BACKGROUND:Patients with relapsed/refractory (R/R) systemic light chain (AL) amyloidosis, particularly after daratumumab failure, face limited treatment options and challenging outcomes. B-cell maturation antigen (BCMA)-directed bispecific antibodies (BsAbs) have emerged as a potent strategy in multiple myeloma, yet their collective performance in AL amyloidosis remains to be systematically evaluated. METHODS:Following PRISMA guidelines, we analyzed 8 independent cohorts (80 patients) treated with teclistamab or elranatamab. A random-effects model with Hartung-Knapp adjustment was employed to pool outcomes. RESULTS:The pooled hematologic overall response rate (ORR) was 91% (95% CI: 87%-93%), with a deep hematologic complete response (hCR) rate of 64% (95% CI: 42%-82%). Rapid organ recovery was a hallmark of treatment: the pooled cardiac and renal response rates reached 59% (95% CI: 32%-82%) and 34% (95% CI: 14%-62%), cytokine release syndrome (CRS) was frequent but manageable (60%; 95% CI: 53%-67%), while immune effector cell-associated neurotoxicity syndrome (ICANS) remained rare (7%). However, Grade ≥ 3 infections were observed in 25% (95% CI: 15%-40%) of patients, potentially associated with T-cell dysfunction and therapy-induced hypogammaglobulinemia. CONCLUSION:BCMA-directed BsAbs demonstrate potent hematologic efficacy in R/R AL, achieving deep and rapid light-chain clearance. This hematologic response translates into significant organ functional recovery. However, the high incidence of severe infections necessitates proactive antimicrobial prophylaxis, dose optimization, and immunoglobulin supplementation.

Therapeutic relapse driven by bortezomib resistance represents a formidable clinical barrier in the management of multiple myeloma (MM). Here, a carrier-free, supramolecular nanoplatform was engineered through the spontaneous co-assembly of two natural alkaloids, berberine (BBR) and nitidine chloride (NC), termed BBR/NC-SAPs, to counter this malignancy. Driven by cooperative π-π stacking and van der Waals forces, BBR/NC-SAPs display superior anti-MM efficacy and optimized biosafety as compared to the free-drug combination. Quantitative proteomics and functional landscapes showed that BBR/NC-SAPs robustly activate iron-dependent ferroptosis, as evidenced by massive lipid peroxidation, intracellular Fe2+ overload, and mitochondrial depolarization. Mechanistically, integrated target deconvolution and atomistic molecular modeling identified NR2F2 as a direct target of BBR/NC-SAPs. Functional knock-out and rescue evaluations definitively validated that NR2F2 is an essential mediator governing the therapeutic response, as NR2F2 depletion occluded the ferroptotic cascade, and lentiviral reconstitution fully restored cellular sensitivity and GPX4-associated ferroptosis activation. Further, BBR/NC-SAPs markedly suppressed tumor growth and prolonged survival in bortezomib-resistant MM xenograft models, a therapeutic benefit actively reversed by the ferroptosis inhibitor ferrostatin-1. Collectively, this work highlights a paradigm of natural product-derived nanotechnology that targets the NR2F2-GPX4 axis, offering a promising supramolecular strategy to overcome drug resistance in refractory hematological tumors.

Microplastics (MPs) have been detected in human organs and peripheral blood, but their presence in the fetal circulation and their direct biomolecular interactions remain unknown. This study combined Raman spectroscopy, Py-GC/MS, and SEM to detect and quantify MPs in human umbilical cord blood (UCB), and employed limited proteolysis-coupled mass spectrometry (LiP-MS) to identify direct protein targets. MPs were ubiquitous in all UCB samples (n = 10), with a mean concentration of 41.128 µg/g. Polystyrene (PS), polyethylene (PE), polyvinyl chloride (PVC), and polypropylene (PP) were the predominant polymers. Notably, LiP-MS revealed 84 proteins that directly bound to MPs, with a significant enrichment in proteins involved in the hypoxia-inducible factor (HIF) signaling pathway. Subsequent in vitro experiments demonstrated that MPs suppressed the self-renewal and clonogenic capacity of UCB-derived hematopoietic stem cells (HSCs) in a concentration-dependent manner, concomitant with the inhibition of the HIF pathway. Genetic ablation of HIF-1α abolished the MP-induced suppression, establishing a causal role for this pathway. Our findings provide the first evidence of systemic MP infiltration into the fetal circulation and delineate a direct mechanistic link to impaired hematopoiesis via HIF-1α signaling, highlighting a potential risk for developmental toxicity.

BACKGROUND:Necrosis by sodium overload (NECSO) is a poorly understood, novel form of cell death implicated in cancer. TRPM4 is the only protein currently linked to NECSO and is downregulated in bortezomib-resistant multiple myeloma (MM) patients and cell lines. PURPOSE:To investigate the potential of cinobufagin to overcome bortezomib resistance in MM and elucidate its underlying mechanism of action, particularly regarding TRPM4 and NECSO induction. STUDY DESIGN:This study combined in vitro investigations using bortezomib-resistant MM cell lines (8226-BTZR, KMS-11-BTZR) and in vivo xenograft mouse models with comprehensive molecular interaction studies. METHODS:Cell proliferation assays, xenograft tumor growth monitoring, and immunohistochemistry (CD138/Ki67) were used to assess cinobufagin's effects. NECSO induction was evaluated mechanistically. TRPM4 expression was analyzed. The interaction between cinobufagin and its target was identified using LiP-MS, molecular docking, and molecular dynamics simulations, and validated by MST and CETSA assays. Protein-protein interactions (SEC62/TRPM4), ubiquitination status, and proteasomal degradation of TRPM4 were assessed by SPR, molecular dynamics simulations and immunoprecipitation assay. The role of SEC62 was confirmed using knockdown experiments. RESULTS:Cinobufagin effectively inhibited proliferation of bortezomib-resistant MM cells in vitro and suppressed tumor growth while reducing CD138/Ki67 expression in vivo. Mechanistically, cinobufagin induced NECSO. It upregulated TRPM4 expression and was found to directly bind SEC62. SEC62 interacts with TRPM4, promoting its ubiquitination and proteasomal degradation. Cinobufagin disrupts the SEC62/TRPM4 interaction, thereby stabilizing TRPM4 by inhibiting its ubiquitin-proteasome-mediated degradation. SEC62 knockdown attenuated cinobufagin's effects, confirming SEC62's role in mediating the reversal of bortezomib resistance. CONCLUSION:These findings identify TRPM4 as a promising therapeutic target in bortezomib-resistant MM. Cinobufagin overcomes bortezomib resistance by modulating the SEC62-TRPM4 axis, stabilizing TRPM4, and uniquely inducing the previously unexploited NECSO cell death pathway. This highlights cinobufagin's significant therapeutic potential.

Treatment-free remission (TFR) is a new long-term goal for treating selected patients with chronic myeloid leukemia in the chronic phase (CML-CP). Still, the appropriate group in which TFR can be attempted and the factors influencing it have not yet been identified. This meta-analysis aimed to explore TFR in CML-CP patients who achieved a deep molecular response (DMR) before Tyrosine kinase inhibitors (TKIs) discontinuation and to explore possible factors influencing TFR and the safety of discontinuation. We performed a systematic review and single-arm meta-analysis with a systematic search of published literature up to September 2023 in PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. The assessment was performed using the MINORS scale. Random-effects models were used to calculate outcome metrics, including overall mean TFR rates at 12 and 24 months and subgroup differences. Data synthesis and analysis were done by Stata17.0 software. A total of 19 single-arm trials involving 2336 patients were included in this meta-analysis, with an overall mean TFR rate of 59 https://www.crd.york.ac.uk/prospero/ (Registration No. CRD42023471334).

Xylene exposure is known to induce toxicity in hematopoietic stem and progenitor cells (HSPCs), leading to bone marrow suppression and potential leukemogenesis. However, research on the gene expression profiles associated with xylene-induced toxicity in HSPCs, and effective therapeutic interventions, remains scarce. In our study, we employed single-cell RNA sequencing to capture the transcriptomic shifts within bone marrow HSPCs both prior to and following treatment with coniferyl ferulate (CF) in a mouse model of xylene-induced hematotoxicity. Subsequently, we pinpointed CF as a targeted agent using SPR-LC/MS analysis. This enabled us to confirm the link between the gene Mgst2 and specific cellular subtypes. Our data revealed that CF significantly countered the reduction of both monocyte and neutrophil progenitor cells, which are commonly affected by xylene toxicity. Through targeted analysis, we identified Mgst2 as a direct molecular target of CF. Notably, Mgst2 is preferentially expressed in neutrophil progenitor cells and is implicated in mitochondrial metabolic processes. By selectively inhibiting Mgst2 in bone marrow, we observed amelioration of xylene-induced hematotoxic effects. In summary, our findings suggest that coniferyl ferulate can mitigate the detrimental impact of xylene on hematopoietic stem and progenitor cells by targeting Mgst2, particularly within subpopulations of neutrophil progenitors. This discovery not only advances our comprehension of the cellular response of HSPCs to xenobiotic stressors like xylene but also identifies CF and Mgst2 as potential therapeutic targets for alleviating xylene-induced hematotoxicity.

Microplastics (MPs) are increasingly recognized as contaminants present in various environments and are widely acknowledged as potential hazards to the mammalian immune system. In our study of chimeric antigen receptor T cell (CAR-T) therapy, we observed the presence of MP in CAR-T cell products for the first time. It is worth exploring whether MP could enter CAR-T cells and how they might affect CAR-T cells’ functionality. Therefore, we analyzed how MP affected CD19 and BCMA-CAR-T cells. Based on flow cytometry, ELISA, and cytotoxicity analysis of in vitro and in vivo experiments, MP suppressed the activity of CAR-T cells. Subsequent investigation revealed that the exposure of CAR-T cells to varying concentrations of MP resulted in a notable increase in apoptosis, ferroptosis, and exhaustion levels. Furthermore, the hyperactivation of the mTOR signaling pathway in MP-treated CAR-T cells was verified. The partial restoration of CAR-T cell function in MP was achieved by inhibiting the mTOR pathway. MP present a threat to CAR-T cell function due to their role in inducing CAR-T cell apoptosis, ferroptosis, and T-cell exhaustion through the hyperactivation of mTOR signaling pathways.

Multiple myeloma (MM) is regarded as a hematological malignancy and it is challenging to cure, largely caused by the increased risk of relapse or the emergence of resistance to the existing therapies. In MM immunotherapy, the utilization of programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) blocking therapy has been a significant cornerstone. However, currently, there is an urgent demand for small-molecule checkpoint inhibitors with advantageous pharmacokinetic properties compared to antibodies that are currently being targeted. In this study, Momordin Ic was detected to be a negative regulator of PD-L1. Momordin Ic improved the sensitivity of MM cells to co-cultured T-cells through reducing the level of PD-L1 in MM cells. Momordin Ic made its antitumor impact on 8226 tumor xenograft mice and patient-derived xenografts (PDX) model by improving tumor infiltrating T-cell immunity and reducing the activation of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs). Momordin Ic induced PD-L1 degradation via ubiquitin (Ub)/proteasome-dependent pathway. Momordin Ic facilitates the recruitment of E3 ligase SYVN1, contributing to the ubiquitination and subsequent degradation of PD-L1. Moreover, the current work is the first to demonstrate that Momordin Ic possesses therapeutic potential for treating MM by targeting the degradation of PD-L1 through the recruitment of SYVN1.

Circulating tumor DNA (ctDNA) was demonstrated as a biomarker for predicting clinical outcomes in B-cell lymphoma (BCL) patients. However, ctDNA and its minimum number of mutant genes that stratify relapsed or refractory BCL (R/R BCL) patients receiving chimeric antigen receptor (CAR)-T cell therapy remains unknown. The plasma ctDNA of 10 patients with R/R BCL receiving CAR-T cell therapy from our clinical center was adopted for targeted exome sequencing. Regarding R/R BCL patients who received CAR-T cell therapy, their 6-, 12- and 18-month overall survival (OS) rates were 90%, 80% and 64%, respectively, while their complete remission (CR) rate was 70%. There was a clear trend suggesting that ctDNA negative was related to favorable OS, even though it was not of significance at that point (P = 0.09). To be specific, BCL2, NRAS, and TBL1XR1 in ctDNA were the optimal combination for predicting OS of R/R BCL patients (P = 0.009). Importantly, ctDNA and BCL2/ NRAS/ TBL1XR1 were all positively correlated with 18 fluorodeoxyglucose positron emission tomography/computed tomography (18 FDG-PET/CT) in evaluating the effectiveness of CAT-T cell therapy (P < 0.05). We identified ctDNA and BCL2/NRAS/TBL1XR1 mutations that can predict the prognosis for R/R BCL patients, which might assist to better select R/R BCL patients for CAR T-cell therapy.

Since multiple myeloma (MM) remains a cureless malignancy of plasma cells to date, it becomes imperative to develop novel drugs and therapeutic targets for MM. We screened a small molecule library comprising 3633 natural product drugs, which demonstrated that Nitidine Chloride (NC), an extract from traditional Chinese medicine Zanthoxylum nitidum. We used Surface Plasmon Resonance-High Performance Liquid Chromatography-Protein Mass Spectrometry (SPR-HPLC-MS), Cellular Thermal Shift Assay (CETSA), molecular docking, and SPR assay to identify the potential targets of NC, in which ABCB6 was the unique target of NC. The effects of ABCB6 on cellular proliferation and drug resistance were determined by CCK8, western blot, flow cytometry, site-mutation cells, transmission electron microscopy, immunohistochemistry staining and xenograft model in vitro and in vivo. NC induced MM cell death by promoting ferroptosis. ABCB6 is the direct target of NC. ABCB6 expression was increased in MM samples compared to normal controls, which was significantly associated with MM relapse and poor outcomes. VGSK was the inferred binding epitope of NC on the ABCB6 protein. In the ABCB6-mutated MM cells, NC did not display cancer resistance, implying the vital role of ABCB6 in NC's bioactivity. Moreover, the silencing of ABCB6 significantly inhibited MM cell growth. Mechanistically, the direct binding of NC to ABCB6 suppressed PI3K/AKT signaling pathway to promote ferroptosis. In conclusion, ABCB6 can be a potential therapeutic target and prognostic biomarker in MM, while NC can be considered a novel drug for MM treatment.

Background: Acute myeloid leukemia (AML) is a heterogeneous disorder with an unpredictable prognosis. Ferroptosis, the iron-dependent cell death program, could serve as an alternative for overcoming drug resistance. However, its effect on AML remains largely unclear.Methods: We collected RNA sequencing data and relevant clinical information of AML patients from The Cancer Genome Atlas to construct a prognosis prediction model. Risk score was calculated with eight prognosis-related ferroptosis genes (PRFGs) discovered through univariate analysis and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression. A nomogram was constructed by incorporating LASSO risk score, age, and cytogenetic risk based on univariate/multivariate Cox regression.Results: Of the 33 AML PRFGs identified from the TCGA-derived dataset, 8 genes were used to construct a gene signature to predict AML prognosis. Principal component analysis and heatmap showed significant differences between the low and high risk score groups. Next, LASSO risk score, age, and cytogenetic risk were incorporated into the nomogram to predict the overall survival (OS) of AML patients. According to survival analysis, patients with a low risk score had markedly increased OS as compared to those with a high risk score. Based on the results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, the differences between the two risk groups showed a close relationship with immune-related pathways and membrane transportation. The analysis of tumor-infiltrating immune cells and immune checkpoints revealed that the immunosuppressive tumor microenvironment possibly facilitated different prognostic outcomes between the two groups. Gene expression analyses showed that the mRNA expression levels of PARP1 and PARP3 (PARPs) were closely related to the different clinical subgroups and the analyzed OS in AML patients. Finally, the PARP inhibitor talazoparib and the ferroptosis inducer erastin exerted a synergistic anti-proliferative effect on AML cells.Conclusion: We constructed a nomogram by incorporating PRFGs, and the constructed nomogram showed a good performance in AML patient stratification and prognosis prediction. The combination of PARP inhibitors with ferroptosis inducers could be a novel treatment strategy for treating AML patients.

Olverembatinib represents the third-generation breakpoint cluster region protein-Abelson-murine leukemia 1 (BCR-ABL1) tyrosine kinase inhibitor with oral bioavailability, which can be used to overcome the T315I mutation in Philadelphia chromosome–positive (Ph +) leukemia. BCR-ABL-independent resistance to olverembatinib has been reported among patients in various clinical cases. However, the mechanism of olverembatinib resistance has rarely been reported. This study has illustrated bone marrow cell transcriptome and metabolome profiles among Ph + acute lymphoblastic leukemias (ALL) cases pre- and post-olverembatinib resistance. The transcriptome studies demonstrated that PI3K/AKT, purine metabolism, and other signaling pathways could play a vital role in olverembatinib resistance. As suggested by metabolomics, olverembatinib resistance in Ph + ALL was associated with purine metabolism alterations. Subsequently, high-performance liquid chromatography along with real-time quantitative PCR was utilized to measure purine metabolism-related mRNA levels and metabolism expression levels between olverembatinib resistance and sensitive cell lines. Our results elucidate the mechanism of olverembatinib resistance in Ph + ALL at transcriptome and metabolome levels, which facilitate a better understanding of olverembatinib resistance and hence may prove crucial in identifying novel drugs to tackle this conundrum.

目的:探讨泽布替尼联合利妥昔单抗（ZR）方案治疗TP53突变极高危慢性淋巴细胞白血病（CLL）患者的效果。方法:回顾性分析2021年5月广东省第二人民医院收治的1例TP53突变极高危CLL患者的临床资料，并复习相关文献。结果:患者为62岁女性，因左侧颈部肿物诊断为CLL，伴幼稚淋巴细胞增多，Binet分期C期，Rai分期Ⅳ期，CLL-IPI 9分，极高危。接受2个疗程ZR方案化疗后行泽布替尼单药治疗，3个月后进行疗效评估，肿瘤负荷情况达部分缓解，骨髓造血情况达完全缓解。结论:泽布替尼联合利妥昔单抗化疗可作为TP53突变极高危CLL患者的治疗优选。对于有合并症的患者，泽布替尼逐步增量至标准剂量是更为安全的用药方式；发生出血不良事件，泽布替尼需酌情减量。

Background:Centromere protein I (CENPI) has been shown to affect the tumorigenesis of breast and colorectal cancers. However, its biological role and prognostic value in other kinds of cancer, especially adrenocortical carcinoma (ACC), remained to be further investigated.Methods:Various bioinformatics tools were adopted for exploring the significance of differential expression of CENPI in several malignant tumors from databases such as Depmap portal, GTEx, and TCGA. ACC was selected for further analyzed, and information such as clinicopathological features, the prognostic outcome of diverse subgroups, differentially expressed genes (DEGs), co-expression genes, as well as levels of tumor-infiltrating immune cells (TIIC), was extracted from multiple databases. To verify the possibility of CENPI as a therapeutic target in ACC, drug sensitivity assay and si-RNA mediate knockdown of CENPI were carried out.Results:The pan-cancer analyses showed that the CENPI mRNA expression levels differed significantly among most cancer types. Additionally, a high precision in cancer prediction and close relation with cancer survival indicated that CENPI could be a potential candidate biomarker to diagnose and predict cancer prognosis. In ACC, CENPI was closely related to multiple clinical characteristics, such as pathological stage and primary therapy outcome. High CENPI levels predicted poor overall survival (OS), progression-free interval (PFI), and disease-specific survival (DSS) of ACC patients, particularly for different clinical subgroups. Moreover, the expression of CENPI showed positive relationship to Th2 cells but negatively related to most of the TIICs. Furthermore, drug sensitivity assay showed that vorinostat inhibit CENPI expression and ACC cell growth. Additionally, si-RNA mediated knockdown of CENPI inhibited ACC cell growth and invasion and showed synergistic anti-proliferation effect with AURKB inhibitor barasertib.Conclusion:Pan-cancer analysis demonstrated that CENPI is a potential diagnostic and prognostic biomarker in various cancers as well as an anti-ACC therapeutic target.

Targeted therapy for acute myeloid leukemia (AML) is an effective strategy, but currently, there are very limited therapeutic targets for AML treatment. Ferroptosis is strongly related to drug resistance and carcinogenesis. However, there are few reports about ferroptosis in AML. This article explores the relationship between ferroptosis-related gene (FRG) expression and prognosis in AML patients from the FerrDb and the Cancer Genome Atlas (TCGA) databases. The ferroptosis-related gene ARNTL was observed to have high expression and poor prognosis in AML. Receiver operating characteristic curve (ROC) analysis revealed the predictive accuracy of the signature. The area under the time-dependent ROC curve (AUC) was 0.533 at one year, 0.619 at two years, and 0.622 at three years within the training cohort. Moreover, we found that the ARNTL expression is closely associated with tumor-infiltrating immune cells like the macrophages and NK cells. Inhibiting the ARNTL expression suppressed colony formation and induced ferroptosis in AML cells. Overall, the survival prediction model constructed based on ARNTL accurately predicted the survival in AML patients, which could be a potential candidate for diagnosing and treating AML.

Despite high remission rates following chimeric antigen receptor T cell (CAR-T) cell therapy in B-cell acute lymphoblastic leukemia (B-ALL), relapse due to loss of the targeted antigen is increasingly recognized as a mechanism of immune escape. We hypothesized that simultaneous targeting of CD19 and CD22 may improve the CAR-T effect. The in vitro and in vivo leukemia model was established, and the anti-tumor effects of BiCAR-T, CD19 CAR-T, CD22 CAR-T, and LoopCAR6 cells were observed. We found that the BiCAR-T cells showed significant cytotoxicity in vitro and in vivo. The CD19/CD22 bivalent CAR provides an opportunity to test whether simultaneous targeting may reduce the risk of antigen loss.

Acute myeloid leukemia (AML) represents a frequently occurring adulthood acute leukemia (AL). Great progresses have been achieved in the treatment of AML, but its pathogenic mechanism remains unclear. This study reported the biological functions of lncRNA DUBR in AML pathogenic mechanism. As a result, lncRNA DUBR showed high expression level within AML, resulting in poor prognosis, especially in M4 AML. In vitro studies elucidated that knockdown of DUBR with small interfering RNA (siRNA) resulted in the suppression of survival and colony formation ability, as well as induction of apoptosis, in AML cells. RNA pull-down assay and computational revealed that DUBR could sponge with miRNA-142-3P and interact with FUS protein. MiRNA-142-3P have a negative correlation with DUBR and overexpression of miRNA-142-3P inhibited cell growth in AML. Meanwhile, DUBR promoted the expression of FUS protein, targeting inhibition of FUS significantly promoted cell apoptosis in AML cell lines. In conclusion, these results revealed new mechanism of lncRNA DUBR in AML malignant behavior, and suggested that the manipulation of DUBR expression could serve as a potential strategy in AML therapy.