPMs) account for an increasing proportion of human malignancies. We estimated the incidence, risk factors and outcomes in lymphoma survivors with SPMs. METHODS: Patients diagnosed with SPMs after primary lymphoma from 2010 to 2021 were included in this study. The incidence, mortality and clinical characteristics of SPMs in our center and Surveillance, Epidemiology, and End Results database were delineated and analyzed. Standardized incidence ratio quantified second cancer risk. RESULTS: A total of 2912 patients of lymphoma were included, 63 cases of SPM met the inclusion criteria, with the prevalence of SPMs after lymphoma was 2.16%. The male-to-female ratio of 2.32:1. The majority of these patients were older (≥60 years old, 61.90%) and previously treated with chemotherapy (68.25%). The common types among SPMs were digestive system tumors (42.86%), respiratory system tumors (20.63%) and urinary system tumors (12.70%). Additionally, cancer risks were significantly elevated after specific lymphoma though calculating the expected incidence. In terms of mortality, the diagnosis of SPMs was significantly associated with an increased risk of death over time. Moreover, although the outcome was favorable in some SPM subtypes (thyroid and breast cancer), other SPMs such as stomach and lung tumors had a dismal prognosis. CONCLUSION: With the improvement of medical standards, the survival of lymphoma patients has been prolonged. However, the incidence of SPM is increasing, particularly among men and older lymphoma survivors. Therefore, more attention should be invested in the SPM to further improve the prognosis of these patients.

Patterns of SPM incidence varied between China and Northern America.The incidence of SPM was higher among men and older lymphoma survivors.Patients with SPM are divided into low-risk and high-risk according to survival analysis.

Activation of STING by SAMHD1 Deficiency Promotes PANoptosis and Enhances Efficacy of PD-L1 Blockade in Diffuse Large B-cell Lymphoma.

Genomic instability is a significant driver of cancer. As the sensor of cytosolic DNA, the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a critical role in regulating anti-tumor immunity and cell death. However, the role and regulatory mechanisms of STING in diffuse large B-cell lymphoma (DLBCL) are still undefined. In this study, we reported that sterile alpha motif and HD domain-containing protein 1 (SAMHD1) deficiency induced STING expression and inhibited tumor growth in DLBCL. High level of SAMHD1 was associated with poor prognosis in DLBCL patients. Down-regulation of SAMHD1 inhibited DLBCL cell proliferation both in vitro and in vivo. Moreover, we found that SAMHD1 deficiency induced DNA damage and promoted the expression of DNA damage adaptor STING. STING overexpression promoted the formation of Caspase 8/RIPK3/ASC, further leading to MLKL phosphorylation, Caspase 3 cleavage, and GSDME cleavage. Up-regulation of necroptotic, apoptotic, and pyroptotic effectors indicated STING-mediated PANoptosis. Finally, we demonstrated that the STING agonist, DMXAA, enhanced the efficacy of a PD-L1 inhibitor in DLBCL. Our findings highlight the important role of STING-mediated PANoptosis in restricting DLBCL progression and provide a potential strategy for enhancing the efficacy of immune checkpoint inhibitor agents in DLBCL.

Targeting Hippo signaling in cancer: novel perspectives and therapeutic potential.

As highly conserved among diverse species, Hippo signaling pathway regulates various biological processes, including development, cell proliferation, stem cell function, tissue regeneration, homeostasis, and organ size. Studies in the last two decades have provided a good framework for how these fundamental functions of Hippo signaling are tightly regulated by a network with numerous intracellular and extracellular factors. The Hippo signaling pathway, when dysregulated, may lead to a wide variety of diseases, especially cancer. There is growing evidence demonstrating that dysregulated Hippo signaling is closely associated with tumorigenesis, cancer cell invasion, and migration, as well as drug resistance. Therefore, the Hippo pathway is considered an appealing therapeutic target for the treatment of cancer. Promising novel agents targeting the Hippo signaling pathway for cancers have recently emerged. These novel agents have shown antitumor activity in multiple cancer models and demonstrated therapeutic potential for cancer treatment. However, the detailed molecular basis of the Hippo signaling-driven tumor biology remains undefined. Our review summarizes current advances in understanding the mechanisms by which Hippo signaling drives tumorigenesis and confers drug resistance. We also propose strategies for future preclinical and clinical development to target this pathway.

Histone regulator KAT2A acts as a potential biomarker related to tumor microenvironment and prognosis of diffuse large B cell lymphoma.

BACKGROUND: Recent studies have indicated that epigenetic alterations contribute significantly to lymphoma pathogenesis. A type of epigenetic regulation known as histone acetylation plays a crucial role in transcriptional regulation in eukaryotic cells. Specifically, a significant effect of histone acetylation modifications on the abnormal progression and microenvironment of diffuse large B-cell lymphoma (DLBCL) has been observed. METHODS: To provide insight into the significance of histone acetylation-related genes, we developed a HAscore model for analyzing histone acetylation patterns in DLBCL samples. Furthermore, KAT2A, a regulator of histone acetylation, was knocked down in DLBCL cell lines to investigate its role in proliferation, cell cycle, and apoptosis. RESULTS: The HAscore model has been demonstrated to provide insight into the significance of these patterns, showing that patients with a low HAscore have distinct tumor immune microenvironments and poorer prognoses. Besides, KAT2A was identified as a potential biomarker related to immune infiltration and malignant pathways in DLBCL. CONCLUSION: According to these findings, it is evident that the histone acetylation pattern score model is helpful in describing the immune status of DLBCL and that KAT2A may be used as a biomarker for its treatment.

Targeting YTHDF2 inhibits tumorigenesis of diffuse large B-cell lymphoma through ACER2-mediated ceramide catabolism.

INTRODUCTION: Epigenetic alterations play crucial roles in diffuse large B-cell lymphoma (DLBCL). Disturbances in lipid metabolism contribute to tumor progression. However, studies in epigenetics, especially its critical regulator YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), on lipid metabolism regulation in DLBCL are unidentified. OBJECTIVES: Elucidate the prognostic value and biological functions of YTHDF2 in DLBCL and illuminate the underlying epigenetic regulation mechanism of lipid metabolism by YTHDF2 in DLBCL development. METHODS: The expression and clinical value of YTHDF2 in DLBCL were performed in public databases and clinical specimens. The biological functions of YTHDF2 in DLBCL were determined in vivo and in vitro through overexpression and CRISPR/Cas9-mediated knockout of YTHDF2. RNA sequencing, lipidomics, methylated RNA immunoprecipitation sequencing, RNA immunoprecipitation-qPCR, luciferase activity assay, and RNA stability experiments were used to explore the potential mechanism by which YTHDF2 contributed to DLBCL progression. RESULTS: YTHDF2 was highly expressed in DLBCL, and related to poor prognosis. YTHDF2 overexpression exerted a tumor-promoting effect in DLBCL, and knockdown of YTHDF2 restricted DLBCL cell proliferation, arrested cell cycle in the G2/M phase, facilitated apoptosis, and enhanced drug sensitivity to ibrutinib and venetoclax. In addition, YTHDF2 knockout drastically suppressed tumor growth in xenograft DLBCL models. Furthermore, a regulatory role of YTHDF2 in ceramide metabolism was identified in DLBCL cells. Exogenous ceramide effectively inhibited the malignant phenotype of DLBCL cells in vitro. The binding of YTHDF2 to m6A sites on alkaline ceramidase 2 (ACER2) mRNA promoted its stability and expression. Enhanced ACER2 expression hydrolyzed ceramides, disrupting the balance between ceramide and sphingosine-1-phosphate (S1P), activating the ERK and PI3K/AKT pathways, and leading to DLBCL tumorigenesis. CONCLUSION: This study demonstrated that YTHDF2 contributed to the progression of DLBCL by regulating ACER2-mediated ceramide metabolism in an m6A-dependent manner, providing novel insights into targeted therapies.

Recent advances of ferroptosis in tumor: From biological function to clinical application.

Ferroptosis is a recently recognized form of cell death with distinct features in terms of morphology, biochemistry, and molecular mechanisms. Unlike other types of cell death, ferroptosis is characterized by iron dependence, reactive oxygen species accumulation and lipid peroxidation. Recent studies have demonstrated that selective autophagy plays a vital role in the induction of ferroptosis, including ferritinophagy, lipophagy, clockophagy, and chaperone-mediated autophagy. Emerging evidence has indicated the involvement of ferroptosis in tumorigenesis through regulating various biological processes, including tumor growth, metastasis, stemness, drug resistance, and recurrence. Clinical and preclinical studies have found that novel therapies targeting ferroptosis exert great potential in the treatment of tumors. This review provides a comprehensive overview of the molecular mechanisms in ferroptosis, especially in autophagy-driven ferroptosis, discusses the recent advances in the biological roles of ferroptosis in tumorigenesis, and highlights the application of novel ferroptosis-targeted therapies in the clinical treatment of tumors.

Identification of pyroptosis-related signature and development of a novel prognostic model in diffuse large B-cell lymphoma.

PURPOSE: Emerging evidence suggests that pyroptosis plays an essential role in the development and progression of multiple cancers. However, the role of pyroptosis remains elusive in diffuse large B-cell lymphoma (DLBCL). METHODS: The expression profile data of DLBCL and normal samples of pyroptosis-related genes (PRGs) were analyzed, and the clinical characteristics of DLBCL patients were further investigated. A prognostic model was established using LASSO-Cox regression analysis. The expression of these PRGs was validated by qRT-PCR in DLBCL cell lines. Cell proliferation assay and flow cytometry were utilized to explore the impact of pyroptosis inhibitor (disulfiram, DSF) combined with PD1/PD-L1 inhibitor (BMS1166) on DLBCL cell proliferation. RESULTS: Most PRGs were dysregulated in DLBCL samples and associated with overall survival (OS). Six PRGs were selected to construct a prognostic risk score model. The qRT-PCR analysis revealed that CASP8, CASP9, NLRP1, NLRP6, and TIRAP are downregulated, while SCAF11 was significantly upregulated in DLBCL cell lines. This prognostic model divided DLBCL patients into low-risk and high-risk groups. Patients in the low-risk group exhibited lower mortality and longer OS than those in the high-risk group. The ROC curve and nomogram demonstrated this model's excellent predictive performance. GO and KEGG enrichment indicated that the differentially expressed genes (DEGs) between subgroups were associated with cellular protein modification processes and JAK-STAT signaling pathway regulation. Moreover, the risk score was correlated with the immune profile. Cell proliferation assay and flow cytometry further validated the synergistic anti-tumor effects of DSF and BMS1166 on DLBCL cells. CONCLUSION: In summary, we developed a comprehensive prognostic model based on PRGs characteristics, which accurately predicted the prognosis of DLBCL patients. Pyroptosis-targeting coupled with immunotherapies would be a promising therapeutic strategy for DLBCL.

The epidemiological patterns of non-Hodgkin lymphoma: global estimates of disease burden, risk factors, and temporal trends.

Background: The incidence of non-Hodgkin's lymphoma (NHL) has increased steadily over the past few decades. Elucidating its global burden will facilitate more effective disease management and improve patient outcomes. We explored the disease burden, risk factors, and trends in incidence and mortality in NHL globally. Methods: The up-to-date data on age-standardized incidence and mortality rates of NHL were retrieved from the GLOBOCAN 2020, CI5 volumes I-XI, WHO mortality database, and Global Burden of Disease (GBD) 2019, focusing on geographic disparities worldwide. We reported incidence and mortality by sex and age, along with corresponding age-standardized rates (ASRs), the average annual percentage change (AAPC), and future burden estimates to 2040. Results: In 2020, there were an estimated 545,000 new cases and 260,000 deaths of NHL globally. In addition, NHL resulted in 8,650,352 age-standardized DALYs in 2019 worldwide. The age-specific incidence rates varied drastically across world areas, at least 10-fold in both sexes, with the most pronounced increase trend found in Australia and New Zealand. By contrast, North African countries faced a more significant mortality burden (ASR, 3.7 per 100,000) than highly developed countries. In the past decades, the pace of increase in incidence and mortality accelerated, with the highest AAPC of 4.9 (95%CI: 3.6-6.2) and 6.8 (95%CI: 4.3-9.2) in the elderly population, respectively. Considering risk factors, obesity was positively correlated with age-standardized incidence rates (P< 0.001). And North America was the high-risk region for DALYs due to the high body mass index in 2019. Regarding demographic change, NHL incident cases are projected to rise to approximately 778,000 by 2040. Conclusion: In this pooled analysis, we provided evidence for the growing incidence trends in NHL, particularly among women, older adults, obese populations, and HIV-infected people. And the marked increase in the older population is still a public health issue that requires more attention. Future efforts should be directed at cultivating health awareness and formulating effective and locally tailored cancer prevention strategies, especially in most developing countries.

α-KG inhibits tumor growth of diffuse large B-cell lymphoma by inducing ROS and TP53-mediated ferroptosis.

Metabolic reprogramming is a hallmark of human malignancies. Dysregulation of glutamine metabolism is essential for tumorigenesis, microenvironment remodeling, and therapeutic resistance. Based on the untargeted metabolomics sequencing, we identified that the glutamine metabolic pathway was up-regulated in the serum of patients with primary DLBCL. High levels of glutamine were associated with inferior clinical outcomes, indicative of the prognostic value of glutamine in DLBCL. In contrast, the derivate of glutamine alpha-ketoglutarate (α-KG) was negatively correlated with the invasiveness features of DLBCL patients. Further, we found that treatment with the cell-permeable derivative of α-KG, known as DM-αKG, significantly suppressed tumor growth by inducing apoptosis and non-apoptotic cell death. Accumulation of a-KG promoted oxidative stress in double-hit lymphoma (DHL), which depended on malate dehydrogenase 1 (MDH1)-mediated 2-hydroxyglutarate (2-HG) conversion. High levels of reactive oxygen species (ROS) contributed to ferroptosis induction by promoting lipid peroxidation and TP53 activation. In particular, TP53 overexpression derived from oxidative DNA damage, further leading to the activation of ferroptosis-related pathways. Our study demonstrated the importance of glutamine metabolism in DLBCL progression and highlighted the potential application of α-KG as a novel therapeutic strategy for DHL patients.

Derivation and validation of a nutrition-covered prognostic scoring system for extranodal NK/T-cell lymphoma.

Introduction: Patients with aggressive lymphomas are at high risk of losing body resources, resulting in malnutrition, immunodeficiency and inferior outcomes. Nutritional status is closely associated with survival, but often neglected in the prognostic assessment. This study aimed to explore the significance of nutritional status in extranodal NK/T-cell lymphoma (ENKTL). Methods: Univariate and multivariate Cox regression analyses were conducted to examine the significance of nutritional index on overall survival (OS) and progression-free survival (PFS). A nutrition-incorporated score system was constructed based on the multivariate results, and its calibration, discrimination and clinical utility were tested in the training and validation cohort. Results: Multivariate analysis revealed controlling nutritional status (CONUT) score could independently predict OS (HR 10.247, P=0.001) and PFS (HR 5.587, P=0.001) in addition to prognostic index of natural killer lymphoma plus EBV (PINK-E). Herein, a reformative model, CONUT-PINK-E, was developed and further verified in external validation cohort. CONUT-PINK-E classified patients into three risk grades with significant survival differences (P < 0.001). Compared with the current models, CONUT-PINK-E presented superior discrimination, calibration and clinical benefit. Discussion: In this study, we firstly verified that CONUT score was efficient to screen prognosis-related malnutrition in ENKTL. Moreover, we developed the first nutritional assessment-covered scoring system, CONUT-PINK-E, which might be a promising tool to provide references for clinical decision-making of ENKTL patients.

Single-cell transcriptome analysis profiles the expression features of TMEM173 in BM cells of high-risk B-cell acute lymphoblastic leukemia.

BACKGROUND: As an essential regulator of type I interferon (IFN) response, TMEM173 participates in immune regulation and cell death induction. In recent studies, activation of TMEM173 has been regarded as a promising strategy for cancer immunotherapy. However, transcriptomic features of TMEM173 in B-cell acute lymphoblastic leukemia (B-ALL) remain elusive. METHODS: Quantitative real-time PCR (qRT-PCR) and western blotting (WB) were applied to determine the mRNA and protein levels of TMEM173 in peripheral blood mononuclear cells (PBMCs). TMEM173 mutation status was assessed by Sanger sequencing. Single-cell RNA sequencing (scRNA-seq) analysis was performed to explore the expression of TMEM173 in different types of bone marrow (BM) cells. RESULTS: The mRNA and protein levels of TMEM173 were increased in PBMCs from B-ALL patients. Besides, frameshift mutation was presented in TMEM173 sequences of 2 B-ALL patients. ScRNA-seq analysis identified the specific transcriptome profiles of TMEM173 in the BM of high-risk B-ALL patients. Specifically, expression levels of TMEM173 in granulocytes, progenitor cells, mast cells, and plasmacytoid dendritic cells (pDCs) were higher than that in B cells, T cells, natural killer (NK) cells, and dendritic cells (DCs). Subset analysis further revealed that TMEM173 and pyroptosis effector gasdermin D (GSDMD) restrained in precursor-B (pre-B) cells with proliferative features, which expressed nuclear factor kappa-B (NF-κB), CD19, and Bruton's tyrosine kinase (BTK) during the progression of B-ALL. In addition, TMEM173 was associated with the functional activation of NK cells and DCs in B-ALL. CONCLUSIONS: Our findings provide insights into the transcriptomic features of TMEM173 in the BM of high-risk B-ALL patients. Targeted activation of TMEM173 in specific cells might provide new therapeutic strategies for B-ALL patients.

KIAA1429-mediated m6A modification of CHST11 promotes progression of diffuse large B-cell lymphoma by regulating Hippo-YAP pathway.

BACKGROUND: N6-methyladenosine (m6A) has been shown to participate in various essential biological processes by regulating the level of target genes. However, the function of m6A modification mediated by KIAA1429 [alias virus-like m6A methyltransferase-associated protein (VIRMA)] during the progression of diffuse large B-cell lymphoma (DLBCL) remains undefined. METHODS: The expression and clinical significance of KIAA1429 were verified by our clinical data. CRISPR/Cas9 mediated KIAA1429 deletion, and CRISPR/dCas9-VP64 for activating endogenous KIAA1429 was used to evaluate its biological function. RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP) assays, luciferase activity assay, RNA stability experiments, and co-immunoprecipitation were performed to investigate the regulatory mechanism of KIAA1429 in DLBCL. Tumor xenograft models were established for in vivo experiments. RESULTS: Dysregulated expression of m6A regulators was observed, and a novel predictive model based on m6A score was established in DLBCL. Additionally, elevated KIAA1429 expression was associated with poor prognosis of patients with DLBCL. Knockout of KIAA1429 repressed DLBCL cell proliferation, facilitated cell cycle arrest in the G2/M phase, induced apoptosis in vitro, and inhibited tumor growth in vivo. Furthermore, carbohydrate sulfotransferase 11 (CHST11) was identified as a downstream target of KIAA1429, which mediated m6A modification of CHST11 mRNA and then recruited YTHDF2 for reducing CHST11 stability and expression. Inhibition of CHST11 diminished MOB1B expression, resulting in inactivation of Hippo-YAP signaling, reprogramming the expression of Hippo target genes. CONCLUSIONS: Our results revealed a new mechanism by which the Hippo-YAP pathway in DLBCL is inactivated by KIAA1429/YTHDF2-coupled epitranscriptional repression of CHST11, highlighting the potential of KIAA1429 as a novel predictive biomarker and therapeutic target for DLBCL progression.

Prognosis and complications of patients with primary gastrointestinal diffuse large B-cell lymphoma: Development and validation of the systemic inflammation response index-covered score.

BACKGROUND: This study aimed to evaluate the predictive value of systemic inflammation response index (SIRI) in primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) patients and establish a highly discriminating risk prediction model. METHODS: This retrospective analysis included 153 PGI-DCBCL patients diagnosed between 2011 and 2021. These patients were divided into a training set (n = 102) and a validation set (n = 51). Univariate and multivariate Cox regression analyses were conducted to examine the significance of variables on overall survival (OS) and progression-free survival (PFS). An inflammation-covered score system was established according to the multivariate results. RESULTS: The presence of high pretreatment SIRI (≥1.34, p < 0.001) was significantly associated with poorer survival and identified as an independent prognostic factor. Compared with NCCN-IPI, the prognostic and discriminatory capability of the novel model SIRI-PI showed a more precise high-risk assessment with a higher area under the curve (AUC) (0.916 vs 0.835) and C-index (0.912 vs 0.836) for OS in the training cohort, and similar results were obtained in the validation cohort. Moreover, SIRI-PI also showed good discriminative power for efficacy assessment. This new model identified patients at risk of developing severe gastrointestinal complications following chemotherapy. CONCLUSIONS: The results of this analysis suggested that the pretreatment SIRI may be a potential candidate for identifying patients with a poor prognosis. And we established and validated a better-performing clinical model, which facilitated the prognostic stratification of PGI-DLBCL patients and can serve as a reference for clinical decision-making.

PGD2 displays distinct effects in diffuse large B-cell lymphoma depending on different concentrations.

Prostaglandin D2 (PGD2), an arachidonic acid metabolite, has been implicated in allergic responses, parasitic infection and tumor development. The biological functions and molecular mechanisms of PGD2 in diffuse large B-cell lymphoma (DLBCL) are still undefined. In this study, we firstly found the high concentration of serum PGD2 and low expression of PGD2 receptor CRTH2 in DLBCL, which were associated with clinical features and prognosis of DLBCL patients. Interestingly, different concentration of PGD2 displayed divergent effects on DLBCL progression. Low-concentration PGD2 promoted cell growth through binding to CRTH2 while high-concentration PGD2 inhibited it via regulating cell proliferation, apoptosis, cell cycle, and invasion. Besides, high-concentration PGD2 could induce ROS-mediated DNA damage and enhance the cytotoxicity of adriamycin, bendamustine and venetoclax. Furthermore, HDAC inhibitors, vorinostat (SAHA) and panobinostat (LBH589) regulated CRTH2 expression and PGD2 production, and CRTH2 inhibitor AZD1981 and high-concentration PGD2 enhanced their anti-tumor effects in DLBCL. Altogether, our findings demonstrated PGD2 and CRTH2 as novel prognostic biomarkers and therapeutic targets in DLBCL, and highlighted the potency of high-concentration PGD2 as a promising therapeutic strategy for DLBCL patients.

Ferroptosis-related STEAP3 acts as predictor and regulator in diffuse large B cell lymphoma through immune infiltration.

Diffuse large B cell lymphoma (DLBCL) is a usual-seen hematological malignant tumor possessing molecular and genetic heterogeneity. Ferroptosis induction has been increasingly acknowledged to be an advantageous therapeutic method in tumor treatment by triggering cell death of tumor cells. However, studies on the function of ferroptosis in DLBCL remain scarce, especially the interaction with the tumor immune microenvironment (TIME). The clinical and biological functions of ferroptosis-related genes in DLBCL were still warranted to be explored. A ferroptosis-related risk model was constructed, followed by functional enrichment analyses and evaluation of immune profile. Quantitative real-time PCR, western blotting, and immunohistochemistry were conducted to examine the RNA and protein levels. Dysregulated expression of the major ferroptosis-related genes was found in DLBCL. A prognostic risk model based on 10 ferroptosis-related genes was constructed. The risk score served as an independent prognostic indicator for DLBCL patients in univariate and multivariate Cox regression analysis. Patients with low-risk scores presented a more favorable prognosis. Functional enrichment analysis revealed that immune-related pathways were significantly enriched, and the high-risk group exhibited less immunocyte infiltration, lower immunoscore, and downregulated PD-L1 expression relative to the low-risk group. Two molecular subtypes were determined through consensus clustering of the expression of ferroptosis-related genes. Cluster 1 was relevant to favorable prognosis, higher immunoscore, and elevated PD-L1 expression. More importantly, STEAP3 was screened as a reliable biomarker for DLBCL, and its enhanced expression levels of mRNA and protein were verified in public databases and clinical specimens. Our study demonstrated the crucial role of ferroptosis-related genes including STEAP3 in the TIME of DLBCL and identified promising novel molecular targets for DLBCL treatment.