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BackgroundThe mechanistic basis for neurocognitive deficits in central nervous system (CNS) lymphoma and other brain tumors is incompletely understood. We tested the hypothesis that tumor metabolism impairs neurotransmitter pathways and neurocognitive function.MethodsWe performed serial cerebrospinal fluid (CSF) metabolomic analyses using liquid chromatography-electrospray tandem mass spectrometry to evaluate changes in the tumor microenvironment in 14 patients with recurrent CNS lymphoma, focusing on 18 metabolites involved in neurotransmission and bioenergetics. These were paired with serial mini-mental state examination (MMSE) and MRI studies for tumor volumetric analyses. Patients were analyzed in the setting of the phase I trial of lenalidomide/rituximab. Associations were assessed by Pearson and Spearman correlation coefficient. Generalized estimating equation (GEE) models were also established, adjusting for within-subject repeated measures.ResultsOf 18 metabolites, elevated CSF lactate correlated most strongly with lower MMSE score (P < 8E-8, ρ = -0.67). High lactate was associated with lower gamma-aminobutyric acid (GABA), higher glutamate/GABA ratio, and dopamine. Conversely, high succinate correlated with higher MMSE scores. Serial analysis demonstrated a reproducible, time-dependent, reciprocal correlation between changes in lactate and GABA concentrations. While high lactate and low GABA correlated with tumor contrast-enhancing volume, they correlated more significantly with lower MMSE scores than tumor volumes.ConclusionsWe provide evidence that lactate production and Warburg metabolism may impact neurotransmitter dysregulation and neurocognition in CNS lymphomas. We identify novel metabolomic biomarkers that may be applied in future studies of neurocognition in CNS lymphomas. Elucidation of mechanistic interactions between lymphoma metabolism, neurotransmitter imbalance, and neurocognition may promote interventions that preserve cognitive function.

Background: There is a wealth of poorly utilized unstructured data on lymphoma metabolism, and scientometrics and visualization study could serve as a robust tool to address this issue. Hence, it was implemented. Methods: After strict quality control, numerous data regarding the lymphoma metabolism were mined, quantified, cleaned, fused, and visualized from documents (n = 2925) limited from 2013 to 2022 using R packages, VOSviewer, and GraphPad Prism. Results: The linear fitting analysis generated functions predicting the annual publication number (y = 31.685x - 63628, R² = 0.93614, Prediction in 2027: 598) and citation number (y = 1363.7x - 2746019, R² = 0.94956, Prediction in 2027: 18201). In the last decade, the most academically performing author, journal, country, and affiliation were Meignan Michel (n = 35), European Journal of Nuclear Medicine and Molecular Imaging (n = 1653), USA (n = 3114), and University of Pennsylvania (n = 86), respectively. The hierarchical clustering based on unsupervised learning further divided research signatures into five clusters, including the basic study cluster (Cluster 1, Total Link Strength [TLS] = 1670, Total Occurrence [TO] = 832) and clinical study cluster (Cluster 3, TLS = 3496, TO = 1328). The timeline distribution indicated that radiomics and artificial intelligence (Cluster 4, Average Publication Year = 2019.39 ± 0.21) is a relatively new research cluster, and more endeavors deserve. Research signature burst and linear regression analysis further confirmed the findings above and revealed additional important results, such as tumor microenvironment (a = 0.6848, R² = 0.5194, p = 0.019) and immunotherapy (a = 1.036, R² = 0.6687, p = 0.004). More interestingly, by performing a "Walktrap" algorithm, the community map indicated that the "apoptosis, metabolism, chemotherapy" (Centrality = 12, Density = 6), "lymphoma, pet/ct, prognosis" (Centrality = 11, Density = 1), and "genotoxicity, mutagenicity" (Centrality = 9, Density = 4) are crucial but still under-explored, illustrating the potentiality of these research signatures in the field of the lymphoma metabolism. Conclusion: This study comprehensively mines valuable information and offers significant predictions about lymphoma metabolism for its clinical and experimental practice. [ABSTRACT FROM AUTHOR]

Simple Summary: The role of metabolism in normal and malignant B-cell biology is an area of rapid evolution and interest. While previous research has focused on glycolysis, glutaminolysis and oxidative phosphorylation, recent advances have demonstrated the importance of additional metabolic pathways and how these interact with oncogenic drivers and cellular signaling. This article reviews the current understanding of normal germinal center metabolism and how this relates to the metabolism of germinal center-derived lymphomas. There is increasing interest in the potential of targeting metabolic pathways for anti-cancer therapy, with some new agents already entering clinical trials. This article will also review novel enzymatic targets and pathways, and how existing agents modulate metabolism. There have been significant recent advances in the understanding of the role of metabolism in normal and malignant B-cell biology. Previous research has focused on the role of MYC and mammalian target of rapamycin (mTOR) and how these interact with B-cell receptor signaling and hypoxia to regulate glycolysis, glutaminolysis, oxidative phosphorylation (OXPHOS) and related metabolic pathways in germinal centers. Many of the commonest forms of lymphoma arise from germinal center B-cells, reflecting the physiological attenuation of normal DNA damage checkpoints to facilitate somatic hypermutation of the immunoglobulin genes. As a result, these lymphomas can inherit the metabolic state of their cell-of-origin. There is increasing interest in the potential of targeting metabolic pathways for anti-cancer therapy. Some metabolic inhibitors such as methotrexate have been used to treat lymphoma for decades, with several new agents being recently licensed such as inhibitors of phosphoinositide-3-kinase. Several other inhibitors are in development including those blocking mTOR, glutaminase, OXPHOS and monocarboxylate transporters. In addition, recent work has highlighted the importance of the interaction between diet and cancer, with particular focus on dietary modifications that restrict carbohydrates and specific amino acids. This article will review the current state of this field and discuss future developments. [ABSTRACT FROM AUTHOR]

Targeting mitochondrial metabolism represents a promising approach for cancer treatment. Here, we investigated the mitotoxic potential of the polybrominated diphenyl ether bromoxib, a natural compound isolated from the marine sponge Dysidea family. We could show that bromoxib comprised strong cytotoxicity in different leukemia and lymphoma cell lines (such as HL60, HPBALL, Jurkat, K562, KOPTK1, MOLT4, SUPB15 and Ramos), but also in solid tumor cell lines (such as glioblastoma cell lines SJ-GBM2 and TP365MG). Bromoxib activated the mitochondrial death pathway as evidenced by the rapid translocation of Bax to the mitochondria and the subsequent mitochondrial release of Smac. Accordingly, bromoxib-induced apoptosis was blocked in caspase 9 deficient Jurkat cells and Jurkat cells overexpressing the antiapoptotic protein Bcl-2. In addition, we could show that bromoxib functioned as an uncoupler of the electron transport chain with similar rapid kinetics as CCCP in terms of dissipation of the mitochondrial membrane potential (ΔΨm), processing of the dynamin-like GTPase OPA1 and subsequent fragmentation of mitochondria. Beyond that, bromoxib strongly abrogated ATP production via glycolysis as well as oxidative phosphorylation (OXPHOS) by targeting electron transport chain complexes II, III, and V (ATP-synthase) in Ramos lymphoma cells. Thus, bromoxib's potential to act on both cytosolic glycolysis and mitochondrial respiration renders it a promising agent for the treatment of leukemia and lymphoma., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: The metabolic response of primary central nervous system lymphoma (PCNSL) patients has yet to be evaluated. This study aimed to assess the prognostic value of a novel scoring scale, the intracranial metabolic score (IMS), in PCNSL patients receiving end-of-therapy 18 F-FDG PET/CT (EOT-PCT) and PET/MR (EOT-PMR)., Methods: The IMS was determined based on the metabolism of normal intracranial structures, including gray matter, white matter, and cerebrospinal fluid. The EOT-PCT cohort was evaluated using the IMS and commonly used Deauville score (DS). Another cohort of patients who underwent the EOT-PMR was used to validate the accuracy of the IMS., Results: In total, 83 patients were included in the study (38 in PET/CT cohort, and 45 in PET/MR cohort). The area under the curve (AUC) values of the IMS for predicting PFS and OS were superior to those of the DS. When patients in the PET/CT cohort were stratified into five groups (respectively labeled IMS 1-5), three groups (IMS1-2, IMS 3-4, and IMS 5), or two groups (IMS1-3 and IMS4-5; IMS 1-4 and IMS 5), a higher IMS score was significantly correlated with poorer PFS and OS (p < 0.001). Similar results were observed for PFS in the PET/MR cohort (p < 0.001). The IMS and DS scale were found to be independent prognostic indicators for PFS and OS in the PET/CT cohort, and the IMS was identified as the sole independent prognostic indicator for PFS in the PET/MR cohort., Conclusion: The IMS as a novel and effective prognostic tool for PCNSL patients, showing superior predictive value for patients' outcomes compared to the DS when assessed with EOT-PET scans., Competing Interests: Declarations Ethics approval and consent to participate All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This retrospective study was performed with the Ethics Committee approval and a waiver of the requirement for patients’ informed consent. Ethical approval was also obtained from the Ethics Committee of Sun Yat-Sen University Cancer Center. (approval number: SL-B2023-691-01) Consent for publication Additional informed consent was obtained from all legal guardians for whom identifying information is included in this article. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Proteolysis targeting chimeras (PROTAC) are bifunctional chimeric molecules capable of directly degrading binding proteins through the ubiquitin-proteasome pathway. PROTACs have demonstrated significant potential in overcoming drug resistance and targeting previously untreatable targets. However, several limitations still need to be addressed, including their high molecular weight resulting in poor membrane permeability and bioavailability. In this study, we proposed that cancer-targeted penetrating peptides could enhance the cell permeability of PROTACs. We developed 26 novel targeted penetrating peptides for leukemia and lymphoma cells, among which C9C-f(3Bta) and Cyclo-C9C-R exhibited superior membrane permeability, targetability, and stability. By combining C9C-f(3Bta) and Cyclo-C9C-R with IMA-PROTAC, we effectively enhanced the anti-proliferative activity of IMA-PROTAC, facilitated degradation of Bcr-Abl protein in K562 cells, and reduced downstream STAT5 phosphorylation. Furthermore, the combined application promoted cell apoptosis while blocking G1 phase progression. HPLC-MRM-MS revealed that the combination of C9C-f(3Bta) or Cyclo-C9C-R with IMA-PROTAC significantly enhanced intracellular IMA-PROTAC content. In summary, our proof-of-concept study validated the hypothesis that combining PROTACs with targeted penetrating peptides can improve protein degradation efficiency as well as anti-proliferative capabilities., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a tumour target currently used for the development of novel therapeutic modalities, such as antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and others. Success of these new drugs depends on the selection of relevant indications based on ROR1 tumour prevalence, staining heterogeneity, and subcellular localization, among other parameters. We investigated ROR1 immunophenotype using validated antibody clones for immunohistochemistry (IHC) and flow cytometry (FC), analyzing 292 tumour specimens from 7 haematological malignancies and triple negative breast cancer (TNBC) as a reference solid tumour indication. ROR1 prevalence varied significantly across distinct tumour types, showing 100% of ROR1 positivity in all chronic lymphocytic leukaemia (n = 48) and hairy cell leukaemia (n = 14) specimens analyzed via FC with ranges between 1.1-99.8% and 0.8-62.1%, respectively. Samples analysed via IHC showed ROR1 membrane/cytoplasmic positivity in 44% of mantle cell lymphoma tumour samples (n = 27; H-score range: 10-285 in positive cases); 30% in TNBC (n = 46; H-score range: 1-200); 15% in diffuse large B-cell lymphoma (n = 45; H-score: 40-250); and 11% in follicular lymphoma (n = 34; H-score: 2-300). Finally, all acute myeloid leukaemia (n = 52) and most T-cell non-Hodgkin lymphoma (n = 31/32) tested samples were negative for ROR1 via IHC. In conclusion, ROR1 shows a heterogeneous tumour cell expression profile across multiple leukaemias and lymphomas, making it a tumour target that would require different patient selection strategies to develop novel therapeutic modalities., Competing Interests: This work was funded by Boehringer-Ingelheim GmbH, the employer of Manuel A. Silva, Lorenz Waldmeier and Yarúa Jaimes. Shuntae Williams, Sylvie Hauert, and Hytham Al-Masri are employed by Hematogenix. Benjamin Ovadia and Indu Gupta are employed by NeoGenomics. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Silva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Marek's disease (MD), an immunosuppressive disease induced by the Marek's disease virus (MDV), is regarded as an ideal model for lymphoma research to elucidate oncogenic and anti-oncogene genes. Using this model, we found that circRUNX2.2, derived from exon 6 of RUNX2, was significantly upregulated in MDV-infected tumorous spleens. In this study, we deeply analyzed the potential role of circRUNX2.2 in lymphoma cells. An open reading frame (ORF) in circRUNX2.2 with no stop codon was predicted, and small peptides (named circRUNX2.2-rt) presenting multiple ladder-like bands with different molecular weights encoded by circRUNX2.2 were detected via Western blotting assay. The polysome fraction assay reconfirmed the translation ability of circRUNX2.2, which could be detected in polysome fractions. Subsequent analysis verified that it translated in a rolling circle manner, rather than being assisted by the internal ribosome entry site (IRES) or m6A-mediated mechanism. Furthermore, we found that circRUNX2.2-rt was potently induced in MSB1 cells treated with sodium butyrate (NaB), which reactivated MDV and forced the MDV transition from the latent to reactivation phase. During this phase, MDV particles were clearly observed by electron microscopy, and the viral gene pp38 was also significantly upregulated. A biological function study showed that circRUNX2.2-rt promoted cell proliferation and cell cycle transition from the S to G2 phase and inhibited the apoptosis of MSB1. Further immunoprecipitation and mass spectrometry assays showed that 168 proteins potentially interacting with circRUNX2.2-rt were involved in multiple pathways related to cell cycle regulation, which proved that circRUNX2.2-rt could bind or recruit proteins to mediate the cell cycle.

Boesenbergia rotunda, commonly known as fingerroot, is a medicinal and culinary plant native to the Indochina Peninsula. We found that panduratin A (Pan-A), one of the compounds present in the rhizome extract of fingerroot, inhibited cell proliferation, induced apoptosis, and promoted cell cycle arrest at G0/G1 phase in multiple hematologic malignant cell lines including leukemia and lymphoma lines. Pan-A inhibited these activities in leukemia and lymphoma cells in a concentration-dependent manner. High-throughput transcriptome analysis indicated that Pan-A is involved in the cell cycle, cellular senescence, apoptosis, and multiple canonical signaling pathways in lymphoma cells. The Forkhead box O (FOXO) transcription factor family was identified as a potential target of Pan-A. Western blot showed elevated caspase 7 and cPARP/PARP in the B-cell lymphoma cells after treatment with Pan-A. The inhibitory effects were accompanied by stimulation of Akt signaling and phosphorylation of FOXO3. Immunohistochemistry of tissues from patients with B-cell lymphoma revealed detectable levels of FOXO3 protein specifically in neoplastic B cells. Overall, our results highlight FOXO3 as a player underlying antileukemia/lymphoma effects of Pan-A., (© 2024. The Author(s).)

Background: Accurate lymphoma classification is critical for effective treatment and immunohistochemistry is a cost-effective and time-saving approach. Although several machine learning algorithms showed effective results, they focused on a specific task of classification but not the whole classification workflow, thus impractical to be applied in clinical settings. Thus, we aim to develop an effective and economic machine learning-assisted system that can streamline the lymphoma differential diagnostic workflow using EBER in situ hybridization and immunohistochemical markers., Methods: We included pathological reports diagnosed as lymphomas from two cancer centers (Sun Yat-sen University Cancer Center and Peking University Cancer Hospital & Institute). We proposed a hierarchical approach that mimicked the human diagnostic process and employed simplified panels of markers to perform a series of interpretable classification. The diagnostic accuracy for lymphoma pathological subtypes and the markers saving ratio were investigated in both temporal independent population and external medical center., Results: A total of 14,927 patients and corresponding immunohistochemical results from two cancer centers were included. The proposed system had high discriminative ability for differentiating lymphoma pathological subtypes (measured by mean AUC in three validation cohorts, non-Hodgkin and Hodgkin lymphoma: 0.959; non-Hodgkin subtypes: 0.983; B-lymphoma subtypes: 0.868; T-lymphoma subtypes: 0.962; DLBCL subtypes: 0.957). In addition, the system's well selected characteristics can contribute to the development of agreement on panels of markers for differential diagnosis and help minimize cost of immunohistochemical marker techniques (measured by marker saving ratio compared to real clinical settings, internal primary-stage cohort: 16.45% saved, p < 0.001; internal later-stage cohort: 21.73% saved, p < 0.001; external cohort: 3.67% saved, p < 0.001)., Conclusions: Machine learning-based hierarchical system using EBER in situ hybridization and IHC markers was developed, which could streamline the workflow by sequentially determining each lymphoma pathological subtype. The proposed system proved to be effective and cost-saving in independent and external validation, thus could be adopted affordably in future clinical practice., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Antibody-drug conjugates (ADC) represent one of the most successful therapeutic approaches introduced into clinical practice in the last few years. Loncastuximab tesirine (ADCT-402) is a CD19-targeting ADC in which the antibody is conjugated through a protease cleavable dipeptide linker to a pyrrolobenzodiazepine dimer warhead (SG3199). Based on the results of a phase II study, loncastuximab tesirine was recently approved for adult patients with relapsed/refractory large B-cell lymphoma. We assessed the activity of loncastuximab tesirine using in vitro and in vivo models of lymphomas, correlated its activity with levels of CD19 expression, and identified combination partners providing synergy with the ADC. Loncastuximab tesirine was tested across 60 lymphoma cell lines. It had strong cytotoxic activity in B-cell lymphoma cell lines. The in vitro activity was correlated with the level of CD19 expression and intrinsic sensitivity of cell lines to the ADC's warhead. Loncastuximab tesirine was more potent than other anti-CD19 ADC (coltuximab ravtansine, huB4-DGN462), although the pattern of activity across cell lines was correlated. The activity of loncastuximab tesirine was also largely correlated with cell line sensitivity to R-CHOP. Combinatorial in vitro and in vivo experiments identified the benefit of adding loncastuximab tesirine to other agents, especially BCL2 and PI3K inhibitors. Our data support the further development of loncastuximab tesirine for use as a single agent and in combination for patients affected by mature B-cell neoplasms. The results also highlight the importance of CD19 expression and the existence of lymphoma populations characterized by resistance to multiple therapies.

Despite selective HDAC3 inhibition showing promise in a subset of lymphomas with CREBBP mutations, wild-type tumors generally exhibit resistance. Here, using unbiased genome-wide CRISPR screening, we identify GNAS knockout (KO) as a sensitizer of resistant lymphoma cells to HDAC3 inhibition. Mechanistically, GNAS KO-induced sensitization is independent of the canonical G-protein activities but unexpectedly mediated by viral mimicry-related interferon (IFN) responses, characterized by TBK1 and IRF3 activation, double-stranded RNA formation, and transposable element (TE) expression. GNAS KO additionally synergizes with HDAC3 inhibition to enhance CD8 + T cell-induced cytotoxicity. Moreover, we observe in human lymphoma patients that low GNAS expression is associated with high baseline TE expression and upregulated IFN signaling and shares common disrupted biological activities with GNAS KO in histone modification, mRNA processing, and transcriptional regulation. Collectively, our findings establish an unprecedented link between HDAC3 inhibition and viral mimicry in lymphoma. We suggest low GNAS expression as a potential biomarker that reflects viral mimicry priming for enhanced response to HDAC3 inhibition in the clinical treatment of lymphoma, especially the CREBBP wild-type cases., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

This mini-review addresses lipoxygenases and receptors for leukotrienes in hematological malignancies. Potential novel biomarkers and drug targets in leukemia and B-cell lymphoma are discussed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The interaction between cancer cells and stromal cells contributes to the pathogenesis of various types of tumors in the tumor microenvironment (TME). Macrophages (Mφs), a type of stromal cell, are transformed into tumor-associated Mφs (TAMs) after integrating within solid tumors. TAMs are known to interact with cancer cells and induce tumor progression. Thus, the cancer cells construct an organ-specific TME, which is advantageous for the survival of cancer cells in the TME. The density of stromal cells is known to be involved in the prognosis of patients with lymphomas. A higher density of stromal cells increases the interaction between lymphoma cells and stromal cells, promoting lymphoma progression. This review focuses on stromal cells in lymphoid tissues, such as TAMs, fibroblastic reticular cells (FRCs), and follicular dendritic cells (FDCs). This review also focuses on the signal transduction caused by stromal cells and tumor cells via factors such as cytokines. IL-10 and other cytokines secreted by TAMs activate the JAK/STAT pathway in lymphoma cells of follicular lymphoma, classic Hodgkin lymphoma, and diffuse large B-cell lymphoma. FRCs play roles in tumor promotion in follicular lymphoma and diffuse large B-cell lymphoma. Cytokines/chemokines secreted by FDCs play essential roles in lymphoma cell survival, proliferation, invasion, and migration in follicular lymphoma. In conclusion, TAMs, FRCs, and FDCs play crucial roles in the TME of lymphomas. Furthermore, histological spatial analysis revealing the positional relationship of each cell could highlight lymphoma-stromal interactions.

Chimeric antigen receptor-modified T cell (CAR-T) immunotherapy has revolutionised blood cancer treatment. Parsing the genetic underpinnings of T cell quality and CAR-T efficacy is challenging. Transcriptomics inform CAR-T state, but the nature of dynamic transcription during activation hinders identification of transiently or minimally expressed genes, such as transcription factors, and over-emphasises effector and metabolism genes. Here we explore whether analyses of transcriptionally repressive and permissive histone methylation marks describe CAR-T cell functional states and therapeutic potential beyond transcriptomic analyses. Histone mark analyses improve identification of differences between naïve, central memory, and effector memory CD8 + T cell subsets of human origin, and CAR-T derived from these subsets. We find important differences between CAR-T manufactured from central memory cells of healthy donors and of patients. By examining CAR-T products from a clinical trial in lymphoma (NCT01865617), we find a novel association between the activity of the transcription factor KLF7 with in vivo CAR-T accumulation in patients and demonstrate that over-expression of KLF7 increases in vitro CAR-T proliferation and IL-2 production.  In conclusion, histone marks provide a rich dataset for identification of functionally relevant genes not apparent by transcriptomics., (© 2024. The Author(s).)

Background: Double-hit lymphoma (DHL) with c-MYC gene translocation is highly aggressive and has a poor prognosis. In DHL cells, activation-induced cytidine deaminase (AID) promotes antibody class switch recombination (CSR), ultimately leading to c-MYC gene translocation caused by Myc/IgH DNA double-strand breaks. However, currently there is still no method to suppress the expression of AID., Methods: In this study, we compared the clinical significance of AID expression in DHL, Additionally, two human double-hit lymphoma cell lines were used to analyze the effect of imatinib mesylate on c-MYC in vitro, and the therapeutic effect was also evaluated in xenograft mouse models., Results: Imatinib mesylate downregulated the AID and c-MYC proteins in patients with chronic myelogenous leukemia associated with DHL. In addition, imatinib mesylate reduced AID and c-MYC expression in SU-DHL-4 and OCI-Ly18 DHL cells. Imatinib mesylate exerted significant inhibitory effects on the proliferation and metastasis of SU-DHL-4 and OCI-Ly18 cells. Finally, imatinib mesylate reduced not only tumor burden in DHL mouse models, but also AID and c-MYC expression in vivo., Conclusion: These findings reveal that imatinib mesylate effectively reduces the carcinogenic function of c-MYC in DHL, providing novel strategies for developing therapies targeting c-MYC-driven DHL., (© 2024. The Author(s).)

Recent advances in high-resolution mapping of spatial interactions among regulatory elements support the existence of complex topological assemblies of enhancers and promoters known as enhancer-promoter hubs or cliques. Yet, organization principles of these multi-interacting enhancer-promoter hubs and their potential role in regulating gene expression in cancer remain unclear. Here, we systematically identify enhancer-promoter hubs in breast cancer, lymphoma, and leukemia. We find that highly interacting enhancer-promoter hubs form at key oncogenes and lineage-associated transcription factors potentially promoting oncogenesis of these diverse cancer types. Genomic and optical mapping of interactions among enhancer and promoter elements further show that topological alterations in hubs coincide with transcriptional changes underlying acquired resistance to targeted therapy in T cell leukemia and B cell lymphoma. Together, our findings suggest that enhancer-promoter hubs are dynamic and heterogeneous topological assemblies with the potential to control gene expression circuits promoting oncogenesis and drug resistance., (© 2024. The Author(s).)

Total metabolic tumor volume (TMTV) is prognostic in lymphoma. However, cutoff values for risk stratification vary markedly, according to the tumor delineation method used. We aimed to create a standardized TMTV benchmark dataset allowing TMTV to be tested and applied as a reproducible biomarker. Methods: Sixty baseline 18 F-FDG PET/CT scans were identified with a range of disease distributions (20 follicular, 20 Hodgkin, and 20 diffuse large B-cell lymphoma). TMTV was measured by 12 nuclear medicine experts, each analyzing 20 cases split across subtypes, with each case processed by 3-4 readers. LIFEx or ACCURATE software was chosen according to reader preference. Analysis was performed stepwise: TMTV1 with automated preselection of lesions using an SUV of at least 4 and a volume of at least 3 cm 3 with single-click removal of physiologic uptake; TMTV2 with additional removal of reactive bone marrow and spleen with single clicks; TMTV3 with manual editing to remove other physiologic uptake, if required; and TMTV4 with optional addition of lesions using mouse clicks with an SUV of at least 4 (no volume threshold). Results: The final TMTV (TMTV4) ranged from 8 to 2,288 cm 3 , showing excellent agreement among all readers in 87% of cases (52/60) with a difference of less than 10% or less than 10 cm 3 In 70% of the cases, TMTV4 equaled TMTV1, requiring no additional reader interaction. Differences in the TMTV4 were exclusively related to reader interpretation of lesion inclusion or physiologic high-uptake region removal, not to the choice of software. For 5 cases, large TMTV differences (>25%) were due to disagreement about inclusion of diffuse splenic uptake. Conclusion: The proposed segmentation method enabled highly reproducible TMTV measurements, with minimal reader interaction in 70% of the patients. The inclusion or exclusion of diffuse splenic uptake requires definition of specific criteria according to lymphoma subtype. The publicly available proposed benchmark allows comparison of study results and could serve as a reference to test improvements using other segmentation approaches., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Since the survival of lymphoma patients who experience disease progression or relapse remains very poor, new therapeutic approaches and effective drugs are urgently needed. Here we show that auranofin (AF), an anti-rheumatoid drug thought to inhibit thioredoxin reductases (TXNRDs) as its mechanism of action, exhibited potent activity against multiple cancer types, especially effective against B cell lymphoma. Surprisingly, a knockdown of TXNRD1 and TXNRD2 did not cause significant cytotoxicity, suggesting that abrogation of TXNRD enzyme per se was insufficient to cause cancer cell death. Further mechanistic study showed that the interaction of AF with TXNRD could convert this antioxidant enzyme to a ROS-generating molecule via disrupting its electron transport, leading to a leak of electrons that interact with molecular oxygen to form superoxide. AF also suppressed energy metabolism by inhibiting both mitochondria complex II and the glycolytic enzyme GAPDH, leading to a significant depletion of ATP and inhibition of cancer growth in vitro and in vivo. Importantly, we found that the AF-mediated ROS stress could induce PD-L1 expression, revealing an unwanted effect of AF in causing immune suppression. We further showed that a combination of AF with anti-PD-1 antibody could enhance the anticancer activity in a syngeneic immune-competent mouse B-cell lymphoma model. Our study suggests that AF could be a potential drug for lymphoma treatment, and its combination with immune checkpoint inhibitors would be a logical strategy to increase the therapeutic activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The aim of this study was to develop and validate radiomics signatures based on MRI for preoperative prediction of Ki-67 proliferative index (PI) expression in primary central nervous system lymphoma (PCNSL)., Methods: A total of 341 patients with PCNSL were retrospectively analyzed, including 286 patients in one center as the training set and 55 patients in another two centers as the external validation set. Radiomics features were extracted and selected from preoperative contrast-enhanced T1-weighted images, fluid attenuation inversion recovery to build radiomics signatures according to the Ki-67 PI. The predictive performances of the radiomics model were evaluated using four classifiers including random forest, K-Nearest Neighbors, Neural Network and Decision Tree. A combined model was built by incorporating radiomics signature, clinical variables and MRI radiological characteristics using multivariate logistic regression analysis, and a nomogram was established to predict the expression of Ki-67 individually. The predictive performances of the models were evaluated using area under receiver operating characteristic curve (AUC) and decision curve analysis (DCA)., Results: Radiomics signatures were independent predictors of the expression level of Ki-67 (OR: 2.523, P < 0.001). RF radiomics models had the highest accuracy (0.934 in the training set and 0.811 in the external validation set) and F1 Score (0.920 in the training set and 0.836 in the external validation set). The clinic-radiologic-radiomics nomogram showed better predictive performance with AUCs of 0.877(95 % CI: 0.837-0.918) in the training set and 0.866(95 % CI: 0.774-0.957) in the external validation set. The calibration curve and DCA demonstrated goodness-of-fit and improved benefits in clinical practice of the nomogram., Conclusions: Nomograms integrating MRI-based radiomics and clinical-radiological characteristics could effectively predict Ki-67 PI in primary PCNSL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Estrogen drives the growth of some cancers, such as breast cancer, via estrogen receptor alpha (ERα). Estrogen also activates ERβ, but whether ERβ is expressed and has a role in different cancers is debated. The use of nonspecific antibodies has contributed to the confusion, and this review delves into ERβ's controversial role in cancer and focuses on tumor expression that can be supported by non-antibody-dependent assays. We discuss its expression at the transcript level and focus on its potential role in lymphoma, granulosa cell tumors, testicular, and adrenal cancers, emphasizing recent findings and the complexities that necessitate further research., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The advent of high-throughput and unbiased proteogenomic screens promises to rapidly advance our understanding of the molecular mechanisms underpinning pathogenesis of lymphoid malignancies. The wealth of data generated from these studies requires methods to rapidly confirm and extend findings into cell line models and primary patient samples. The proximity ligation assay (PLA) is a method that can visualize protein-protein interactions in situ. PLA can capture transient interactions and characterize constituents of stable biomolecular condensates, both of which pose technical difficulties for traditional biochemical and fluorescence imaging techniques., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Response to anticancer agents is often restricted to subsets of patients. Recognition of factors underlying this heterogeneity and identification of biomarkers associated with response to drugs would greatly improve the efficacy of drug treatment. Platforms that can comprehensively map cellular response to compounds in high-throughput provide a unique tool to identify associated biomarkers and provide hypotheses for mechanisms underlying variable response. Such screens can be performed on cell lines and short-term cultures of primary cells to take advantage of the respective models' strength, which include, e.g., the ability to silence genes or introduce somatic mutations to cell lines. Cohorts of patient samples represent the natural diversity of cancers, including rarer mutations and combinatorial patterns of mutations that are often absent from existing cell lines. We here summarize a simple and scalable method for the measurement of viability after drug exposure based on ATP measurements as a surrogate for viability, which we use to measure and understand drug response in cell lines and primary cells., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Cellular fate is regulated by intricate signal transduction mediated by posttranslational protein modifications like phosphorylation to transmit information. As other cancer types, lymphomas frequently show dysregulation of signaling pathways that contribute to malignant transformation and tumor progression. For example, in diffuse large B-cell lymphoma the B-cell antigen receptor was identified as an oncogenic driver mediating cellular growth and survival signals. Thus, the elucidation of these complex signaling networks is crucial to gain insight into the mechanisms underlying tumorigenesis and to identify target proteins for innovative therapeutic approaches.Here, we describe a mass spectrometry-based phosphoproteomic approach for the global analysis of intracellular signaling events and their dynamics. The workflow combines phosphopeptide enrichment and fractionation with liquid chromatography-coupled mass spectrometry for the amino acid site-specific identification and quantification of thousands of phosphorylation events. Such global signaling analyses have great potential for the elucidation of oncogenic pathomechanisms, diagnostic biomarkers, and drug targets., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

In recent years, the incidence and mortality rates of lymphoma have gradually increased worldwide. Tumorigenesis and drug resistance are closely related to intracellular inflammatory pathways in lymphoma. Therefore, understanding the biological role of inflammatory pathways and their abnormal activation in relation to the development of lymphoma and their selective modulation may open new avenues for targeted therapy of lymphoma. The biological functions of inflammatory pathways are extensive, and they are central hubs for regulating inflammatory responses, immune responses, and the tumour immune microenvironment. However, limited studies have investigated the role of inflammatory pathways in lymphoma development. This review summarizes the relationship between abnormal activation of common inflammatory pathways and lymphoma development to identify precise and efficient targeted therapeutic options for patients with advanced, drug-resistant lymphoma.

Purpose: The aim of this study was to evaluate metabolism change in reference organs (liver and mediastinum) and lymphoid cell-rich organs (spleen and bone marrow) during programmed cell death-1 immunotherapy in relapsed or refractory lymphoma patients., Methods: A total of 66 patients with baseline and serial monitoring fluorodeoxyglucose (FDG) PET/computed tomography scans were retrospectively enrolled. Mean standardized uptake value (SUV) and maximum SUV of evaluated organs were obtained by two reviewers, and their association with tumor burden and clinical response were evaluated. Immune-related adverse events detected by FDG PET/computed tomography were also recorded., Results: The SUV values of reference organs and lymphoid cell-rich organs did not change significantly during the immunotherapy process. The intersubject variability of these values ranged from 13.0 to 28.5%. Meanwhile, metabolism of reference organs was affected by neither the tumor burden nor clinical response. SUV change of lymphoid cell-rich organs was associated with clinical response to immunotherapy. Responders showed decreased metabolism, while nonresponders showed a reverse trend (spleen SUV max : -0.30 ± 0.47 vs. 0.18 ± 0.39, P  = 0.001, spleen SUV mean : -0.24 ± 0.39 vs. 0.14 ± 0.31, P  = 0.001; and bone marrow SUV max : -0.14 ± 0.37 vs. 0.07 ± 0.46, P  = 0.042, respectively). The influence of immune-related adverse events on the SUV change in evaluated organs was not significant., Conclusion: During programmed cell death-1 immunotherapy, metabolism change of reference organs is influenced neither by tumor burden nor by clinical response, while FDG uptake change of lymphoid cell-rich organs is significantly associated with clinical response., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Lymphoid tumor patients often exhibit resistance to standard therapies or experience relapse post-remission. Relapse is driven by Tumor Initiating Cells (TICs), a subset of tumor cells capable of regrowing the tumor and highly resistant to therapy. Growing cells in 3D gels is a method to discern tumorigenic cells because it strongly correlates with tumorigenicity. The finding that TICs, rather than differentiated tumor cells, grow in 3D gels offers a unique opportunity to unveil TIC-specific signaling pathways and therapeutic targets common to various cancer types. Here, we show that culturing lymphoid cells in 3D gels triggers reactive oxygen species (ROS) production, leading to non-tumor lymphoid cell death while enabling the survival and proliferation of a subset of lymphoma/leukemia cells, TICs or TIC-like cells. Treatment with the antioxidant N-acetylcysteine inhibits this lethality and promotes the growth of primary non-tumor lymphoid cells in 3D gels. A subset of lymphoma cells, characterized by an increased abundance of the antioxidant glutathione, escape ROS-induced lethality, a response not seen in non-tumor cells. Reducing glutathione production in lymphoma cells, either through pharmacological inhibition of glutamate cysteine ligase (GCL), the enzyme catalyzing the rate-limiting step in glutathione biosynthesis, or via knockdown of GCLC, the GCL catalytic subunit, sharply decreased cell growth in 3D gels and xenografts. Tumor cells from B-cell lymphoma/leukemia patients and λ-MYC mice, a B-cell lymphoma mouse model, overproduce glutathione. Importantly, pharmacological GCL inhibition hindered lymphoma growth in female λ-MYC mice, suggesting that this treatment holds promise as a therapeutic strategy for female lymphoma/leukemia patients., (© 2024. The Author(s).)

Current treatments for lymphoma are plagued by substantial toxicity and the inability to overcome drug resistance, leading to eventual relapse and rationalizing the development of novel, less toxic therapeutics and drug combinations. Histone deacetylase inhibitors (HDACis) are a broad class of epigenetic modulators that have been studied in multiple tumor types, including lymphoma. Currently, HDACis are FDA-approved for treating relapsed T-cell lymphomas and multiple myeloma, with ongoing trials in other lymphomas and solid tumors. As single agents, HDACis frequently elicit toxic side effects and have limited efficacy; therefore, many current treatment strategies focus on combinations to boost efficacy while attempting to minimize toxicity. Fermented wheat germ extract (FWGE) is a complementary agent that has shown efficacy in several malignancies, including lymphoma. Here, we utilize a more potent FWGE derivative, known as fermented wheat germ protein (FWGP), in combination with the HDACi AR42, to assess for enhanced activity. We report increased in vitro killing, cell cycle arrest, and in vivo efficacy for this combination compared to each agent alone with minimal toxicity, suggesting a potentially new, minimally toxic treatment modality for lymphoma.

Ubiquitination and related cellular processes control a variety of aspects in human cell biology, and defects in these processes contribute to multiple illnesses. In recent decades, our knowledge about the pathological role of ubiquitination in lymphoid cancers and therapeutic strategies to target the modified ubiquitination system has evolved tremendously. Here we review the altered signalling mechanisms mediated by the aberrant expression of cancer-associated E2s/E3s and deubiquitinating enzymes (DUBs), which result in the hyperactivation of oncoproteins or the frequently allied downregulation of tumour suppressors. We discuss recent highlights pertaining to the several different therapeutic interventions which are currently being evaluated to effectively block abnormal ubiquitin-proteasome pathway and the use of heterobifunctional molecules which recruit the ubiquitination system to degrade or stabilize non-cognate substrates. This review aids in comprehension of ubiquitination aberrance in lymphoid cancers and current targeting strategies and elicits further investigations to deeply understand the link between cellular ubiquitination and lymphoid pathogenesis as well as to ameliorate corresponding treatment interventions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Pieter Eichhorn reports financial support was provided by Curtin University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The interaction of programmed death-1 (PD-1) on T lymphocytes with its ligands Programmed Death Ligand 1 (PD-L1) and Programmed Death Ligand 2 (PD-L2) on tumor cells and/or tumor-associated macrophages results in inhibitory signals to the T-cell receptor pathway, consequently causing tumor immune escape. PD-L1/PD-L2 are currently used as predictive tissue biomarkers in clinical practice. Virtually PD-L1 levels expressed by tumor cells are associated with a good response to immune checkpoint blockade therapies targeting the PD-1/PD-L1 axis. These therapies restore T-cell antitumor immune response by releasing T-lymphocytes from the inhibitory effects of tumor cells. Immune checkpoint therapies have completely changed the management of patients with solid cancers. This therapeutic strategy is less used in hematological malignancies, although good results have been achieved in some settings, such as refractory/relapsed classic Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Variable results have been obtained in diffuse large B-cell lymphoma and T-cell lymphomas. Immunohistochemistry represents the main technique for assessing PD-L1 expression on tumor cells. This review aims to describe the current knowledge of PD-L1 expression in various types of lymphomas, focusing on the principal mechanisms underlying PD-L1 overexpression, its prognostic significance and practical issues concerning the evaluation of PD-L1 immunohistochemical results in lymphomas.

The therapeutic potential of chemically synthesized AuNPs has been demonstrated in various types of cancer. However, gold nanoparticles (AuNPs) synthesized using typical chemical methods have concerns regarding their environmental safety and adverse impact on human well-being. To overcome this issue, we used an environmentally friendly approach in which gold nanoparticles were synthesized using Moringa oleifera leaf extract (MLE). The present research was mainly focused on the biosynthesis and characterization of gold nanoparticles (AuNPs) using Moringa oleifera leaf extract (MLE-AuNPs) and explore its anticancer potential against Dalton's Lymphoma (DL) cells. Characterization of the MLE-AuNPs was conducted using UV-Vis Spectroscopy to confirm the reduction process, FTIR analysis to ascertain the presence of functional groups, and XRD analysis to confirm the crystallinity. SEM and TEM images were used to examine size and morphology. After characterization, MLE-AuNPs were evaluated for their cytotoxic effects on Dalton's lymphoma cells, and the results showed an IC 50 value of 75 ± 2.31 µg/mL; however, there was no discernible cytotoxicity towards normal murine thymocytes. Furthermore, flow cytometric analysis revealed G2/M phase cell cycle arrest mediated by the downregulation of cyclin B1 and Cdc2 and upregulation of p21. Additionally, apoptosis induction was evidenced by Annexin V Staining, accompanied by modulation of apoptosis-related genes including decreased Bcl-2 expression and increased expression of Bax, Cyt-c, and Caspase-3 at both the mRNA and protein levels. Collectively, our findings underscore the promising anti-cancer properties of MLE-AuNPs, advocating their potential as a novel therapeutic avenue for Dalton's lymphoma., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Nucleoside analogs are a common form of chemotherapy that disrupts DNA replication and repair, leading to cell cycle arrest and apoptosis. Reactive oxygen species (ROS) production is a significant mechanism through which these drugs exert their anticancer effects. This study investigated a new nucleoside analog called FNC or Azvudine, and its impact on ROS production and cell viability in Dalton's lymphoma (DL) cells. The study found that FNC treatment resulted in a time- and dose-dependent increase in ROS levels in DL cells. After 15 and 30 min of treatment with 2 and 1 mg/ml of FNC, mitochondrial ROS production was observed in DL cells. Furthermore, prolonged exposure to FNC caused structural alterations and DNA damage in DL cells. The results suggest that FNC's ability to impair DL cell viability may be due to its induction of ROS production and indicate a need for further investigation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Obg-like ATPase 1 (OLA1) is a binding protein of Breast cancer gene 1 (BRCA1), germline pathogenic variants of which cause hereditary breast cancer. Cancer-associated variants of BRCA1 and OLA1 are deficient in the regulation of centrosome number. Although OLA1 might function as a tumor suppressor, the relevance of OLA1 deficiency to carcinogenesis is unclear. Here, we generated Ola1 knockout mice. Aged female Ola1 +/- mice developed lymphoproliferative diseases, including malignant lymphoma. The lymphoma tissues had low expression of Ola1 and an increase in the number of cells with centrosome amplification. Interestingly, the proportion of cells with centrosome amplification in normal spleen from Ola1 +/- mice was higher in male mice than in female mice. In human cells, estrogen stimulation attenuated centrosome amplification induced by OLA1 knockdown. Previous reports indicate that prominent centrosome amplification causes cell death but does not promote tumorigenesis. Thus, in the current study, the mild centrosome amplification observed under estrogen stimulation in Ola1 +/- female mice is likely more tumorigenic than the prominent centrosome amplification observed in Ola1 +/- male mice. Our findings provide a possible sex-dependent mechanism of the tumor suppressor function of OLA1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Anticancer nucleosides are effective against solid tumors and hematologic malignancies, but typically are prone to nucleoside metabolism resistance mechanisms. Using a nucleoside-specific multiplexed high-throughput screening approach, we discovered 4'-ethynyl-2'-deoxycytidine (EdC) as a third-generation anticancer nucleoside prodrug with preferential activity against diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). EdC requires deoxycytidine kinase (DCK) phosphorylation for its activity and induces replication fork arrest and accumulation of cells in S-phase, indicating it acts as a chain terminator. A 2.1Å cocrystal structure of DCK bound to EdC and UDP reveals how the rigid 4'-alkyne of EdC fits within the active site of DCK. Remarkably, EdC was resistant to cytidine deamination and SAMHD1 metabolism mechanisms and exhibited higher potency against ALL compared with FDA-approved nelarabine. Finally, EdC was highly effective against DLBCL tumors and B-ALL in vivo. These data characterize EdC as a preclinical nucleoside prodrug candidate for DLBCL and ALL., (©2023 American Association for Cancer Research.)

Cancer treatment is greatly challenged by drug resistance, highlighting the need for novel drug discoveries. Here, we investigated novel organoarsenic compounds regarding their resistance-breaking and apoptosis-inducing properties in leukemia and lymphoma. Notably, the compound (2,6-dimethylphenyl)arsonic acid (As2) demonstrated significant inhibition of cell proliferation and induction of apoptosis in leukemia and lymphoma cells while sparing healthy leukocytes. As2 reached half of its maximum activity (AC50) against leukemia cells at around 6.3 µM. Further experiments showed that As2 overcomes multidrug resistance and sensitizes drug-resistant leukemia and lymphoma cell lines to treatments with the common cytostatic drugs vincristine, daunorubicin, and cytarabine at low micromolar concentrations. Mechanistic investigations of As2-mediated apoptosis involving FADD (FAS-associated death domain)-deficient or Smac (second mitochondria-derived activator of caspases)/DIABLO (direct IAP binding protein with low pI)-overexpressing cell lines, western blot analysis of caspase-9 cleavage, and measurements of mitochondrial membrane integrity identified the mitochondrial apoptosis pathway as the main mode of action. Downregulation of XIAP (x-linked inhibitor of apoptosis protein) and apoptosis induction independent of Bcl-2 (B-cell lymphoma 2) and caspase-3 expression levels suggest the activation of additional apoptosis-promoting mechanisms. Due to the selective apoptosis induction, the synergistic effects with common anti-cancer drugs, and the ability to overcome multidrug resistance in vitro, As2 represents a promising candidate for further preclinical investigations with respect to refractory malignancies.

Background: Vitamin D deficiency is prevalent among the Indonesian population, particularly in individuals diagnosed with leukemia-lymphoma. The regulation of vitamin D metabolism is influenced by the expression of several enzymes, such as CYP2R1, CYP24A1, and the vitamin D receptor (VDR). This study aimed to scrutinize the gene expression profiles in both mRNA and protein levels of VDR, CYP2R1, and CYP24A1 in leukemia and lymphoma patients., Method: The research was a cross-sectional study conducted at Cipto Mangunkusumo Hospital (RSCM) in Jakarta, Indonesia. The study included a total of 45 patients aged over 18 years old who have received a diagnosis of lymphoma or leukemia. Vitamin D status was measured by examining serum 25 (OH) D levels. The analysis of VDR, CYP2R1, and CYP24A1 mRNA expression utilized the qRT-PCR method, while protein levels were measured through the ELISA method., Conclusion: The study revealed a noteworthy difference in VDR protein levels between men and women. The highest mean CYP24A1 protein levels were observed in the age group > 60 years. This study found a significant, moderately positive correlation between VDR protein levels and CYP24A1 protein levels in the male and vitamin D sufficiency groups. In addition, a significant positive correlation was found between VDR mRNA levels and CYP2R1 mRNA levels, VDR mRNA levels and CYP2R1 mRNA levels, and CYP2R1 mRNA levels and CYP24A1 mRNA levels. However, the expression of these genes does not correlate with the protein levels of its mRNA translation products in blood circulation., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Natural killer (NK) cell immunotherapy has gained attention as a promising strategy for treatment of various malignancies. In this study, we used a genome-wide CRISPR screen to identify genes that provide protection or susceptibility to NK cell cytotoxicity. The screen confirmed the role of several genes in NK cell regulation, such as genes involved in interferon-γ signaling and antigen presentation, as well as genes encoding the NK cell receptor ligands B7-H6 and CD58. Notably, the gene TMEM30A , encoding CDC50A-beta-subunit of the flippase shuttling phospholipids in the plasma membrane, emerged as crucial for NK cell killing. Accordingly, a broad range of TMEM30A knock-out (KO) leukemia and lymphoma cells displayed increased surface levels of phosphatidylserine (PtdSer). TMEM30A KO cells triggered less NK cell degranulation, cytokine production and displayed lower susceptibility to NK cell cytotoxicity. Blockade of PtdSer or the inhibitory receptor TIM-3, restored the NK cell ability to eliminate TMEM30A -mutated cells. The key role of the TIM-3 - PtdSer interaction for NK cell regulation was further substantiated by disruption of the receptor gene in primary NK cells, which significantly reduced the impact of elevated PtdSer in TMEM30A KO leukemic cells. Our study underscores the potential significance of agents targeting the interaction between PtdSer and TIM-3 in the realm of cancer immunotherapy., Competing Interests: Competing interests statement:The authors declare no competing interest.

Membrane nanotubes (NTs) are dynamic communication channels connecting spatially separated cells even over long distances and promoting the transport of different cellular cargos. NTs are also involved in the intercellular spread of different pathogens and the deterioration of some neurological disorders. Transport processes via NTs may be controlled by cytoskeletal elements. NTs are frequently observed membrane projections in numerous mammalian cell lines, including various immune cells, but their functional significance in the 'antibody factory' B cells is poorly elucidated. Here, we report that as active channels, NTs of B-lymphoma cells can mediate bidirectional mitochondrial transport, promoted by the cooperation of two different cytoskeletal motor proteins, kinesin along microtubules and myosin VI along actin, and bidirectional transport processes are also supported by the heterogeneous arrangement of the main cytoskeletal filament systems of the NTs. We revealed that despite NTs and axons being different cell extensions, the mitochondrial transport they mediate may exhibit significant similarities. Furthermore, we found that microtubules may improve the stability and lifespan of B-lymphoma-cell NTs, while F-actin strengthens NTs by providing a structural framework for them. Our results may contribute to a better understanding of the regulation of the major cells of humoral immune response to infections.

Purpose: The International Extranodal Lymphoma Study Group (IELSG) score is widely used in clinical practice to stratify the risk of primary central nervous system lymphoma (PCNSL) patients. Our study aims to confirm and improve the IELSG score in PCNSL patients based on Chinese populations., Materials and Methods: A total of 79 PCNSL patients were retrospectively analyzed. All patients treated with high-dose methotrexate (HD-MTX)-based therapy collected clinical data. The receiver-operating characteristic (ROC) curve was used to determine the optimal cut-off values for the factors in IELSG score. Progression of disease (POD) at the most landmark time point was determine by Epanechnikov kernel and the area under the ROC curve (AUROC). Kaplan-Meier and multivariable regression methods were used to analyze survival data. Nomogram was generated for calculating the weight of each selected factor., Results: The traditional IELSG score had no significant difference on OS and PFS except ECOG ≥ 2 and could not stratify the risk groups in PCNSL. The improved IELSG scoring system was established, which incorporated age ≥ 54 years, ECOG ≥ 2, deep brain structure, elevated CSF protein, and LDH/ULN > 0.75. On the other hand, POD18 was identified as a new powerful prognostic factor for PCNSL. In multivariate analysis, POD18 and the improved IELSG scoring system were independent prognostic factors for OS. Nomogram including the two significant variables showed the best performance (C-index = 0.828)., Conclusions: In this study, the IELSG score was improved and a new prognostic indicator POD18 was incorporated to construct a nomogram prognostic model, thereby further improving the predictive ability of the model., (© 2023. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

Abstract: CD19 chimeric antigen receptor (CAR) T cells and CD20 targeting T-cell-engaging bispecific antibodies (bispecs) have been approved in B-cell non-Hodgkin lymphoma lately, heralding a new clinical setting in which patients are treated with both approaches, sequentially. The aim of our study was to investigate the selective pressure of CD19- and CD20-directed therapy on the clonal architecture in lymphoma. Using a broad analytical pipeline on 28 longitudinally collected specimen from 7 patients, we identified truncating mutations in the gene encoding CD20 conferring antigen loss in 80% of patients relapsing from CD20 bispecs. Pronounced T-cell exhaustion was identified in cases with progressive disease and retained CD20 expression. We also confirmed CD19 loss after CAR T-cell therapy and reported the case of sequential CD19 and CD20 loss. We observed branching evolution with re-emergence of CD20+ subclones at later time points and spatial heterogeneity for CD20 expression in response to targeted therapy. Our results highlight immunotherapy as not only an evolutionary bottleneck selecting for antigen loss variants but also complex evolutionary pathways underlying disease progression from these novel therapies., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: It remains challenging to obtain positive outcomes with chimeric antigen receptor (CAR)-engineered cell therapies in solid malignancies, like colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC). A major obstacle is the lack of targetable surface antigens that are not shared by healthy tissues. CD70 emerges as interesting target, due to its stringent expression pattern in healthy tissue and its apparent role in tumor progression in a considerable amount of malignancies. Moreover, CD70 is also expressed on cancer-associated fibroblasts (CAFs), another roadblock for treatment efficacy in CRC and PDAC. We explored the therapeutic potential of CD70 as target for CAR natural killer (NK) cell therapy in CRC, PDAC, focusing on tumor cells and CAFs, and lymphoma., Methods: RNA-seq data and immunohistochemical analysis of patient samples were used to explore CD70 expression in CRC and PDAC patients. In addition, CD70-targeting CAR NK cells were developed to assess cytotoxic activity against CD70 + tumor cells and CAFs, and the effect of cytokine stimulation on their efficacy was evaluated. The in vitro functionality of CD70-CAR NK cells was investigated against a panel of tumor and CAF cell lines with varying CD70 expression. Lymphoma-bearing mice were used to validate in vivo potency of CD70-CAR NK cells. Lastly, to consider patient variability, CD70-CAR NK cells were tested on patient-derived organoids containing CAFs., Results: In this study, we identified CD70 as a target for tumor cells and CAFs in CRC and PDAC patients. Functional evaluation of CD70-directed CAR NK cells indicated that IL-15 stimulation is essential to obtain effective elimination of CD70 + tumor cells and CAFs, and to improve tumor burden and survival of mice bearing CD70 + tumors. Mechanistically, IL-15 stimulation resulted in improved potency of CD70-CAR NK cells by upregulating CAR expression and increasing secretion of pro-inflammatory cytokines, in a mainly autocrine or intracellular manner., Conclusions: We disclose CD70 as an attractive target both in hematological and solid tumors. IL-15 armored CAR NK cells act as potent effectors to eliminate these CD70 + cells. They can target both tumor cells and CAFs in patients with CRC and PDAC, and potentially other desmoplastic solid tumors., (© 2024. The Author(s).)

Background: Angioimmunoblastic T-cell lymphoma (AITL) is a malignancy with very poor survival outcome, in urgent need of more specific therapeutic strategies. The drivers of malignancy in this disease are CD4 + follicular helper T cells (Tfh). The metabolism of these malignant Tfh cells was not yet elucidated. Therefore, we decided to identify their metabolic requirements with the objective to propose a novel therapeutic option., Methods: To reveal the prominent metabolic pathways used by the AITL lymphoma cells, we relied on metabolomic and proteomic analysis of murine AITL (mAITL) T cells isolated from our established mAITL model. We confirmed these results using AITL patient and healthy T cell expression data., Results: Strikingly, the mAITL Tfh cells were highly dependent on the second branch of the Kennedy pathway, the choline lipid pathway, responsible for the production of the major membrane constituent phosphatidylcholine. Moreover, gene expression data from Tfh cells isolated from AITL patient tumors, confirmed the upregulation of the choline lipid pathway. Several enzymes involved in this pathway such as choline kinase, catalyzing the first step in the phosphatidylcholine pathway, are upregulated in multiple tumors other than AITL. Here we showed that treatment of our mAITL preclinical mouse model with a fatty acid oxydation inhibitor, significantly increased their survival and even reverted the exhausted CD8 T cells in the tumor into potent cytotoxic anti-tumor cells. Specific inhibition of Chokα confirmed the importance of the phosphatidylcholine production pathway in neoplastic CD4 + T cells, nearly eradicating mAITL Tfh cells from the tumors. Finally, the same inhibitor induced in human AITL lymphoma biopsies cell death of the majority of the hAITL PD-1 high neoplastic cells., Conclusion: Our results suggest that interfering with choline metabolism in AITL reveals a specific metabolic vulnerability and might represent a new therapeutic strategy for these patients., (© 2024. The Author(s).)

Introduction: Non-Hodgkin Lymphoma (NHL) is a heterogeneous lymphoproliferative malignancy with B cell origin. Combinatorial treatment of rituximab, cyclophsphamide, hydroxydaunorubicin, oncovin, prednisone (R-CHOP) is the standard treatment regimen for NHL, yielding a complete remission (CR) rate of 40-50%. Unfortunately, considerable patients undergo relapse after CR or initial treatment, resulting in poor clinical implications. Patient's response to chemotherapy varies widely from static disease to cancer recurrence and later is primarily associated with the development of multi-drug resistance (MDR). The immunosuppressive cells within the tumor microenvironment (TME) have become a crucial target for improving the therapy efficacy. However, a better understanding of their involvement is needed for distinctive response of NHL patients after receiving chemotherapy to design more effective front-line treatment algorithms based on reliable predictive biomarkers., Methods: Peripheral blood from 61 CD20 + NHL patients before and after chemotherapy was utilized for immunophenotyping by flow-cytometry at different phases of treatment. In-vivo and in-vitro doxorubicin (Dox) resistance models were developed with murine Dalton's lymphoma and Jurkat/Raji cell-lines respectively and impact of responsible immune cells on generation of drug resistance was studied by RT-PCR, flow-cytometry and colorimetric assays. Gene silencing, ChIP and western blot were performed to explore the involved signaling pathways., Results: We observed a strong positive correlation between elevated level of CD33 + CD11b + CD14 + CD15 - monocytic MDSCs (M-MDSC) and MDR in NHL relapse cohorts. We executed the role of M-MDSCs in fostering drug resistance phenomenon in doxorubicin-resistant cancer cells in both in-vitro, in-vivo models. Moreover, in-vitro supplementation of MDSCs in murine and human lymphoma culture augments early expression of MDR phenotypes than culture without MDSCs, correlated well with in-vitro drug efflux and tumor progression. We found that MDSC secreted cytokines IL-6, IL-10, IL-1β are the dominant factors elevating MDR expression in cancer cells, neutralization of MDSC secreted IL-6, IL-10, IL-1β reversed the MDR trait. Moreover, we identified MDSC secreted IL-6/IL-10/IL-1β induced STAT1/STAT3/NF-κβ signaling axis as a targeted cascade to promote early drug resistance in cancer cells., Conclusion: Our data suggests that screening patients for high titre of M-MDSCs might be considered as a new potential biomarker and treatment modality in overcoming chemo-resistance in NHL patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dhar, Chakravarti, Ganguly, Saha, Dasgupta, Bera, Sarkar, Roy, Das, Bhuniya, Ghosh, Sarkar, Hajra, Banerjee, Pal, Saha, Mukherjee, Baral and Bose.)

Background: The burden of malignant lymphoma in China is greater than the global equivalent. The randomized controlled trials provide medical evidence that TCM can improve the response and survival in patients with lymphoma. However, the mechanisms underlying remain undefined., Objective: Evidence-based data mining for traditional Chinese medicine (TCM) on improving response and survival in malignant lymphoma treatment was performed in this study. In addition, the mechanisms of TCM through network pharmacology and molecular docking were explored., Methods: The China national knowledge infrastructure, Wanfang Data, China Science and Technology Journal Database, PubMed, and Web of Science databases were searched to select TCM formulas with response and survival benefits in the treatment of malignant lymphomas. We then analyzed and visualized the tropism of taste, frequency of drug use, dosage, clustering, association rules mining (minimum support threshold as 0.20, the minimum confidence threshold as 0.80 and lift >1), and complex networks for potential core herb compositions using Excel, IBM SPSS Statistics 26, and IBM SPSS Modeler 18. TCM systems pharmacology, GeneCards, Online Mendelian Inheritance in Man, and other databases were used to screen potential core active ingredients and malignant lymphoma-related targets. The intersection targets were used to construct a protein interaction network using Cytoscape to obtain the key targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were used to analyze the core target, and molecular docking of key components and targets was performed using CB-Dock2., Results: Twenty-four Chinese herbal formulae were included, encompassing 107 herbs with mainly cold and warm properties and bitter and sweet flavors. They were associated with the yin meridians of the liver, spleen, and lungs. The TCMs underwent association rule analysis, identified 27 association rules, including 12 herb pairs and 13 angle medicine, and clustered into eight classes by clustering analysis. Combined with the results from mining analysis, Pinelliae (Ban-xia), Poria (Fu-ling), Atractylodis macrocephalae (Bai-zhu), Curcumae (E-zhu), and Sparganii (San-leng) were the potential core herbs According to network pharmacology and molecular docking, the main core components of the potential core drugs are hederagenin, cerevisterol, 14- acetyl-12-senecioyl-2E,8E,10E-atractylentriol, 12,13-epoxy-9-hydroxynonadeca-7,10-dienoic acid, cavidine, and baicalein. These core drugs are mainly involved in the pathways of EGFR tyrosine kinase inhibitor resistance, PD-1/L1, natural killer cell-mediated cytotoxicity, NF-κB, epithelial cell signaling in H. pylori infections, and Th17 cell differentiation. They aid in regulating the transmembrane receptor protein tyrosine kinase signaling pathway, ERBB signaling pathway, PI3K signaling pathway, and phosphorylation process. Ten key components and eight key targets, including baicalein and hederagenin, demonstrated strong binding activity., Conclusion: Collectively, some core herbs exerted anti-tumor effects through immune and inflammatory pathway modulation, inhibition of immune escape, and induction of cell apoptosis. These findings support future evidence-based research on malignant lymphoma treatment using TCM., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

ETS proto-oncogene 1 (ETS1) is a transcription factor (TF) critically involved in lymphoid cell development and function. ETS1 expression is tightly regulated throughout differentiation and activation in T-cells, natural killer (NK) cells, and B-cells. It has also been described as an oncogene in a range of solid and hematologic cancer types. Among hematologic malignancies, its role has been best studied in T-cell acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia/lymphoma (ATLL), and diffuse large B-cell lymphoma (DLBCL). Aberrant expression of ETS1 in these malignancies is driven primarily by chromosomal amplification and enhancer-driven transcriptional regulation, promoting the ETS1 transcriptional program. ETS1 also facilitates aberrantly expressed or activated transcriptional complexes to drive oncogenic pathways. Collectively, ETS1 functions to regulate cell growth, differentiation, signaling, response to stimuli, and viral interactions in these malignancies. A tumor suppressor role has also been indicated for ETS1 in select lymphoma types, emphasizing the importance of cellular context in ETS1 function. Research is ongoing to further characterize the clinical implications of ETS1 dysregulation in hematologic malignancies, to further resolve binding complexes and transcriptional targets, and to identify effective therapeutic targeting approaches., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Lymphoma, a blood tumor, has become the ninth most common cancer in the world in 2020. Targeted inhibition is one of the important treatments for lymphoma. At present, there are many kinds of targeted drugs for the treatment of lymphoma. Studies have shown that Histone deacetylase, Bruton's tyrosine kinase and phosphoinositide 3-kinase all play an important role in the occurrence and development of tumors and become important and promising inhibitory targets. This article mainly expounds the important role of these target protein in tumors, and introduces the mechanism of action, structure-activity relationship and clinical research of listed small molecule inhibitors of these targets, hoping to provide new ideas for the treatment of lymphoma.

Purpose of Review: Largely, treatment advances in relapsed and/or refractory acute lymphoblastic leukemia (ALL) have been made in B cell disease leaving T cell ALL reliant upon high-intensity chemotherapy. Recent advances in the understanding of the biology of T-ALL and the improvement in immunotherapies have led to new therapeutic pathways to target and exploit. Here, we review the more promising pathways that are able to be targeted and other therapeutic possibilities for T-ALL., Recent Findings: Preclinical models and early-phase clinical trials have shown promising results in some case in the treatment of T-ALL. Targeting many different pathways could lead to the next advancement in the treatment of relapsed and/or refractory disease. Recent advances in cellular therapies have also shown promise in this space. When reviewing the literature as a whole, targeting important pathways and antigens likely will lead to the next advancement in T-ALL survival since intensifying chemotherapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In immunotherapy with T cells genetically modified to express chimeric antigen receptors (CAR), autologous lymphocytes are extracted from the patient, genetically modified to obtain CAR-T cells, and reintroduced into the patient to attack cancer cells. The success of this therapy has been achieved in the area of CD19-positive leukemias and lymphomas, being approved for the treatment of non-Hodgkin's lymphomas, acute lymphoblastic leukemia, and multiple myeloma. CARs are proteins that combine antibody specificity with T-cell cytotoxicity. The most common toxicities associated with therapy were not predicted by preclinical testing and include cytokine release syndrome, neurotoxicity, and cytopenias. These toxicities are usually reversible. One of the main challenges facing the field is the high economic cost that therapy entails, so the search for ways to reduce this cost must be a priority. In addition, other challenges to overcome include the situation that not all patients are supplied with the product and the existence of long waiting times for the start of therapy. The aim of this review is to present the development of the structure of CAR-T cells, the therapies approved to date, the toxicity associated with them, and the advantages and limitations that they present as immunotherapy., (©2023 American Association for Cancer Research.)

EZH2 is a member of PcG and can induce the occurrence of cancer when it is highly expressed. As an EZH2 inhibitor, Tazemetostat (EPZ6438) can inhibit the methylation catalytic activity of EZH2. However, many studies have shown that inhibition of EZH2 alone does not efficiently block tumor development. Therefore, in this study, proteolytic targeting chimera technology was employed to enhance the antiproliferative potency of EPZ6438 by degrading the oncogenic activity of EZH2. Several PROTACs have been synthesized by combining EPZ6438 with four E3 ligase ligands based on VHL, CRBN, MDM2, and cIAP E3 ligase systems. In our study, compound E-3P-MDM2 is the most active PROTAC molecule. It degraded EZH2 of the SU-DHL-6 cells in a concentration and dose-dependent manner and also degraded both EED and SUZ12 protein without affecting their mRNA levels, then significantly inhibited the expression of H3K27me3. The in vitro antiproliferative activity of E-3P-MDM2 was much stronger than that of EPZ6438., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)