Bingzong Li

Could ferroptosis, a novel cell death pathway, offer a potential therapeutic strategy for multiple myeloma (MM)? Our previous research showed that ferroptosis is suppressed in MM patients, with varying sensitivities among MM cells. In this study, metabolomic analysis highlighted the pivotal role of amino acid metabolism, rather than lipid metabolism, in determining MM cells’ sensitivity to ferroptosis. We further analyzed iron metabolism, another key factor influencing ferroptosis sensitivity, by collecting peripheral blood samples from 120 MM patients. Our analysis revealed a significant reduction in the levels of transferrin (TF), an essential iron-transporting protein. Moreover, low TF levels were associated with significantly worse progression-free survival and overall survival. Erastin treatment together with TF supplementation markedly enhanced ferroptosis in MM cells in vitro and in xenograft models. MM cells suppressed TF secretion by monocytes in the bone marrow microenvironment, contributing to the decreased TF levels in MM patients. The transcription factor CEBPB, found in MM cell-derived extracellular vesicles, plays a key role in this process. In conclusion, Our findings identify amino acid metabolism and iron metabolism as distinct metabolic features associated with ferroptosis sensitivity in MM. Ferroptosis, induced by erastin and TF, holds promise as a potential therapeutic strategy for MM and provides new insights for developing more effective therapies. Graphical abstract

Comprehensive Driver Mutation Landscape of DLBCL Informed by Integrated Tissue and Circulating DNA Analyses

Multiple myeloma (MM) progression involves extensive immunosuppressive remodeling of the bone marrow microenvironment. In this study, we performed a comprehensive mass spectrometry-based proteomic analysis of exosomes derived from MM cells (MM-Exos), revealing that these exosomal proteins are predominantly enriched in pathways associated with immune regulation. We demonstrated that MM-Exos effectively drive macrophage polarization toward the M2 phenotype, thereby facilitating the establishment and maintenance of an immunosuppressive tumor microenvironment. Mechanistically, we identified the ERK1/2 signaling pathway as a critical mediator of MM-Exo-induced macrophage polarization. Importantly, we found that simvastatin, a widely used inhibitor of cholesterol biosynthesis, effectively impaired exosome secretion from MM cells and subsequently reduced M2 macrophage polarization. Collectively, our study reveals a novel mechanism of immune evasion in MM, in which MM-Exos promote the polarization of macrophages toward the M2 phenotype via ERK1/2 pathway activation. These findings underscore the therapeutic potential of targeting exosome-mediated intercellular communication within the MM bone marrow microenvironment to improve clinical outcomes.

Background Circulating tumor DNA (ctDNA) is a promising biomarker for monitoring minimal residual disease (MRD), assessing disease status, and guiding treatment in diffuse large B-cell lymphoma (DLBCL). Current ctDNA assays rarely detect immunoglobulin (IG) fusions. This study evaluates a novel assay that simultaneously detects mutations, IG fusions, and IG V(D)J clonality in plasma and cerebrospinal fluid (CSF) to enhance molecular profiling and CNS monitoring. Methods A prospective analysis was conducted in 57 DLBCL patients. Genomic alterations in plasma and CSF ctDNA were compared to those in tumor tissue using targeted next-generation sequencing (NGS). Results Mutations, IG fusions, and IG V(D)J clonality were detected in 100%, 72.2%, and 78.6% of plasma ctDNA samples, respectively. Plasma ctDNA also revealed additional mutations absent in tumor tissue, reflecting clonal heterogeneity. The incorporation of IG fusion detection enabled molecular subtyping without requiring FISH. In CSF, ctDNA analysis identified genomic alterations in 8 cases, whereas conventional imaging and cytology confirmed CNS involvement in only 3, demonstrating the superior sensitivity of ctDNA for CNS surveillance. Conclusion This ctDNA assay offers a non-invasive, integrated approach for genomic profiling and disease monitoring in DLBCL, with improved sensitivity for CNS detection and potential to inform personalized treatment strategies.

Lymphoma‐associated hemophagocytic lymphohistiocytosis (LA‐HLH) is a life‐threatening hyperinflammatory syndrome, and hierarchical management based on a prognostic model is important. The endothelial activation and stress index (EASIX) score has demonstrated prognostic utility in recipients of allogeneic stem cell transplantation and chimeric antigen receptor (CAR) T‐cell therapy. However, its role in LA‐HLH remains unestablished. We conducted a multicenter retrospective analysis of patients with LA‐HLH from 28 medical centers to explore the prognostic impacts of EASIX in LA‐HLH. EASIX was calculated using baseline lactate dehydrogenase, serum creatinine, and platelet counts. A total of 490 patients with LA‐HLH were included and stratified by EASIX quartiles (Q1–Q4). Patients with a higher EASIX score had significantly inferior 2‐month survival and overall survival, according to the Kaplan–Meier analysis (log‐rank p < 0.001). In multivariable analyses, after adjustment for age, gender, lymphoma type, splenomegaly, bone marrow infiltration, lymphoma status (treatment‐naïve versus relapsed/refractory), hemoglobin, absolute neutrophil count, serum ferritin levels, and aspartate aminotransferase, the highest EASIX quartile (Q4) exhibited a 7.01‐fold risk of death compared to the lowest quartile (Q1) (Hazard ratio [HR] = 7.01, 95% confidence interval [CI]: 3.98–12.36; p < 0.001). Additionally, the restricted cubic splines (RCS) analysis illustrated an increase in the risk of mortality with an increasing EASIX score. Our findings support EASIX being a robust, universally accessible prognostic marker for LA‐HLH, strongly associated with early mortality risk. This index can be used to stratify the risk levels of patients with LA‐HLH and predict their survival outcomes.