BACKGROUND:Immune checkpoint inhibitors achieve high response rates in relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL), but few treatment options are available for patients who experience failure after PD-1/PD-L1 blockade. T cell immunoglobulin and mucin-domain containing-3, a key mediator of immune escape from PD-1/PD-L1 inhibition, is targeted by TQB2618, a humanized IgG4 monoclonal antibody. This phase Ib study aimed to evaluate the safety and efficacy of TQB2618 in combination with the anti-PD-1 antibody penpulimab in patients with r/r cHL. METHODS:This multicenter phase 1b study was conducted from June 2022 to September 2024 at 12 sites in China (NCT05400876). The study included a dose-escalation phase in which patients with r/r lymphoma received TQB2618 (600 or 1200 mg, every 3 weeks, Q3W) plus penpulimab (200 mg, Q3W) to evaluate dose-limiting toxicities and determine the recommended phase II dose (RP2D). The subsequent dose-expansion phase enrolled patients with r/r cHL previously treated with PD-1/PD-L1 inhibitors to assess the objective response rate (ORR). RESULTS:10 patients with r/r lymphoma were enrolled in the dose-escalation phase, and TQB2618 (600 mg, Q3W) plus penpulimab (200 mg, Q3W) was selected as the RP2D. In the dose-expansion phase, 18 additional patients with r/r cHL previously treated with PD-1/PD-L1 inhibitors were enrolled. Among the total 21 r/r cHL patients, the median age was 32 years (range, 22-65), and 12 (57%) were male. The ORR was 52%, including 1 complete response and 10 partial responses. Treatment-related adverse events (TRAEs) occurred in 18 patients (86%), with grade ≥3 TRAEs in 5 (24%). The most common TRAEs (≥20%) were platelet count decreased (24%), anemia (24%), and aspartate aminotransferase increased (24%). As of the data cut-off in December 2024, the median follow-up was 14.1 months, the median duration of response and the median overall survival had not yet been reached. CONCLUSIONS:TQB2618 in combination with penpulimab was well tolerated and demonstrated promising efficacy in patients with cHL who had failed prior anti-PD-1/PD-L1 therapy, supporting its potential as a therapeutic option for this difficult-to-treat population. TRIAL REGISTRATION NUMBER:NCT05400876.

Acute myeloid leukaemia (AML) is a common haematological malignancy with an unsatisfactory prognosis despite recent therapeutic advances. Neddylation and ferroptosis have been implicated in the regulation of malignant cell proliferation, survival and therapy response. However, the relationship between neddylation-related dysregulation and ferroptosis-associated pathways in AML remains poorly understood. Transcriptomic data from TCGA-AML and GTEx normal controls were integrated for differential expression and functional enrichment analyses. Prognostic neddylation-related genes were identified using univariate Cox regression, LASSO regression and multivariate Cox regression analyses. The expression and regulatory association of EXOSC4 with NEDD8 and Cullin1 neddylation were validated in clinical samples and AML cell lines using qRT-PCR and Western blotting. CCK-8 assays were performed to evaluate the effects of EXOSC4 overexpression, MLN4924, erastin and Ferrostatin-1 on AML cell viability. A ceRNA regulatory network was constructed based on the key neddylation-related genes. GO and KEGG enrichment analyses showed that differentially expressed neddylation-related genes were mainly enriched in post-translational modification-related biological processes and pathways. Cox regression analyses identified EXOSC4 as a prognostic neddylation-related gene significantly associated with AML prognosis. Validation in clinical samples showed that EXOSC4 and NEDD8 were differentially expressed at both the mRNA and protein levels. In vitro experiments further showed that EXOSC4 expression was positively associated with NEDD8 protein levels and Cullin1 neddylation, suggesting that EXOSC4 may be involved in neddylation-related regulation in AML. Correlation analysis indicated a potential association between neddylation-related dysregulation and ferroptosis-associated pathways. Moreover, CCK-8 assays showed that EXOSC4 overexpression enhanced AML cell viability, whereas MLN4924 suppressed this effect and further enhanced erastin-induced reduction in cell viability, suggesting a potential role of EXOSC4 in ferroptosis-related cellular responses. In conclusion, this study reveals a potential association between neddylation-related dysregulation and ferroptosis-associated pathways in AML. EXOSC4 was identified as a candidate regulatory molecule that may connect neddylation activity with ferroptosis-related cellular responses. These findings provide new insights into the molecular mechanisms of AML and support further investigation of EXOSC4 as a potential therapeutic target.

HO-1 (HMOX1) is a stress-inducible, rate-limiting heme catabolic enzyme aberrantly upregulated across hematologic malignancies and frequently associated with progression, relapse, and poor therapeutic response. This review integrates clinical and experimental evidence and frames HO-1 as a multidimensional resistance hub operating through three interconnected axes. (1) Enzymatic axis: heme degradation products (CO, biliverdin/bilirubin, and Fe2+) buffer therapy-induced oxidative stress, modulate apoptosis/autophagy, and tune ferroptosis susceptibility in a context- and dose-dependent manner. (2) Non-enzymatic axis: stress-induced truncation and nuclear translocation of HO-1 rewire transcriptional programs by stabilizing NRF2 and engaging epigenetic regulators, converting transient stress cues into durable resistance states. (3) Microenvironmental axis: HO-1 activity in stromal and immune compartments reshapes cytokine networks and suppresses immune recognition (e.g., HLA-C and CD48), reinforcing immune-evasive niches. We systematically summarize translational strategies at three levels: (1) agents directly targeting the HO-1 protein, (2) therapies targeting upstream regulatory pathways, and (3) approaches targeting downstream effectors and the HO-1-shaped immunosuppressive microenvironment.

Progression and chemoresistance is the main cause of acute lymphoblastic leukemia(ALL) treatment failure. However, its mechanism has not been fully understood. Herein, Annexin A1 (ANXA1) overexpression was found by bioinformatic analysis in B-ALL cells. Clinical specimens were collected to preliminarily explore the role of ANXA1 in B-ALL. It showed that ANXA1 was obviously upregulated in bone marrow samples from B-ALL patients with chemoresistance and correlated with relapse or resistance. Then, we performed cell proliferation and apoptosis assays in CCRF-SB and Nalm6 cells lines in vitro. Overexpression of ANXA1 protected the B-ALL cells from apoptosis induced by dexamethasone and promoted cell cycle progression in vitro. We also found that ANXA1 promoted B-ALL cell proliferation, which correlated with the activated fatty acid metabolism in vitro. Moreover, the content of neutral lipids and the protein expression levels of fatty acid metabolism related ACC1 and FASN proteins were significantly decreased following downregulation of ANXA1. Additionally, high expression of ANXA1 promoted leukemia cell progression by regulating fatty acid metabolism through activating PI3K/AKT signaling pathway. Then in vivo results indicated that downregulation of ANXA1 in B-ALL cells could significantly reduce leukemic cell burden and increase dexamethasone sensitivity. Therefore, ANXA1 was identified as an oncogene in the development and progression of B-ALL and might be a promising biomarker for treating B-ALL.

BackgroundComorbidities increasingly complicate targeted therapy for chronic-phase chronic myeloid leukemia (CP-CML). This study evaluated three comorbidity scoring systems (CCI, ACE-27, and CIRS-G) to predict molecular responses in flumatinib-treated CP-CML patients.MethodsRetrospective data from 559 patients (2018–2024) were analyzed. Machine learning algorithms, including XGBoost, were trained to predict 12-month major molecular response (MMR). SHapley Additive exPlanations (SHAP) analysis was employed to interpret non-linear associations and feature interactions.ResultsThe XGBoost model demonstrated the highest predictive performance (AUC = 0.852). Integrating CIRS-G into the baseline clinical model provided the most substantial incremental value (ΔAUC = 0.078, p = 0.006), outperforming CCI and ACE-27. SHAP analysis revealed a non-linear threshold effect, suggesting that a CIRS-G score ≥ 8 may severely compromise therapeutic efficacy. Furthermore, interaction plots indicated an exploratory model-based association where advanced age and severe comorbidity clustered with lower predicted probabilities, while reduced dose interventions coincided with altered model predictions in this specific subpopulation.ConclusionCIRS-G showed the strongest incremental predictive value among the evaluated comorbidity scores in this single-center cohort. Machine learning and SHAP analysis provide exploratory insights for individualized risk stratification, though the reported predictive performance may overestimate prospective validity due to temporal variations and retrospective design.

Ruxolitinib is first-line therapy for intermediate/high-risk myelofibrosis (MF), but ∼50% of patients discontinue within 1 year due to loss of efficacy or intolerance. Four JAK inhibitors (gecacitinib, fedratinib, pacritinib, momelotinib) are approved for ruxolitinib-pretreated MF, with no head-to-head trials comparing their efficacy and safety. This study used matching-adjusted indirect comparison (MAIC) to compare these four agents, aiming to provide evidence-based insights for treatment decision-making in ruxolitinib-resistant or intolerant MF. Individual patient data (IPD) of gecacitinib (100 mg BID; ZGJAK006/ZGJAK017, n = 78) and published data of comparators (fedratinib: JAKARTA-2/FREEDOM2; pacritinib: PAC203; momelotinib: SIMPLIFY-2/MOMENTUM) were analyzed. Eight baseline characteristics were matched. Efficacy outcomes (week-24 SVR35, TSS50, transfusion independence [TI]) were reported as odds ratios (ORs); safety as risk differences (RDs). Gecacitinib showed superior SVR35 versus fedratinib (JAKARTA-2: OR = 3.96, 95% CI = 1.37-11.39, P = 0.0108), pacritinib (PAC203: OR = 6.10, 95% CI = 1.54-24.23, P = 0.0101), and momelotinib (SIMPLIFY-2: OR = 8.65, 95% CI = 1.86-40.31, P = 0.0060), and superior TSS50 versus pacritinib (OR = 7.62 95% CI = 1.84-31.51, P = 0.0050) and momelotinib (MOMENTUM: OR = 7.52, 95% CI = 1.63-34.61, P = 0.0096). Numerically, gecacitinib had better TI. It also had significantly lower incidences of diarrhea, nausea, and AE-related treatment discontinuation. Hematologic AE profiles of gecacitinib varied by comparator cohort. Gecacitinib showed favorable efficacy and tolerability signals versus several comparators, suggesting it may be a valuable second-line option.

Despite advances in treatment, acute myeloid leukemia (AML) remains a formidable therapeutic challenge, highlighting the urgent need for novel biomarkers and therapeutic targets. The choline transporter SLC44A1 has been implicated in cancer progression; however, its role in AML remains largely unexplored. Here, we investigated the clinical relevance and molecular mechanisms of SLC44A1 in AML. Analysis of The Cancer Genome Atlas (TCGA) datasets revealed significant upregulation of SLC44A1 in AML patients, correlating with poor patient prognosis. Functional studies demonstrated that SLC44A1 knockdown markedly inhibited AML cell proliferation and enhanced chemosensitivity to cytarabine and venetoclax. RNA sequencing and pathway analysis identified the NOTCH signaling pathway as a key downstream target of SLC44A1, which was further validated by western blot. Collectively, our findings establish SLC44A1 as a crucial regulator of AML progression and chemoresistance, highlighting its dual potential as a prognostic biomarker and a therapeutic target.

Acute myeloid leukemia (AML) is a hematological cancer prevalent worldwide. Anoikis-related genes (ARGs) are crucial in the progression of cancer and metastasis of tumors. However, their role in AML needs to be clarified. In the present study, differential analysis was performed on data from The Cancer Genome Atlas database to identify differentially expressed ARGs (DE-ARGs). Subsequently, a prognostic model for patients with AML was constructed using univariate Cox, Least Absolute Shrinkage and Selection Operator and multivariate Cox regression analyses. This model was based on four key DE-ARGs [lectin galactoside-binding soluble 1 (LGALS1), integrin subunit alpha 4 (ITGA4), hepatocyte growth factor (HGF) and Ras homolog gene family member C (RHOC)]. Independent prognostic factors for AML included prior treatment, age, risk scores and diagnosis. A nomogram was constructed based on these factors to aid clinical decision-making. Furthermore, bone marrow samples were collected from individuals diagnosed with AML and healthy donors to validate the expression of the identified ARGs using reverse transcription-quantitative PCR. The mRNA levels of LGALS1 and RHOC were significantly higher, while those of ITGA4 and HGF were significantly lower in patients with AML than in healthy donors (all P<0.05). The results of the present study expands the understanding of the function of ARGs in AML, providing a new theoretical basis for the treatment of AML.

[This retracts the article DOI: 10.3892/etm.2015.2209.].

Background: Hodgkin lymphoma (HL) represents a significant malignancy, yet comprehensive data on its epidemiological evolution are lacking. This study quantifies the global, regional, and national burden of HL from 1990 to 2021 and projects trends to 2050. Methods: Using population-based registry data from the 2021 Global Burden of Disease (GBD) study (204 countries/territories), we computed age-standardized rates (ASRs) per 100,000 for incidence, prevalence, mortality, and disability-adjusted life-years (DALYs). Bayesian meta-regression tools modeled 2050 projections. Results: In 2021, an estimated 65182.01 incident cases of HL were recorded globally. The highest ASR per 100,000 were observed for prevalence (4.42, 95% CI, 3.75-5.09), mortality (0.34, 95% CI: 0.25-0.43), DALYs (14.82, 95% CI:10.43-18.96), and incidence (0.79, 95% CI: 0.64-0.94). Males exhibited significantly higher disease burden compared to females. While absolute incident cases increased by 19.23% (54,671 in 1990 → 65,182 in 2021), ASIR declined by 0.1% annually. This divergence was primarily driven by population growth and aging, offset by epidemiological improvements reflected in falling ASIR, ASMR, and DALY rates. Health inequality analysis revealed a disproportionately high burden in countries with high sociodemographic index (SDI) levels. Frontier analysis identified nations with substantial potential to reduce the burden of Hodgkin lymphoma. By 2050, incidence rates attributable to Hodgkin lymphoma are projected to increase.Interpretation: These findings indicate that males and people in high SDI countries will likely face an increasing Hodgkin lymphoma burden. There is an urgent need for effective prevention and management strategies targeting high-risk groups. Keywords: Hodgkin lymphoma, GBD, mortality, DALYs, ASR, prevalence

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. We previously discovered that heme oxygenase 1 (HO1) is crucial for chemoresistance in AML, but the detailed molecular mechanism of that remains unclear. RNA sequencing was conducted to assess transcriptomic changes in three pairs of AML cells after regulating the expression of HO1. The molecular mechanism by which HO1 induces gilteritinib resistance in FLT3-ITD (FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD)) AML was evaluated by quantitative real-time PCR (qRT-PCR), CCK-8, flow cytometry, and western blotting. FLT3-ITD AML mouse models were established to investigate the effects of HO1 expression on gilteritinib resistance in vivo. In these three pairs of AML cells, we discovered that HO1-mediated drug resistance is connected to the interleukin-4-mediated signaling pathway (specifically STAT6) only in MV4-11 cells with the FLT3-ITD mutation. Further findings revealed that HO1 overexpression confers gilteritinib resistance in FLT3-ITD AML cell lines and primary individual specimens. While suppression of HO1 sensitized FLT3-ITD AML cell lines and primary individual specimens to gilteritinib. Mechanistically, western blotting and flow cytometry confirmed that HO1-mediated gilteritinib resistance is related to STAT6 phosphorylation in FLT3-ITD AML cell lines and primary individual specimens. Moreover, tumor-bearing mice were employed to determine that HO1 overexpression conferred gilteritinib resistance in vivo. Collectively, these studies illustrate that HO1 may act as a successful treatment target for gilteritinib-resistant FLT3-ITD AML patients.

BackgroundTumor microenvironment (TME) represents the key factor inducing leukemia development. As stromal cells within the leukemia microenvironment, Bone Marrow Mesenchymal Stem Cells (BM-MSCs) can trigger leukemia progression under certain conditions. As a critical transcription factor, nuclear factor erythroid related factor 2 (Nrf2) can modulate antioxidant response and antioxidant enzyme gene expression, and prevent various oxidative changes. We previously identified a novel mechanism by which Nrf2 promotes leukemia resistance, providing a potential therapeutic target for the treatment of drug-resistant/refractory leukemias. However, the role of Nrf2 in BM-MSCs from B-cell acute lymphoblastic leukemia (B-ALL) patients has not been clearly reported. The present work focused on investigating the effect of Nrf2 overexpression within MSCs on leukemia cell invasion, extramedullary infiltration and proliferation as well as its downstream pathway.MethodsThrough clinical sample detection, in vitro cell experiments and in vivo animal experiments, the role of Nrf2 within MSCs within adult B-ALL cell migration and invasion and its potential molecular mechanism was explored through transcriptome sequencing analysis, RT-PCR, Western blot, cell migration, cell invasion, lentivirus transfection and other experiments.ResultsNrf2 was highly expressed in BM-MSCs from patients with B-ALL as well as in BM-MSCs co-cultured with leukemia cells. Overexpression of Nrf2 within MSCs significantly promoted leukemia cell migration, invasion and proliferation. The extramedullary organ infiltration rate in B-ALL model mice receiving the combined infusion of both cell types dramatically increased relative to that of leukemia cells alone, accompanied by the significantly shortened survival time. Mechanism study found that Nrf2 overexpression within MSCs promoted PI3K-AKT/ERK1/2 phosphorylation in the downstream pathway by activating SDF-1/CXCR4 axis, ultimately leading to extramedullary infiltration of leukemia cells.ConclusionHigh Nrf2 expression with in MSCs enhances leukemia cell invasion and migration, which then accelerates infiltration in leukemic extramedullary organs. Targeting Nrf2 or inhibiting its downstream signal molecules may be the effective interventions for B-ALL patients treatment.

Introduction Despite recent advances in treating myelofibrosis (MF)-associated splenomegaly and symptoms, disease- and treatment-associated cytopenias remain challenging.Gecacitinib (GCA), a JAK and ACVR1 dual inhibitor, demonstrated spleen, symptom, and anemia benefits in intermediate- and high-risk MF. A matching-adjusted indirect comparison of GCA versus ruxolitinb (presented on 2025 EHA congress; PS1839) reported GCA offered a trend of higher splenic benefits and was associated with significantly less grade 3/4 anemia and neutropenia compared with ruxolitinib (RUX). To evaluate the efficacy and safety of GCA in patients with MF and thrombocytopenia (platelet counts <100 × 109/L), we conducted a post-hoc analyses with pooled data sets from 4 clinical studies: ZGJAK016 (phase 3; GCA versus hydroxyurea; JAK inhibitor naïve), ZGJAK002 (phase 2; GCA optimal dosing frequency exploration; JAK inhibitor naïve), ZGJAK006 (phase 2; GCA single arm; intolerant to RUX), and ZGJAK017 (phase 2; GCA single arm; refractory or relapsed to RUX). Methods Detailed study designs for these studies have been published. In the ZGJAK016 study, patients received randomized treatment for 24 weeks (main study period); thereafter, patients who didn't achieved a 35% reduction in spleen volume from baseline (SVR35) at week 24 could receive open-label GCA 100 mg BID for an extension period, whereas patients who achieved a SVR35 could continue receiving the initially assigned treatment. In the other 3 studies, patients received open-label GCA at different doses (100 mg BID, 150 mg QD and 100 mg QD) for 24 weeks (main study period) and then could continue in the extension period. The primary endpoint of these study was 24-week rate of SVR35. The key secondary endpoints included 24-week rate of total symptom score reduction by 50% or more (TSS50), improvement in anemia at week 24 (including the conversion rate of baseline transfusion-dependence to independence, proportion of non-transfusion-dependent patients with baseline hemoglobin ≤100 g/L achieving an increase of ≥20 g/L, and reduction in red blood cell transfusion frequency or unit by ≥50%). Data were pooled from patients with platelet counts <100 × 109/L at baseline who received at least one dose of GCA, with enrollment dates from 2019 to 2022. Only 1 patient in the hydroxyurea group from ZGJAK016 had platelet counts <100 × 109/L, thereby being excluded. These post hoc, exploratory, efficacy and safety analyses are descriptive. Results A total of 24 of 273 patients (9%) received GCA in ZGJAK016 (n=1), ZGJAK002 (n=3), ZGJAK006 (n=12) and ZGJAK017 (n=8) had baseline platelet counts <100 × 109/L (moderate thrombocytopenia) and only 1 patient (6%) had baseline platelet counts <50 × 109/L (severe thrombocytopenia). Of the 24 patients, 19 patients received 100 mg BID as initial dose (JAKi-naïve, n=4; RUX-intolerant, n=7; RUX-refractory/relapsed, n=8), 4 and 1 received 150 mg QD and 100 mg QD (all were RUX-intolerant). The SVR35 rate at week 24 were 75%, 42% and 25% in the JAKi-naïve, RUX-intolerant and RUX-refractory/relapsed patients. The TSS50 rate at week 24 were 50%, 33% and 50%, respectively. The proportion of non-transfusion-dependent patients with baseline hemoglobin ≤100 g/L achieving a ≥20 g/L increase in hemoglobin level by week 24 were numerically higher in the JAKi-naïve patients (67%, 50% and 50%). Mean platelet counts either increased or were maintained from baseline levels over the 24-week main period. Overall, 79% of 24 patients completed the main study period. Half of the patients had dose suspension or reduction due to adverse events and 3 patients with lower starting dose had a dose increase to 100 mg BID (2 in the main period and 1 in the extension period). After study termination, 8 patients continued to take GCA for compassionate use. As of the data cutoff (25 June 2025), 4 patients were receiving GCA, with all remaining on therapy for >4 years. A median duration of treatment was 17.4 months (range, 0.5-69.4 months). The most common (occurring in ≥10% of patients) treatment-emergent adverse events during the initial 24-week treatment were generally consistent with those reported in the overall population. One exception was a higher incidence of thrombocytopenia (Any grade: 67%; Grade ≥3: 46%), however most were manageable and only 2 led to discontinuation. Conclusions GCA represents a safe and effective treatment option for MF patients with moderate thrombocytopenia.

Objective: Diffuse Large B-cell Lymphoma (DLBCL) is a hematologic malignancy characterized by the clonal expansion of myeloid progenitor cells and a highly immunosuppressive tumor microenvironment (TME). Among the key contributors to this immunosuppression are tumor-associated macrophages (TAMs), particularly those polarized toward an M2-like phenotype. These M2 macrophages support leukemia progression by suppressing anti-tumor immunity, promoting angiogenesis, and enhancing resistance to chemotherapy. Heme oxygenase-1 (HO-1), a stress-inducible enzyme known for its antioxidant and anti-inflammatory functions, has been reported to be upregulated in various cancers, including DLBCL. However, the immunological consequences of HO-1 overexpression in DLBCL, especially its impact on TAM polarization and immune evasion, remain poorly understood. This study aimed to investigate the molecular mechanism by which HO-1 modulates macrophage polarization and shapes the immune microenvironment in DLBCL. The ultimate goal is to provide a theoretical basis for targeting HO-1 or TAM phenotypes as a therapeutic strategy to improve clinical outcomes in DLBCL. Methods: A combined bioinformatic and experimental approach was employed. Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) DLBCL cohort and multiple GEO datasets were analyzed. Patients were divided into HO-1^high and HO-1^low groups based on expression levels. Immune cell infiltration was estimated using CIBERSORT and xCell algorithms. Differentially expressed genes (DEGs) between the two groups were identified using DESeq2 and further analyzed through GO and KEGG enrichment to explore biological pathways associated with HO-1. Weighted gene co-expression network analysis (WGCNA) was applied to identify gene modules related to HO-1 and immune infiltration. Protein-protein interaction (PPI) networks were constructed using STRING, and key hub genes were identified using Cytoscape's CytoHubba plugin. For in vitro validation, DLBCL cell lines were transduced with HO-1-overexpressing or control lentiviral vectors. Peripheral blood mononuclear cells (PBMCs) from healthy donors were isolated and induced to differentiate into M0 macrophages with M-CSF. Co-culture assays were performed using transwell systems, exposing macrophages to HO-1-overexpressing DLBCL cells. Macrophage polarization was assessed by qPCR for M1 (TNF-α, IL-12) and M2 (CD163, IL1RN, ARG1) markers, ELISA for cytokine secretion, and flow cytometry for CD86/CD206 surface markers. Results: Patients in the HO-1^high group displayed significantly higher levels of M2 macrophage infiltration and reduced NK cell activation, suggesting a link between HO-1 expression and immunosuppression in DLBCL. DEG analysis revealed enrichment in immune regulatory and vesicle transport pathways. WGCNA and PPI analyses identified HO-1 as closely associated with M2 markers such as CD163 and IL1RN. In vitro co-culture experiments confirmed that HO-1-overexpressing DLBCL cells promoted M2 polarization of macrophages. Macrophages exposed to HO-1^high DLBCL cells exhibited increased CD206, CD163, and IL1RN expression, and decreased IL-12 and TNF-α. Flow cytometry analysis corroborated these findings, showing an elevated proportion of CD206⁺ macrophages. Through qPCR and WB detection, it was found that the expression levels of IL-4 and IL-10 in DLBCL cells in the HO-1 upregulated group increased, and the levels of IL-4 and IL-10 in the supernatant also increased accordingly. Overexpression of HO-1 upregulated the production of interleukin-4 and interleukin-10 in leukemia cells. IL-4 alone could induce similar M2 polarization in macrophages. Neutralizing IL-4 could partially reverse the M2 polarization induced by HO-1, indicating that IL-4 at least partially mediates the immunomodulatory effect of HO-1. Conclusion: This study demonstrates that HO-1 is a critical driver of TAM polarization and immune microenvironment remodeling in DLBCL. Through upregulation of IL-4, HO-1 enhances M2 macrophage polarization, contributing to immune evasion and potentially to treatment resistance. These findings highlight HO-1 as both a biomarker and a promising therapeutic target. Inhibiting HO-1 or reprogramming TAMs from an M2 to an M1 phenotype may improve anti-leukemic immune responses and enhance the efficacy of current DLBCL therapies.

Background: Acute myeloid leukemia (AML) remains a therapeutic challenge due to its genetic complexity and frequent resistance to conventional therapies, frequently associated with impaired tumor suppressor function. DCAF5 (DDB1-CUL4-associated factor 5), a substrate receptor for the CRL4 E3 ubiquitin ligase complex, has been implicated in maintaining oncogenic states through degradation of tumor suppressor complexes, while its biological and therapeutic relevance in AML pathogenesis remains undefined. Purpose: This study aimed to(1) define the functional role of DCAF5 in AML maintenance, (2)elucidate the mechanistic relationship between DCAF5 and p53 regulation, (3)evaluate the therapeutic potential of combined DCAF5 targeting and MDM2 inhibition. Methods: DCAF5 expression and its correlation with clinical outcomes were analyzed in AML patient cohorts using publicly available datasets and patient-derived samples. Genetic perturbation of DCAF5 was performed in AML cell lines using CRISPR/Cas9. In vitro and in vivo AML models were employed to investigate the functional role of DCAF5. Protein interactions were characterized by co-immunoprecipitation and mass spectrometry, while p53 stability was assessed through ubiquitination assays and cycloheximide chase experiments. Functional consequences were evaluated using apoptosis, cell cycle, and differentiation assays. The therapeutic potential was further validated in patient-derived xenograft (PDX) models. Results: DCAF5 expression was significantly elevated in AML and correlated with poor prognosis. Genetic ablation of DCAF5 induced potent anti-leukemic effects, including cell cycle arrest, apoptosis, and myeloid differentiation. Mechanistically, DCAF5 directly interacts with p53, promoting its ubiquitin-mediated proteasomal degradation, consequently suppressing p53 transcriptional networks, while DCAF5 konckout substantially restores p53 related transcriptional expression profile and tumor suppressor function. Strikingly, combined DCAF5 targeting and MDM2 inhibition elicited synergistic lethality both in vitro and in vivo, with reducing leukemic burden and extending survival in AML PDX. Conclusion: Collectively, our study establishes DCAF5 as a critical oncogenic driver in AML through its regulation of p53 proteostasis. DCAF5 ablation reactivates p53 tumor suppressor function and exerts anti-leukemic effects. The mechanistic elucidation of the DCAF5-p53 axis provides preclinical evidence supporting the development of DCAF5 -targeted strategies, particularly for enhancing MDM2 inhibitor sensitivity in AML.

Background:The objective of this research was to investigate the involvement of RAB39B in acute myeloid leukemia (AML) using bioinformatics analysis and in vitro experiments for validation. Methods:In this article, RNA sequencing data from The Cancer Genome Atlas and genotype-tissue expression were utilized to analyze the expression of RAB39BA and identify differentially expressed genes. Results:AML exhibited elevated expression of RAB39B in diverse tumor types. In laboratory experiments, it has been demonstrated that RAB39B exhibits a significant expression level in AML cell lines when compared to normal peripheral blood monocytes. Moreover, RAB39B is closely linked to the growth and programmed cell death of AML cells. Conclusion:In conclusion, RAB39B shows potential as a biomarker for the identification and prediction of AML, contributing to the growth and cell death processes in AML.

BACKGROUND:Acute leukaemia represents a crucial health challenge. However, nationwide data delineating the incidence of acute leukaemia subtypes, as well as mortality and survival outcomes, remain scarce in China. We aimed to provide a comprehensive assessment of the epidemiology of acute leukaemia subtypes across China. METHODS:We conducted a population-based cancer registry analysis and cohort study in China, by integrating data from five national databases through unique national identification numbers. The main outcomes were age-standardised rates (ASRs) for incidence and mortality and overall survival for acute leukaemia subtypes. Acute leukaemia incidence and mortality data in 2019 were extracted from National Cancer Centre (NCC) registries linked to the Hospital Quality Monitoring System (HQMS), stratified by age, sex, and region. ASRs were calculated with Segi's world standard population with 95% CIs across the general population. For the survival analysis, we established a cohort from the Chinese Childhood Leukaemia Registry (33 530 children aged 0-14 years) and National Adult Acute Leukaemia Registry of China (71 477 adults aged ≥15 years) for 2016-20, integrated with the Cause of Death Reporting System and HQMS. Patients were stratified by subtype, age, sex, region, molecular characteristics, treatment modalities, and diagnosis period (2016-18 vs 2019-20). Overall survival and cause-specific survival were assessed with the Kaplan-Meier method at multiple timepoints (1 month, and year 1 to year 5) in our cohort. Multivariate Cox regression analysis was performed to identify prognostic factors. FINDINGS:Based on NCC registries covering a population of 628·4 million, we estimated 43 275 new acute leukaemia cases and 27 049 deaths in 2019 in China, with an ASR for incidence 2·83 (95% CI 2·78-2·88) per 100 000 population and an ASR for mortality of 1·51 (1·48-1·54) per 100 000 population. The ASR for the incidence of non-acute promyelocytic leukaemia-acute myeloid leukaemia was 1·24 (95% CI 1·21-1·26) per 100 000 population, that of acute lymphoblastic leukaemia was 0·92 (0·89-0·95) per 100 000 population, and that of acute promyelocytic leukaemia was 0·22 (0·21-0·23) per 100 000 population. The incidence of acute leukaemia spiked in children aged 1-4 years (4·54 per 100 000), then declined, and then rose markedly after age 60 years, peaking at 9·33 per 100 000 in people aged 75-79 years, before declining, while overall mortality remained relatively low across younger age groups (0-44 years), then increased progressively with advancing age, from 1·23 per 100 000 in adults aged 45-49 years to 8·77 per 100 000 in those aged 80-84 years. In children, 5-year overall survival was 66·5% (95% CI 65·3-67·9) for non-acute promyelocytic leukaemia acute myeloid leukaemia, 91·1% (89·6-92·6) for acute promyelocytic leukaemia, and 85·4% (84·9-85·8) for acute lymphoblastic leukaemia; in adults, 5-year overall survival was 23·9% (23·4-24·3) for non-acute promyelocytic leukaemia acute myeloid leukaemia, 82·5% (81·7-83·4) for acute promyelocytic leukaemia, and 30·1% (29·2-30·9) for acute lymphoblastic leukaemia. Survival improved in the more recent period (2019-20 vs 2016-18: hazard ratio 0·97 [95% CI 0·95-0·99]; p=0·0014), particularly among younger adults with non-acute promyelocytic leukaemia acute myeloid leukaemia (aged <60 years) and acute lymphoblastic leukaemia (aged <40 years), with improvements primarily attributable to expanded application of allogeneic haematopoietic stem-cell transplantation. However, prognosis remained poor in patients with acute leukaemia aged 60 years and older (5-year overall survival 14·9% [95% CI 14·3-15·5] in patients aged 60-74 years, and 4·8% [4·2-5·4] in patients aged ≥75 years). INTERPRETATION:This comprehensive nationwide study of acute leukaemia incidence, mortality and survival outcomes across China establishes age-specific epidemiological benchmarks, enabling ongoing risk factor monitoring, while supporting expanded transplantation access for eligible patients and highlighting the urgent need for novel, less toxic therapies for older patients who bear a disproportionately higher disease burden. FUNDING:State Key Laboratory of Medical Genomics, Double First-Class Project, Overseas Expertise Introduction Project for Discipline Innovation, National Natural Science Foundation of China, Innovative Research Team of High-level Local Universities in Shanghai, Shanghai Guangci Translational Medical Research Development Foundation, and CAMS Innovation Fund for Medical Sciences. TRANSLATIONS:For the Chinese translation of the abstract see Supplementary Materials section.

Although patients with acute myeloid leukaemia (AML) initially respond to conventional treatments, many patients die from AML progression and relapsed/refractory (RR) disease. Eradicating AML thus remains therapeutically challenging. In this study, we found a strong expression of aldehyde dehydrogenase 2 (ALDH2) and increased mitochondrial biosynthesis in samples from patients with drug-resistant AML, and these changes were strongly associated with poor prognosis and recurrence of AML. We examined the clonogenic capacity, growth and apoptosis of AML cells, as well as mitochondrial DNA expression and reactive oxygen species production. Our results revealed that chemotherapeutic agents triggered the activation of NF-E2-related factor 2 (Nrf2) and promoted high expression of ALDH2, mediating the compensatory activation of mitochondrial respiration and resistance to chemotherapeutic agents in RR AML cells. Nrf2 promoted mitochondrial respiration by activating ALDH2 expression and stabilising the expression of DNA polymerase-gamma2 (PolG2) in mitochondria. Inhibition of the Nrf2-ALDH2/PolG2 pathway reduced AML metabolic fitness and oxidative phosphorylation levels, highlighting the key role of this pathway in promoting cell survival. Nrf2 inhibition reduced the translation of ALDH2, induced a unique mitochondrial stress response and inhibited mitochondrial biosynthesis in AML cells. Importantly, tumours in an in vivo xenograft model were sensitive to combined Nrf2 and ALDH2 inhibition. Given the role of the Nrf2-ALDH2/PolG2 pathway in the progression of AML, inhibition of this pathway may prevent disease relapse/resistance and promote sensitisation to chemotherapy.

Introduction LBL-034 is a humanized IgG1 subtype asymmetric bispecific antibody targeting GPRC5D and CD3 with a 2:1 format. Its unique design features affinity optimization and steric hindrance within the anti-CD3 arm, effectively reducing off-target engagement with bystander T cells and minimizing non-specific T cell activation. Additionally, the bivalent, high-affinity anti-GPRC5D Fab domains enable potent, conditional T cell activation exclusively in the presence of GPRC5D-expressing tumor cells. Here, we report the robust clinical efficacy and favorable safety data from the phase I/II study (NCT06049290) in patients with relapsed/refractory multiple myeloma (RRMM). Methods This ongoing phase I/II, open-label study includes a dose escalation stage followed by dose expansion (phase I). Eligible RRMM patients had received ≥3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, with or without an anti-CD38 monoclonal antibody. LBL-034 was administered intravenously at escalating dose levels of 10, 30, 80, 200, 400, 800, and 1200 μg/kg. Dosing occurred on Days 1 and 15 of each 4-week cycle. Starting from the 80 μg/kg cohort, a step-up dosing strategy (10 to 80 μg/kg) was implemented to mitigate CRS risk. Tumor responses were assessed by investigators per IMWG criteria. AEs were graded per CTCAE v5.0, and CRS and ICANS were graded according to the ASTCT consensus. Minimal residual disease (MRD) negativity in bone marrow aspirates was evaluated by next-generation sequencing (Seq-MRD®). Results As of July 15, 2025, 56 patients were enrolled in phase I dose escalation/expansion. The dose distribution was as follows: 10 μg/kg (n=1), 30 μg/kg (n=1), 80 μg/kg (n=6), 200 μg/kg (n=7), 400 μg/kg (n=19), 800 μg/kg (n=11), and 1200 μg/kg (n=11). Median age was 64 years (range 34-79), and patients had received with a median of 5 prior lines of therapy (range 3-11). Most patients were triple-class exposed (n=39, 69.6%) and penta-drug exposed (n=32, 57.1%). Prior therapies included ASCT (n=16, 28.6%) and BCMA-directed CAR-T (n=9, 16.1%). Extramedullary disease (EMD) was present in 13 patients (23.2%). Efficacy: Among 55 efficacy evaluable patients (≥1 post-baseline tumor assessment), ORR was 70.9% (39/55), with dose-dependent trends observed: 200 μg/kg (mFU 11.6 m): ORR 57.1%; ≥VGPR 57.1%; ≥CR 14.3% 400 μg/kg (mFU 10.4 m): ORR 77.8%; ≥VGPR 61.1%; ≥CR 55.6% 800 μg/kg (mFU 5.1 m): ORR 90.9%; ≥VGPR 81.8%; ≥CR 54.5% 1200 μg/kg (mFU 2.7 m): ORR 81.8%; ≥VGPR 63.6%; ≥CR 27.3% MRD negativity was achieved in 84.2% (16/19) at the 10-5 threshold among MRD-evaluable and ≥CR patients. Median time to first CR shortened with higher doses: 6.0 months (m) at 400 μg/kg, 3.4m at 800 μg/kg, and 2.7m at 1200 μg/kg. Notably, strong clinical benefit was observed in difficult-to-treat subgroups at doses ≥400 μg/kg: Penta-drug exposed: ORR 78.1% Post-BCMA-targeted therapy: ORR 85.8% ORR 75.0% The mPFS at doses ≥200 μg/kg (n=47) was 11.7m (8.1, NE) with a median follow-up (mFU) of 6.8m. Safety: All patients experienced TEAEs, with ≥ grade 3 (G3) TEAEs reported in 83.9%. The most frequent ≥ G3 hematologic TEAEs included: Lymphopenia (51.8%) Neutropenia (28.6%) Leukopenia (25.0%) Thrombocytopenia (17.9%) Anemia (16.1%) CRS occurred in 73.2% of patients, predominantly G1 (51.8%) and G2 (19.6%), and was primarily observed during the first few days of Cycle 1. Only one patient experienced G3 (1.8%) CRS, with no ≥ G4 event reported. Quality-of-life related TEAEs included dysgeusia (G1 44.6%, G2 5.4%, ≥G3 none), nail disorder (G1 42.9%, G2 5.4%, ≥G3 none), skin disorder (G1 39.3%, G2 3.6%, ≥G3 none) and decreased appetite (G1 3.6%, G2 7.1%, ≥G3 none), all of which were low grades and manageable. Only one patient discontinued treatment due to a TEAE. No DLTs or dose reduction were reported. Conclusions LBL-034 demonstrated highly encouraging anti-tumor activity in patients with RRMM, including those in difficult-to-treat subgroups with high-risk features. Deep and durable response—including ≥CR and MRD negativity—were achieved across multiple dose levels (200-1200 μg/kg). Its conditionally activated design contributed to a favorable safety profile, particularly at higher dose levels. These compelling efficacy and safety results strongly support the continued clinical development of LBL-034 in RRMM. Updated data, including longer PFS follow-up and extended safety analyses, will be presented at the upcoming ASH Annual Meeting.