Myeloproliferative neoplasms (MPN) are hematological disorders driven by mutated hematopoietic stem cells, characterized by an increased risk of thrombosis and progression to leukemia. Patients with MPN exhibit elevated levels of inflammatory factors, which function as promoters of disease progression and transformation into acute leukemia. Fufang Huangbo formula (FHF) is a classic traditional Chinese herbal medicine widely used in the treatment of inflammation-related diseases, where it has shown considerable therapeutic efficacy. However, its potential effects on MPNs remain unclear. In this study, we demonstrate for the first time across multiple animal models that FHF significantly alleviates MPN progression, including EPO-induced polycythemia vera (PV)-like, JAK2V617F-driven PV, and MPLW515L-driven essential thrombocythemia (ET) models. FHF effectively reduced erythrocyte aggregation-induced thrombosis in PV and reversed myelofibrosis in ET. To explore the therapeutic effects, active components, and mechanisms of FHF in MPNs, we performed network pharmacology and RNA-seq analyses, with subsequent experimental validation. The results indicate that the therapeutic benefits of FHF are closely associated with cellular senescence and inflammatory responses. Validation experiments showed that FHF induces cellular senescence via activation of the p53/p21 pathway and suppresses inflammation by inhibiting the STAT3 and NF-κB signaling pathways. Our study provides scientific evidence supporting the use of FHF in the treatment of MPNs.

ABSTRACT:Intensive chemotherapy is standard for acute myeloid leukemia (AML) but carries high risks of life-threatening complications, particularly in vulnerable patients. We aimed to compare the efficacy and safety of a low-dose chemotherapy (LDC) regimen for induction of AML. A randomized, multicenter, noninferiority trial was conducted in patients with AML aged <18 years. Patients received low-dose cytarabine, mitoxantrone or idarubicin, and granulocyte colony-stimulating factor (G-CSF) or standard-dose chemotherapy (SDC; cytarabine, daunomycin, and etoposide). All patients received postremission consolidation with standard chemotherapy and/or hematopoietic stem cell transplantation. The primary end point was to compare response rates between treatments. The secondary end points were to compare the outcomes, toxicity, and safety of the LDC and SDC regimens. The 2 treatment arms showed no significant differences in outcomes. Complete remission (CR)/CR with incomplete count recovery rates after induction were 95.1% and 95.3% in the LDC and SDC arms, respectively. Measurable residual disease <0.1% after induction II was observed in 87.4% and 87.1% of patients in the LDC and SDC arms, respectively. Median time to neutrophil and platelet recovery was significantly shorter among patients receiving the LDC regimen. Patients in the LDC arm had a 4-year overall survival (OS) of 81.3% vs 83.6% (P = .611), and a 4-year event-free survival (EFS) of 61.5% vs 63.1% (P = .832). In conclusion, the LDC regimen was well tolerated, and was associated with CR, EFS, and OS rates that were not inferior to those of patients treated with the SDC regimen. The trial was registered at www.chictr.org.cn as ChiCTR1800015883.

MPL (myeloproliferative leukemia virus) is a type I transmembrane glycoprotein acting as the receptor for thrombopoietin (TPO). Increasing evidence indicates that MPL is essential for stem cell maintenance and megakaryopoiesis. Activating mutations in MPL have been identified as the major driver mutations of myeloproliferative neoplasms (MPNs) characterized by excessive proliferation of multiple lineages. Given its dual role in hematopoiesis and MPN pathogenesis, studies of MPL reveal the imbalance between stem cell homeostasis and malignant proliferation. Here, we summarize MPL’s physiological functions and pathogenic roles, with the aim to provide novel insights into disease mechanisms and potential therapeutic strategies.

No standard salvage regimen exists for relapsed/refractory (R/R) pediatric AML. In this prospective, multicenter Phase II trial, 101 evaluable patients (

Autoimmune gastritis (AIG) is a chronic immune-mediated atrophic disease that can induce cancer-related epithelial remodeling, although its association with gastric adenocarcinoma depends on histological and clinical modifiers. Gastric cancer (GC) progression is shaped by the tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs), myeloid cells, and extracellular matrix (ECM) remodeling. Whether AIG-related mucosal remodeling shares stromal programs with GC-associated stromal–myeloid niches remains unclear. We integrated one AIG bulk-transcriptomic cohort and three GC cohorts to identify shared differentially expressed genes (DEGs), followed by LASSO, random forest and protein–protein interaction (PPI) analyses. TIMP1 was evaluated using tissue transcriptomic cohorts, serum RT-qPCR, survival analysis, immune infiltration profiling, scRNA-seq, inferCNV-based epithelial classification, CellChat ligand–receptor inference and spatial transcriptomics. A total of 51 shared DEGs were identified between AIG and GC. TIMP1 was the only candidate supported by both machine-learning screening and PPI hub-gene analysis. TIMP1 was upregulated in GC tissues and serum and showed an exploratory tumor–normal ROC AUC of 0.941 in the TCGA_STAD cohort, while higher TIMP1 expression was associated with poorer overall survival. Functional analyses linked TIMP1-high GC to ECM organization, integrin binding, epithelial-mesenchymal transition (EMT), transforming growth factor-β signaling and immune infiltration. scRNA-seq of 160,812 GC cells localized TIMP1 mainly to CAF and myeloid compartments. In AIG, TIMP1-high fibroblasts displayed enhanced CAF-associated stromal and inflammatory transcriptional programs. CellChat and spatial transcriptomics further linked TIMP1-associated stromal and myeloid states to ECM-dominant communication and fibroblast-rich, myeloid-associated remodeling regions. TIMP1 may mark related stromal–myeloid remodeling states across AIG-associated mucosal remodeling and GC, providing a hypothesis-generating framework potentially relevant to inflammation-associated gastric tumorigenesis.

Typ515 (W515) mutations in the protein MPL are one of the key driver mutations promoting BCR-ABL-negative myeloproliferative neoplasms (MPNs), but, to our knowledge, their effects on hematopoietic stem cells (HSCs) and MPN-related hematological abnormalities have not been studied in physiological contexts. Here, we established a MplW514L knock-in mouse model, which largely mimics human MPLW515L mutation during hematopoiesis. The mutant mice developed an essential thrombocythemia–like (ET-like) MPN phenotype, displaying excess megakaryopoiesis and thrombocytosis and progressive myelofibrosis. Mechanistically, we observed that the MplW514L-conditioned HSC compartment had a unique disease-initiating capacity; however, it did not exhibit a obvious advantage of competitive repopulation over the WT control. Notably, single-cell analysis and flow cytometry profiles support that MplW514L expression led to a significant expansion of megakaryocyte-biased stem cell fate within the HSC pool. Finally, JAK2 inhibitor treatment phenotypically alleviated the ET signs but failed to eliminate the disease-initiating HSCs. These findings underscore the etiology of physiological expression of the MPLW515L mutation in HSCs and also provide a valuable in vivo model to evaluate potential therapeutic options for patients with MPLW515L-positive MPN.

The Warburg effect-induced lactate production in T-cell acute lymphoblastic leukemia (T-ALL) cell proliferation is well established, however, the role of lactate-mediated protein lactylation in this process remains poorly understood. In this study, we demonstrated that inhibiting lactate levels through the lactate dehydrogenase A (LDHA) inhibitor significantly reduced both cell proliferation and protein lactylation levels in T-ALL cells. Lactate deficiency led to a marked decrease in protein lactylation, accompanied by impaired cell proliferation. Meanwhile, lactate deficiency also induced the S‑phase cell cycle arrest and reduced DNA synthesis, which collectively impaired cell proliferation. Mechanistically, we observed that the decreased expression of lactylation in histone H3 at lysine 18 (H3K18lac) reduced the enrichment of this mark on the promoter region of neurotrophic receptor tyrosine kinase 3 (NTRK3), which supported the cell proliferation of T-ALL cells. Moreover, the overexpression of NTRK3 rescued the lactate deficiency-induced proliferation inhibition of T-ALL cells. Furthermore, exogenous lactate supplementation dramatically restored the decreased cell proliferation in T-ALL cells and restored H3K18lac levels. Our findings reveal a novel role of lactate-mediated protein lactylation in regulating T-ALL cell proliferation.

Epstein-Barr virus (EBV) reactivation is a common complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), particularly in patients receiving high-dose anti-thymocyte globulin (ATG)-containing conditioning regimens. If left untreated, EBV reactivation may progress to post-transplant lymphoproliferative disorder (PTLD), a life-threatening condition. While preemptive therapy with the standard dose of rituximab (RTX), 375 mg/m², is recommended for EBV-related complications, such a high dose may be unnecessary in post-transplant settings where the total lymphocyte mass is significantly reduced compared to lymphoma conditions. This retrospective study assessed the efficacy and safety of fixed low-dose RTX (100-200 mg per dose) as an exploratory dose de-escalation preemptive therapy for low-load EBV DNA-emia (<10,000 copies/mL) occurring within four months post-transplantation. Among 83 high-risk patients, RTX achieved a high EBV clearance rate of 93.9% (95% CI: 88.6%-99.2%), with comparable effectiveness observed between the 100 mg and 200 mg dosage groups. Viral clearance was rapid, with most patients becoming EBV-DNA negative after 1 to 2 doses. RTX was well tolerated, with no treatment discontinuations due to adverse events. Despite preemptive RTX, four patients (5%) developed PTLD, which aligns with previously reported rates in similar populations. At a median follow-up of 41.6 months, the 3-year overall survival (OS) rate was 67.7%, with no significant differences in OS, relapse, or nonrelapse mortality between the two dosage cohorts. These findings suggest that a fixed low-dose RTX regimen, as an exploratory dose de-escalation strategy, is safe, effective, and well-tolerated for the preemptive management of low-load EBV DNA-emia in allo-HSCT recipients. While these results are hypothesis-generating, they indicate rapid viral clearance and favorable long-term outcomes, warranting further validation in comparative studies.

BACKGROUND:Higher-risk myelodysplastic syndromes (HR-MDS) carry a high risk of progression to acute myeloid leukemia and poor overall survival. Hypomethylating agents (HMAs), such as azacitidine, remain the standard of care but have limited efficacy. A 15-day venetoclax-azacitidine regimen has shown promising objective response rates (ORR) and potential as a bridge to allogeneic hematopoietic stem cell transplantation (HSCT) in relapsed/refractory HR-MDS. We conducted a prospective multicenter trial to evaluate its efficacy and safety in previously untreated patients. METHODS:This multicenter prospective study enrolled treatment-naïve HR-MDS patients (IPSS-R > 3.5). Venetoclax was administered on days 1-15 (escalated from 100 to 400 mg), combined with azacitidine (75 mg/m2) on days 1-7 of each 28-day cycle. The primary endpoint was ORR (2006 IWG criteria); secondary endpoints included complete remission (CR), overall survival (OS), and AML progression. RESULTS:Twenty-eight patients (median age: 63 years) were enrolled, with a median follow-up of 8.5 months. ORR was 85.7% per 2006 IWG (CR: 35.7%, marrow CR: 50.0%), and 78.6% per 2023 IWG (CR: 35.7%). Responses were consistent across molecular and IPSS-R subgroups. Median OS was not reached. High neutrophil count and high cytogenetic risk were favorable factors; TP53 mutation/deletion was an adverse prognostic marker. Grade 3-4 hematologic toxicities included neutropenia (96.4%), anemia (71.4%), and thrombocytopenia (64.3%). Serious adverse events (35.7%) were mainly infections. No dose-limiting or unexpected toxicities were observed. CONCLUSIONS:The 15-day venetoclax plus azacitidine regimen demonstrated high efficacy and manageable toxicity in treatment-naïve HR-MDS. It may be particularly beneficial for patients with high neutrophil counts, adverse cytogenetics, or those eligible for HSCT, supporting further investigation in larger trials.

T cell exhaustion is a critical obstacle for durable treatment response in hepatocellular carcinoma (HCC). Developing drugs that control tumor growth and simultaneously bolster immune function is of great significance. Although high-mobility group box 2 (HMGB2) has been reported to be crucial to HCC prognosis, its role in the tumor microenvironment remains unclear. Here, we found HMGB2 + CD8 + T cells as being associated with immune exhaustion and resistance to anti–PD-1 treatment through single-cell RNA sequencing. Mechanistically, HMGB2 impaired the oxidative phosphorylation in CD8 + T cells and inactivated the interferon-γ response in tumor cells, reducing the antitumor effector function. Tannic acid, a specific inhibitor of HMGB2, synergized with PD-1 antibody to attenuate tumor growth and reverse T cell exhaustion. Our findings highlight the unique role of HMGB2 as an immune exhaustion associated molecule. Targeting HMGB2 on both CD8 + T cells and tumor cells contributed to promising treatment strategies for HCC.

Introduction Chimeric antigen receptor (CAR) T-cell therapy represents a breakthrough in the treatment of relapsed or refractory (R/R) multiple myeloma (MM), however, severe cytokine release syndrome and neurotoxicity may compromise outcomes. A well-tolerated bridging therapy that controls disease without additional toxicities could improve the safety and efficacy of subsequent CAR-T infusion. Aponermin, a novel circularly permuted TRAIL ligand, induces selective apoptosis in malignant plasma cells through death receptors DR4 and DR5 (Dhillon S, Drugs, 2024; Xia Z, Leng Y, Fang B, BMC Cancer, 2023). The safety and efficacy of aponermin-based regimens as bridging therapy before CAR-T treatment remain to be explored. Methods We performed a retrospective, three-centre cohort study of consecutive RRMM patients who received aponermin-based chemotherapy after leukapheresis and before lymphodepletion (fludarabine 30 mg/m²/day and cyclophosphamide 300 mg/m²/day × 3 days) followed by a single BCMA CAR-T infusion. Safety and efficacy were assessed from the start of bridging therapy until 30 days after CAR-T administration. Results Twenty-eight patients with R/R MM were enrolled. All had received a median of four prior lines of therapy (range 3–7). Among them, 27 patients presented with extramedullary disease. All patients were refractory to proteasome inhibitors, immunomodulatory drugs, and CD38 monoclonal antibodies. Of the 28 patients, 23 received one cycle of bridging therapy, 3 received two cycles, and 1 patient received three cycles. After aponermin-based bridging therapy, the overall response rate (ORR) was 41.7% (7/28), including a complete response (CR) in 7.1% (2/28) patients and a partial response (PR) in 17.9% (5/28) patients. Stable disease (SD) was observed in 17 (60.7%) patients, and 2 (7.1%) patients experienced disease progression after bridging therapy. The safety profile of bridging therapy was favorable, with only one case of hypersensitivity reaction and two cases of elevated transaminases. Notably, six patients with stable disease after bridging therapy experienced significant platelet elevation after bridging therapy, potentially reducing bleeding risk during subsequent CAR-T cell treatment. Among 23 evaluable patients after CAR-T cell treatment, the ORR was 95.7 % (sCR 4.3 %, CR 17.4 %, PR 52.2 %). The median progression-free survival (PFS) was 6.43 months. Conclusion: Aponermin-based bridging therapy is well tolerated, does not exacerbate organ dysfunction or marrow suppression, and provides significant disease control or platelet recovery. These findings support prospective evaluation of aponermin-based regimens as an effective bridge to BCMA CAR-T therapy in R/R MM.

Dysfunction or dysregulation of deubiquitination is closely related to the initiation and development of multiple cancers. Targeted regulation of deubiquitination has been recognized as an important strategy in tumor therapy. However, the mechanism by which drugs regulate deubiquitinase is not clear. Here, we identified ubiquitin-specific peptidase 48 (USP48), a member of the ubiquitin-specific protease family highly expressed in various tumors, as a specific substrate for the activated caspase-3. During drug induced apoptosis of AML cells, activated caspase-3 cleaves USP48 through recognizing the conservative motif DEQD located at 611-614 sites of human USP48. Subsequent analysis showed that the cleavage USP48 N-terminal fragment which contains catalytic active domain is easily degraded by ubiquitination. Meanwhile knockdown experiment showed that inhibiting the expression of USP48 could also promotes apoptosis and enhance the efficacy of chemotherapy drugs. Altogether, these results suggest that targeting USP48 may represent a novel therapeutic strategy in AML.

Background: Our phase 3 randomized trial (CALSIII-AML18; n = 497) previously demonstrated non-inferior complete remission (CR/CRi) rates with low-dose chemotherapy (LDC) compared to standard-dose chemotherapy (SDC) in pediatric acute myeloid leukemia (AML) (ASH 2023). In this expanded retrospective analysis (n = 661), we evaluated induction response, long-term outcomes, toxicity, and subgroup-specific efficacy to define the clinical utility of LDC further. Patients and Methods: We analyzed 661 patients aged <18 years with newly diagnosed AML, treated at 12 centers in China between 2018 and 2024. Patients received either LDC (n = 325)—cytarabine 10 mg/m² subcutaneously every 12 hours for 10 days (20 doses), anthracycline 5 mg/m² intravenously on days 1, 3, and 5, plus G-CSF—or SDC (n = 336)—cytarabine 100 mg/m² intravenously every 12 hours for 10 days (20 doses), combined with daunomycin and etoposide. Post-remission therapy consisted of 2 (low-risk), 3 (intermediate-risk) chemotherapy blocks and hematopoietic stem cell transplantation (HSCT) for patients at high risk of relapse. The median follow-up was 40.4 months (range, 1–80). Endpoints included CR/CRi rates, measurable residual disease (MRD), 4-year event-free survival (EFS), overall survival (OS), cumulative incidence of relapse (CIR), toxicity, and subgroup outcomes. Results: Baseline clinical characteristics were similar between treatment arms. After Induction I, CR/CRi was achieved in 71.4% (LDC) vs. 71.7% (SDC); following Induction II, rates increased to 96.3% and 95.7%, respectively (P = .923 and P = .741). MRD <0.1% by flow cytometry was observed in 55.4% (LDC) vs. 61.3% (SDC) after Induction I, and 86.6% vs. 85.3% after Induction II (P = .139 and P = .667). Grade 3–4 toxicities were significantly lower in the LDC group during induction. Early mortality was also reduced with LDC (1.5% vs. 4.2%, P = .043). Four-year EFS was 63.5% (95% CI, 57.9 – 69.6) for LDC vs. 62.8% (95% CI, 57.5 – 68.5) for SDC (P = .684); 4-year OS was 83.5% (95% CI, 79.2 – 87.9) vs. 85.0% (95% CI, 81.1 – 89.1) (P = .740). CIR was comparable between groups (29.4% [95% CI, 24.0 – 34.9] for LDC vs. 25.4% [95% CI, 20.6 – 30.5] for SDC; P = .270). In multivariate analysis, adjusting for known prognostic factors, the treatment arm was not independently associated with outcome. Subgroup analysis revealed that patients <3 years of age had superior EFS with LDC compared to SDC (80.6% vs. 59.9%; HR 0.38 [95% CI, 0.18–0.79]; P = .009). Improved EFS with LDC was also seen in cases with NUP-rearrangement (68.3% vs. 21.4%; HR 0.18 [95% CI, 0.06–0.53]; P = .002) or WT1 mutations (63.2% vs. 31.5%; HR 0.47 [95% CI, 0.24–0.91]; P = .025). Conversely, patients with core-binding factor (CBF) AML and co-occurring KIT mutations had superior EFS with SDC (69.2% vs. 46.4%; HR 1.85 [95% CI, 1.08–3.18]; P = .026). Conclusions: This expanded retrospective analysis of the CALSIII-AML18 trial confirms that LDC achieves remission rates, survival outcomes, and relapse risk comparable to SDC, with reduced induction toxicity and early mortality. Notably, LDC appears particularly beneficial in younger children and those with NUP rearrangements or WT1 mutations. In contrast, SDC may offer greater benefit for patients with CBF AML harboring KIT mutations. These findings support a risk-adapted approach to induction therapy in pediatric AML.

Abstract Introduction: B-cell lymphoma 2 (BCL2) inhibition is an established treatment strategy in CLL/SLL with the potential to induce deep responses. CLL/SLL treatment guidance in China is similar to that in Western countries; however, novel treatments have limited availability in China. Sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, is a more selective and pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. In a phase 1 study (NCT04883957), sonrotoclax monotherapy was well tolerated and induced deep responses in Chinese patients (pts) with R/R CLL/SLL, with a 72.4% overall response rate (ORR) and a 41.4% best undetectable measurable residual disease (10−4 sensitivity; uMRD4) rate in blood. Presented here are primary efficacy and safety data for BGB-11417-202 (NCT05479994), an open-label, phase 2 study of sonrotoclax in Chinese pts with R/R CLL/SLL. Methods: Eligible pts had Bruton tyrosine kinase (BTK) inhibitor + chemoimmunotherapy (CIT) intolerance/failure (CIT not mandatory if pts ineligible for CIT) and no prior BCL2 inhibitor. Pts received sonrotoclax 320 mg once daily, with ramp-up to the target dose, until progressive disease (PD) or unacceptable toxicity. The primary endpoint was independent review committee (IRC)–assessed ORR per iwCLL 2018 guidelines (CLL) or 2014 Lugano criteria (SLL). Secondary endpoints included IRC- and investigator (INV)–assessed duration of response (DOR), progression-free survival (PFS), time to response (TTR), overall survival (OS), and incidence/severity of treatment-emergent adverse events (TEAEs) and treatment-emergent serious AEs (TESAEs) per NCI-CTCAE v5.0 and the Grading Scale for Hematologic Toxicity in CLL Studies. Tumor lysis syndrome (TLS) was assessed per Howard 2011 criteria. Exploratory endpoints included blood uMRD4 rate evaluated by flow cytometry with ERIC recommended markers. IGHV, TP53, and BTK mutation status were assessed by next-generation sequencing and del(17p) status by florescence in situ hybridization. Results: As of February 7, 2025, 100 pts with R/R CLL/SLL were enrolled and received sonrotoclax 320 mg. Median study follow-up was 14.4 months (range, 0.2-27.5 months). At the data cutoff, 65 pts (65.0%) remained on treatment; the most common reason for treatment discontinuation was PD (20.0%). For all pts, median age was 64.5 years and 61.0% were male. Pts had a median of 2 prior lines of therapy (range, 1-6); 27.0% had ≥3 prior lines, and 46.0% had previously received both a BTK inhibitor and anti-CD20 therapy. At baseline, 62.8% (54/86) of pts with available data had unmutated IGHV, 38.1% (37/97) had del(17p) and/or TP53 mutation, and 25.5% (25/98) had a BTK mutation. In 100 pts, IRC-assessed ORR was 76.0% and complete response rate was 19.0%. Median TTR per IRC was 3.7 months (range, 1.3-11.1 months). Responses per IRC were observed in pts with unmutated IGHV(74.1%; 40/54), del(17p) and/or TP53 mutation (70.3%; 26/37), and BTK mutation (72.0%; 18/25). The best blood uMRD4 rate was 49.0% (49/100). Median time to blood uMRD4 was 5.8 months (range, 3-12 months). Median DOR, PFS and OS were not reached. TEAEs in ≥30% of pts were neutrophil count decreased (54.0%), platelet count decreased (41.0%), anemia (33.0%), hyperuricemia (33.0%), and white blood cell count decreased (30.0%). Grade ≥3 TEAEs occurred in 61.0% of pts and all-grade TESAEs in 38.0%. Grade ≥3 TEAEs in ≥10% of pts were neutrophil count decreased (33.0%), pneumonia (17.0%), platelet count decreased (11.0%), and white blood cell count decreased (10.0%). No clinical TLS occurred; laboratory TLS occurred in 4.0% of pts (all grade 3 and resolved in a median of 3.5 days [range, 2-8 days]); none led to treatment discontinuation or death. TEAEs led to dose reduction in 5.0% of pts and treatment discontinuation in 6.0% of pts. Five pts (5.0%) died due to TEAEs, all considered unrelated to treatment. Conclusions: Sonrotoclax monotherapy demonstrated promising efficacy in heavily pretreated Chinese pts with R/R CLL/SLL, with an IRC-assessed ORR of 76%, and deep, rapid responses regardless of risk status, including subgroups with unmutated IGHV, del(17p) and/or TP53 mutations, and BTK mutations. Sonrotoclax monotherapy was well tolerated, and toxicities were manageable with low rates of dose reduction and treatment discontinuation. These data support the potential of sonrotoclax as a promising therapeutic option for pts with R/R CLL/SLL.

Pediatric lymphoma patients generally demonstrate a favorable long-term survival rate. The use of anti-programmed death-1 (PD-1) monoclonal antibodies has significantly improved the response rates in adult patients with refractory/relapsed lymphoma, particularly those with Hodgkin lymphoma and NK/T cell lymphoma. This study aimed to evaluate the real-world efficacy and safety of PD-1 antibody monotherapy or combination therapy in pediatric lymphoma patients. From March 1, 2017, to October 25, 2022, we retrospectively analyzed data from 41 pediatric lymphoma patients who received PD-1 antibody treatment, including those with Hodgkin lymphoma, extranodal NK/T cell lymphoma, primary mediastinal large B-cell lymphoma, and other subtypes. Kaplan–Meier analysis was used to estimate progression-free survival (PFS) and overall survival (OS). Descriptive statistics were used to report response rates and adverse effects. The median follow-up period was 22.4 months (range, 1.3–67.6 months), and the overall response rate for the entire cohort was 82.9

OBJECTIVE:While long noncoding RNAs (lncRNAs) have emerged as critical regulators in hematological malignancies, their clinical significance in pediatric acute leukemia (AL) remains poorly characterized. This study aimed to (1) systematically profile differentially expressed lncRNAs (DE-lncRNAs) in pediatric AL through comparative analysis of bone marrow samples and (2) functionally characterize the oncogenic role of a top candidate, AC002454.1, to identify potential diagnostic markers and therapeutic targets. METHODS:Using Arraystar Human LncRNA Array V3.0, we analyzed bone marrow samples from 43 pediatric AL patients (21 ALL, 22 AML) and 21 healthy donors. Key DE-lncRNAs were validated by qRT-PCR, with AC002454.1 selected for functional investigation. In NB4 leukemic cells, we performed (1) lentiviral knockdown of AC002454.1, (2) cell proliferation assays (CCK-8), (3) cell cycle analysis (PI staining/flow cytometry), (4) apoptosis assessment (Annexin V-FITC/PI dual staining), and (5) Western blot for CDK6 regulation. RESULTS:Our qRT-PCR validation confirmed 97 differentially expressed lncRNAs (DE-lncRNAs), with lncRNA AC002454.1 showing the most significant differential expression between ALL and AML samples (P=0.040 and P=0.002, respectively, and particular elevation in AML). Functional studies demonstrated that AC002454.1 knockdown in NB4 cells led to (1) reduced cellular viability, (2) G2/M phase cell cycle arrest, and (3) increased apoptosis. Notably, AC002454.1 silencing also down-regulated CDK6 protein expression, suggesting a potential mechanistic link. CONCLUSIONS:We identified AC002454.1 as a functionally significant lncRNA in pediatric AL, demonstrating its oncogenic role through the promotion of proliferation and inhibition of apoptosis in leukemic cells. These findings suggest its potential as both biomarker and therapeutic target.

Acute myeloid leukemia (AML) is an aggressive and heterogenous malignancy, with unsatisfactory clinical outcomes even with very intensive treatment strategies. Previous research has revealed that Prader-Willi/Angelman syndrome 1 (NIPA1) is highly expressed in patients with AML and is negatively correlated with overall survival. However, studies on the molecular mechanism of NIPA1 in AML remain limited. To explore the role of NIPA1and its molecular mechanism in AML, we discovered through cellular experiments that NIPA1 was upregulated in M2 macrophages. NIPA1 knockdown inhibited M2 macrophage polarization and the survival of AML cells. In animal experiments, we also found that NIPA1 depletion restricted tumor growth in mice with AML. Further studies indicated that NIPA1 knockdown inhibited IGFBP2/epidermal growth factor receptor (EGFR) signaling in M2 macrophages, thereby weakening leukemia cell survival and reducing anthracycline resistance. Using both parental HL-60 and an adriamycin-resistant (HL-60/ADR) model, we show that TAM-targeted NIPA1 depletion enhances chemosensitivity and attenuates AML progression. Thus, NIPA1 could be used as a potential therapeutic strategy for immunotherapy in acute myeloid leukemia (AML).

Introduction: Epstein-Barr virus (EBV) reactivation is a common complication following allogeneic hematopoietic stem cell transplantation, with potential progression to PTLD. To prevent EBV-related diseases, the European Conference on Infections in Leukemia recommends regular post-transplant EBV-DNA-emia monitoring and early intervention with preemptive therapy, including rituximab (RTX) and reduction of immunosuppression. RTX is typically administered with 375mg/m² until EBV clearance, while no robust clinical trails confirmed the necessity of this high-dose regimen. Given that RTX may impair post-transplant immune reconstitution and increase infection risk, and considering that EBV-DNA emia primarily occurs within the first four months after allo-HSCT, with high EBV viral load being a risk factor for the development and increasing RTX administration frequency. We hereby report the efficacy and safety of fixed low-dose RTX (100 or 200 mg per dose) in high-risk patients with low-load EBV-DNA-emia who received ATG-containing conditioning regimens. Methods: Among 1755 consecutive patients who received ATG-containing regimens for allo-HSCT at the First Affiliated Hospital of Soochow University between January 2019 and March 2022, we included 77 patients who received fixed low-dose preemptive RTX for EBV-DNA-emia within four months post-transplant in this retrospective study. Patients with a high viral load (>10,000 copies/mL), probable PTLD or late-onset EBV reactivation were excluded. EBV-DNA was monitored with quantitative PCR in whole peripheral blood begins one week after stem cell infusion and was performed weekly for the first four months post-transplantation. EBV-DNA-emia is defined as detectable viremia exceeding 100 copies/mL in two consecutive measurements. Preemptive therapy with a fixed low dose of RTX (100 or 200 mg per dose). Treatment success was defined as achieving negative EBV-DNA results without subsequent development of PTLD. Results: Of 77 patients, 51 cases received 100mg of RTX, while 26 patients received 200mg. 66 patients received haplo-HSCT, 11 patients received URD-HSCT. The median time from transplantation to the first dose of RTX was 51 days (range, 18-113) and median EBV load at RTX initiation was 2260 copies/mL (range,212-9210). Of the 76 evaluable patients, 70 achieved viral clearance (92.1%, 95%CI, 85.9%-98.3%). The clearance rate was similar between the two cohort: 92% (84.2% to 99.8%) in the 100mg RTX cohort, 92.3% (81.3% to 100%) in the 200mg cohort. In the 100mg group, 28 patients tested negative after 1 dose, and 15 patients after 2 doses, while the corresponding numbers in the 200mg group were 8 and 12, respectively. Patients tolerated RTX treatment well, with no treatment discontinuations due to adverse events. Among the 77 patients, 43 underwent peripheral blood B-cell quantification by flow cytometry before and approximately two weeks after initiating RTX therapy. Of these, 41 achieved near-complete CD19+ B-cell depletion. Two (2.6%) patients developed PTLD. The median follow-up time was 44.2 (range,1.5 - 71.4) months. The 3-year OS, NRM and CIR were 70.7% (95%CI, 61.1% - 81.8%), 15.3% (95%CI, 6.0%- 23.6%), and 24.3% (95% CI, 13.5%- 33.8%). Three-year overall survival (100mg: 67.4%; 200mg: 76.9%, P=0.47), non-relapse mortality (100mg: 18.4%; 200mg: 8.9%, P=0.24), and cumulative relapse incidence (CIR) (100mg: 22.2%; 200mg: 28.2%, P=0.35) were statistically similar between two cohorts. In univariate and multivariate analyses, patients with an EBV load ≥2260 copies/ml demonstrated a tendency towards a poorer CIR (HR=0.43, 95%CI =0.16-1.15; P= 0.094). Clinically significant grade II-IV aGVHD occurred in 10 patients (13%) at day 100 after transplantation, with median onset of 44.5 (range 23-98) days. 5 patients developed EBV-viremia in the setting of grade II-IV aGVHD. Among 74 patients who survived for at least 100 days, chronic GVHD was diagnosed in 20 (27 %) patients, with the median onset of 5.8 (3.3-32.2) months. The cumulative incidence of chronic GVHD at third year was 29.1%. No statistically significant difference was observed in the incidence of cGVHD between the two dosage groups. (P=0.55). Conclusions: Low-dose RTX achieved a high EBV clearance rate (92%) with minimal toxicity, supporting its potential as an effective and safer alternative to the conventional high-dose regimen (375 mg/m²). prospective randomized multicentric trial with larger number of patient is needed.

T-cell receptor (TCR) loci undergo complex V(D)J rearrangements during T-cell maturation. However, errors in this process can cause TCR promoters and enhancers to aberrantly fuse with oncogenes, leading to their overexpression and the development of T-cell acute lymphoblastic leukemia (T-ALL). Unexpectedly, in a retrospective study of 97 pediatric B-ALL cases, all diagnosed according to WHO criteria at a single institution, we identified a subgroup of B-ALL harboring TCR fusion. These fusions involved diverse partner genes, including LINC01656, TBC1D10B, TCL1A/TCL1B, CDKN2A, CEBPB/G, and AHI1. Patients with TCR fusions showed a gene expression profile enriched in hematopoietic stem cell (HSC) signatures and frequently carried other adverse genomic markers, such as CDKN2A/B alterations and RAS pathway activation. Clinically, TCR-rearranged B-ALL patients were associated with increased risk (P = 0.005) and had higher minimal residual disease (MRD) at day 19 (P = 0.034), and may benefit from MRD-based risk-directed therapy. Our study highlights frequent TCR fusions in B-ALL, suggesting a stem cell-derived leukemia with potential differentiation into both B-cell and T-cell lineages.

Rare diseases in children have attracted widespread attention worldwide due to their rarity and difficulty in diagnosis and treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is emerging as a promising and curable therapy for multiple rare diseases. However, rare disease research in China is relatively backward, prompting us to construct the first cohort of allo-HSCT for pediatric rare diseases (allo-HSCT-PRD) involving those who underwent allo-HSCT at the Children’s Hospital of Fudan University from 1 January 2014 to 31 October 2024. We concurrently developed a standard data collection, management, and follow-up process, and a dedicated multidisciplinary team to support the work. The allo-HSCT-PRD consisted of 480 participants who were categorized into inborn errors of immunity (IEI) and inborn errors of metabolism (IEM), with 428 and 52 cases, respectively. Among all subjects, the engraftment rate was 84.6