Jianli Ma

Early events that bias germinal‐center B cells toward malignant evolution remain incompletely defined. Here, we uncover Sex‐determining Region Y Box 5 ( SOX5 ) as an early‐stage epigenetic modifier in myelocytomatosis oncogene ( MYC )‐driven B‐cell lymphoma. Single‐cell transcriptomics of lymph nodes from CRISPR/Cas9‐engineered Myc ^Cd19‐Cre B‐cell lymphoma chimeric mice resolve a Ki67–high proliferative compartment at an early stage with enriched SOX5 transcripts. CRISPRa, CRISPR knockout, and multi‐omic profiling reveal a SOX5 ‐centered chromatin program defined by de novo promoter‐proximal occupancy coupled to contraction of promoter accessibility. Mechanistically, SOX5 binding at the Proteolytic Signal‐Containing Nuclear Protein ( PCNP ) promoter represses its transcription, thereby reducing apoptosis and alleviating G2/M arrest. Consequently, B‐cell–targeted adeno‐associated virus 6 (AAV6)‐sh SOX5 reduces Ki67‐positive PAX5 ‐positive malignant B cells and partially restores follicular architecture. Together, SOX5 ‐mediated, promoter‐centric repression of PCNP and other effectors installs and maintains an early‐stage proliferative state in MYC ‐driven B‐cell lymphoma, which nominates SOX5 ‐directed intervention as a candidate therapeutic strategy for further investigation.

Follicular lymphoma (FL) is one of the most common types of indolent non-Hodgkin lymphoma that can undergo rapid progression, which is associated with poor patient outcomes. The homing of B cells into aberrant immunological niches within the germinal center (GC) is a prerequisite for disease development. The C-C chemokine receptor type 7 ( CCR7 ), expressed by circulating B cells, mediates their homing and dissemination to draining lymph nodes (drLNs). Here, we identified activated B cells emerging from adjacent GCs in drLNs as the origin of circulating memory B cells in distant LNs. Transcriptional upregulation of Ccr7 in these memory B cells was found to guide their migration. To model lymphomagenesis, we generated a mouse model with B-cell-specific Myc overexpression, achieved by CRISPR/Cas9-mediated homologous recombination to insert a Myc expression cassette into the Hipp11 locus. Histological signs of aggressive lymphoma were evident in Ccr7 wild-type mice, whereas Ccr7 knockout mice exhibited pre-malignant atypia phenotypes. We in-depth revealed that Ccr7 knockout impeded the differentiation of pre-malignant Rnaseh2a+ memory B cells toward malignant Pax5+ GC B cells. Furthermore, Ccr7 deficiency attenuated the dependency of malignant memory or GC B cells on extensive follicular dendritic cell (FDC) networks and T-cell help. Conversely, IL-1β-induced FDC re-expansion preferentially fostered the proliferation of malignant GC B cells even in the context of Ccr7 knockout. Our findings reveal an unforeseen role for CCR7 in driving the malignant evolution of memory B cells by orchestrating their migratory dynamics and reprogramming the supportive GC niche.

The high heterogeneity of cancer poses significant challenges for precision diagnosis, particularly in tasks such as rare subtype identification, early lesion detection, and tumor grading. Notably, cancer cell biological traits are closely correlated with cell death regulatory mechanisms, and accurate cancer region identification is a pivotal premise for exploring the cancer-cell death intrinsic association. Single-modality methods often struggle to balance sensitivity and accuracy, while existing general multimodal models are poorly adapted to the processing of pathological long texts and high-resolution images, leading to issues of semantic truncation and feature loss. To address these challenges, this study proposes CanLRHI, a multimodal pretraining model tailored for cancer pathology that focuses on the synergistic modeling of long pathological reports and high-resolution images to achieve comprehensive cross-modal alignment and accurate characterization of cancer regions. Experimental results on the CancerPath-170 K-v1 dataset, which contains 170 000 cancer pathology image–text pairs, demonstrate that CanLRHI significantly outperforms mainstream multimodal baselines across various tasks, including Zero-Shot classification and Few-Shot Fine-Tuning. This work provides an extensible technical framework for long-text-driven cross-modal representation learning in medical pathology, and further offers a reliable technical support for cell death-related cancer pathology research via high-precision cancer region detection.

Cuproptosis is a novel form of regulated cell death driven by intracellular copper accumulation, leading to lipoylated protein aggregation and Fe-S cluster destabilization. Dysregulation of this process has been implicated in various pathological conditions, including cancers, neurodegenerative diseases and metabolic diseases. Despite rapidly growing interest in cuproptosis, a systematically curated intelligent agent dedicated to cuproptosis-related genes (CRGs) and their disease associations remains lacking. To address this, we constructed a cuproptosis-related artificial intelligence (AI) knowledge base, named CuAgent, by manually curating 465 experimentally validated CRGs and 163 associated diseases. CuAgent introduces an innovative intelligent agent that enables users to perform natural language queries and receive data-driven responses. In addition, agent offers gene queries and analytical tools (expression profiling, survival analysis, protein interaction network visualization and correlation analysis). This study provides critical insights into cuproptosis progression, presenting a comprehensive and interactive resource to advance the understanding of cuproptosis. URL: https://bioinfor.nefu.edu.cn/CuAgent/home/ .

Hepatitis B virus (HBV) infections are associated with an increased risk of B-cell lymphomas, including follicular lymphoma (FL). Chronic HBV infection and shifts in infection status following treatment can influence lymphomagenesis and immune reprogramming, potentially affecting clinical outcomes. Using the CosMx Spatial Molecular Imaging, after integrated with dynamic HBV infection states and duration of overt infection, this refines four recurrent patterns, especially memory B cell-like malignant cells (MBLM) subtype (PTPRCAP + ) that is traced with atypical features and latent indolence, and virus protein transport-related follicular dendritic cell (FDC) which shows interplay with MBLM. Except for virus-induced immune exhaustion, distinct contributions to POD24 occurrence from malignant cells and immunosuppressive cell communities under distinct HBV infection states are discerned such as through CCL21/CCR7 signaling pathway. Taken together, our spatial multicellular dynamics reveal an increased prevalence of MBLM and variable FDC phenotypes which is associated with POD24 occurrence in HBV-related FL tumors.

Background KN026 is a novel bispecific HER2-targeting antibody for HER2-positive recurrent or metastatic breast cancer that showed prolonged median PFS and lessened distinction of PFS regarding the HR subgroup in our phase II clinical trial, compared with PUFFIN study of first-line trastuzumab combined with pertuzumab therapy. A more detailed discovery of its peculiarity is needed for optimal application of KN026 treatment. Methods We performed whole-transcriptome sequencing of digital spatial profiling (DSP) on 8 pre/post-treatment tumor samples. Mechanistic explorations were conducted by plasmid transfection, co-culture, CCK8 proliferation assay and flow cytometry. Results Compared to the tumor regions with non-objective response (OR), those with OR had high expression of CALML5, TFAP2B, and ERBB2, and relatively low expression of ESR1 in tumor cells at baseline. The expression of ESR1 had a tentative association with PI3K/AKT and NOTCH signaling pathways which were downstream or interactive pathways of HER2 target and also acted as interactive pathways of ER-mediated signaling. The co-expression of ERBB2 and CDK12 emerged as a distinctive signature of OR. KN026 treatment also reshaped intratumoral activated T- and B-cell subtypes in hot-tumor regions, regardless of myeloid-derived cells. Conclusions Both HER2 and ESR1 are determinant of KN026 efficacy in advanced HER2-positive breast cancer, implying the potential of KN026 combined with endocrine therapy in HER2- and ER-positive breast cancer.

Background: Hepatitis B virus (HBV) infection (surface antigen positive, HBsAg+) has been related to the increased risk in follicular lymphoma (FL). The further understanding of features in HBV-associated FL remains lacking. Methods: We explored clinical risk factors in HBsAg-positive patients from multicentric clinical investigation retrospectively (n = 276) and integrated HBV-related factors into Follicular Lymphoma International Prognostic Index (FLIPI) scoring system for risk prediction. The methylation profiles in pre- and paired HBsAg+FL occurring progression of disease within 2 years (POD24) were determined using the Human Methylation 850K BeadChip platform. Bulk RNA sequencing was performed for gene expression in samples from the same patient and confirmed using Myc^Cd19Cre C57BL/6J chimera mice. Results: We found that HBsAg+ FL with a higher incidence of POD24. The high HBV-DNA load (> 10⁵ copies/mL) was identified as a pivotal risk factor. HBsAg+ FL with the rapidly decreasing viral load showed lower incidence of POD24 than those without viral control (P = 0.026). Integrated risk stratification incorporating HBV-related clinical parameters based on FLIPI scoring systems had potential predictive value for high-risk patients (AUC = 0.616, P = 0.002). The methylation profiles in pre-POD24-HBsAg+FL and paired POD24-HBsAg+FL showed distinguished signatures of methylated KMT2A, EP300-AS1, ARID1B, MHC I class molecular genes related to tumor cells, and TNFRSF1A, LTA, IQCE genes related to immune cells. Of note, we confirmed that the crucial CXCR5 mRNA expression with specific methylated regions was inversely correlated to featured MYC mRNA expression as “trans” regulation in both POD24-HBsAg+FL and Myc^Cd19Cre lymphoma model. Conclusion: Integrated clinicopathological features into prediction system may provide precise risk stratification for HBV-positive FL. Modifiable DNA methylation acts as the potential targets for the combined treatment strategy to delay POD24 occurrence. Plain Language Summary: Based on the retrospective clinical data from multiple clinical centers of China, we first present the clinical characteristics associated with chronic hepatitis B virus (HBV) infection and illustrated their prognostic roles in follicular lymphoma. We novelly integrated HBV-related risk factors into the canonical Follicular Lymphoma International Prognostic Index scoring. We revealed that modifiable genes methylation,especially in genes which regulated immune response, was associated with the early relapse of disease. The myelocytomatosis oncogene (MYC) is the driver for the aggressive progression of B-cell lymphoma in multiple clinical guidelines. Of note, we further confirmed that Chemokine C-X-C-Motif Receptor 5 (CXCR5) mRNA expression with specific methylated regions was inversely correlated to MYC mRNA expression during the disease progression, showing the potential promotion of immune activities on tumor progression. Our study provided the potential targets to delay the disease progression within 24 months (POD24) through reversing methylation modification in the further epigenetic molecular treatment.