Hematology最新文献

Objectives: While ferroptosis induction emerges as a therapeutic strategy for solid tumors, its role in acute myeloid leukemia (AML) remains unexplored. This study aimed to investigate the role of MLN4924 in modulating ferroptosis and its molecular targets in AML.

Methods: Transcriptome sequencing and bioinformatics analyses were performed to identify MLN4924 potential targets in ferroptosis. First, ferroptosis-related phenotypic assays were conducted, including assays of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and Fe²⁺ levels. Second, cell viability assays were carried out with the combination of MLN4924 and ferroptosis inducers (Erastin, Sorafenib). Third, rescue experiments were used the ferroptosis inhibitor Ferrostatin-1 after MLN4924 treatment. In vivo efficacy was evaluated in NOD/SCID mice bearing AML xenografts treated with MLN4924, followed by tumor tissue analysis of GSH and Fe²⁺ levels, immunohistochemistry (IHC), and Western blotting for SLC7A11/GPX4 axis components.

Results: Transcriptome sequencing and bioinformatics analyses identified SLC7A11 and GPX4 as key MLN4924 target genes, both of which are glutathione-related proteins. MLN4924 significantly suppressed SLC7A11 and GPX4 expression, decreased GSH activity, and increased ROS, Fe²⁺, and MDA levels. Ferroptosis inducers (Erastin, Sorafenib) further enhanced the antileukemic activity of MLN4924, and ferroptosis inhibitor Ferrostatin-1 partially reversed this toxicity. In vivo, MLN4924 reduced tumor burden, accompanied by SLC7A11/GPX4 downregulation and Fe²⁺ accumulation in xenografts.

Conclusion: This study provides the first evidence that MLN4924 triggers ferroptosis in AML by inhibiting the SLC7A11/GPX4 axis. These findings establish MLN4924 as a ferroptosis sensitizer through synergistic effects with ferroptosis inducers, supporting its therapeutic potential in AML.

Objectives: Autoimmune hemolytic anemia (AIHA) is characterized by autoimmune-mediated destruction of erythrocytes. Both AIHA and Evans syndrome are rare, manifesting a severe clinical course, high relapse rate, and potentially fatal outcomes. Refractory AIHA shows poor responsiveness to multiple treatment regimens, and there is still a lack of effective treatment regimens for serious hemolytic episodes.

Methods: Three refractory AIHA cases with a positive complement component C3d and hemolytic flare were treated with the oral factor B inhibitor ptacopan in conjunction with cyclophosphamide and prednisone.

Results: After treatment with iptacopan plus cyclophosphamide and prednisone, all three patients showed a rapid increase in Hb levels, a decrease in reticulocyte proportion, and a significant reduction in hemolysis manifestations (Lower LDH level and unconjugated bilirubin).

Conclusion: Three refractory cases of AIHA showed good therapeutic efficacy after treatment with iptacopan combined with cyclophosphamide and prednisone. These cases provide a potentially effective treatment option for severe hemolytic episodes in refractory AIHA.

Objectives: To explore the clinical relevance and biological roles of the N6-methyladenosine (m6A) binding protein leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) in multiple myeloma (MM), aiming to offer new insights into its potential as a prognostic marker for MM.

Methods: Bioinformatics methodologies were employed to identify m6A-associated differential expression genes (DEGs) in different kinds of datasets. Quantitative Real-Time PCR (qRT-PCR) were used to analyze DEG LRPPRC in both bone marrow of MM patients and MM cell lines. In vitro experiments, by using LRPPRC knockdown cell line model, CCK-8 assays, cell cycle analyzes, and apoptosis assays, were conducted to assess the biological role of LRPPRC on MM progression.

Results: Bioinformatics analysis identified LRPPRC as a critical m6A DEG in MM. Over-expression LRPPRC was positively correlated with the staging of MM and associated with poorer prognosis in MM patients. Furthermore, we confirmed elevated LRPPRC expression in three MM cell lines U266, RPMI-8226, and MM.1S as well as in the bone marrow of MM patients by real-time PCR or western blot. Additionally, LRPPRC expression demonstrated a positive correlation with the International Staging System (ISS) stages of MM. Furthermore, LRPPRC knockdown inhibited the proliferation of MM cells by CCk-8 assay, enhanced apoptosis, and cell cycle analysis showed that inhibition of LRPPRC increased the proportion of G1-phase cells and decreased the proportion of G2-phase cells in MM cells.

Conclusion: LRPPRC promote tumorigenesis in MM and may serve as a potential prognostic target for MM.

Background: Methyltransferase-like protein 7A (METTL7A), an m6A methyltransferase, is closely associated with various cancers, but its role in acute myeloid leukemia (AML) remains unclear.

Methods: This study employed bioinformatics analysis using the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Furthermore, METTL7A expression levels in AML samples were validated using qRT-PCR.

Results: Analyses of TCGA, GTEx, and a single-center cohort all revealed significantly higher METTL7A expression in AML patients compared to controls. High METTL7A expression correlated with poor prognosis and pathological features. ROC curve analysis confirmed its diagnostic value, while multivariate analysis identified METTL7A as an independent prognostic risk factor, leading to the development of a prognostic nomogram. KEGG and GSEA analyses indicated METTL7A's involvement in immune regulation, which was further supported by immune infiltration analysis showing its association with immune cell infiltration.

Conclusions: High METTL7A expression is associated with poor prognosis in AML and may be a potential diagnostic and prognostic biomarker.

Objectives: The survival and neurological prognosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome have been substantially improved by peripheral blood stem cell transplantation and immunomodulating agents since the 2000s. However, some patients with POEMS syndrome are refractory to these treatments. This study aimed to evaluate the efficacy and safety of monoclonal antibody therapy with daratumumab (anti-cluster of differentiation 38) and elotuzumab (anti signaling lymphocytic activation molecule family member 7) for POEMS syndrome.

Methods: We reviewed patients with refractory POEMS syndrome who received daratumumab- or elotuzumab-based treatment between January 2019 and July 2024. We studied the hematologic, vascular endothelial growth factor (VEGF), and clinical responses; time to the next treatment; and adverse events.

Results: Eight patients received 13 regimens of daratumumab, elotuzumab, or both. All patients were recurrent/refractory to immunomodulatory drugs, proteasome inhibitors, and/or autologous stem cell transplantation. After a median of six cycles of treatment (range, 3-32 cycles), one hematologic (8%), seven VEGF (54%), two neurologic (15%) and eight generalized clinical responses (62%) were observed. Six patients received subsequent treatment, and the median time to the next treatment was 11 months (range, 4-33 months). Grade 3 hematologic toxicity occurred in four regimens and grade 2 infusion-related reactions occurred in five. None of the patients died during the median follow-up period of 39 months (range, 3-66 months).

Conclusion: Daratumumab- and elotuzumab-based regimens may be treatment options for refractory POEMS syndrome.

Objectives: MYH9-related disease (MYH9-RD) is a congenital bleeding disorder characterized by thrombocytopenia, platelet macrocytosis, inclusion bodies in neutrophils.The aim of this study was to investigate a Chinese family with MYH9-RD and to identity potential mutations of the MYH9. This investigation will elucidate the molecular mechanisms involved in disease pathogenesis.

Methods: Whole exome sequencing (WES) followed by Sanger sequencing was conducted on all family members. Multiple bioinformatics tools were programmed to predict the conservation of mutations and the effect on the protein structure, including 3D protein model analysis.

Results: Gene sequencing revealed that the patient carried A de novo missense MYH9 mutation (c.4338T > G, p.Phe1446Leu). Bioinformatics and molecular modeling analyses predict the p.Phe1446Leu variant to be deleterious, with probable disruptive effects on protein structure and consequent functional impairment.

Discussion: Our study suggested that a de novo missense mutation in MYH9 may be causative to MYH9-RD. Furthermore, genetic sequencing is expected to soon become a standard component of the diagnostic evaluation for individuals with platelet disorders.

Purpose: To retrospectively evaluate the efficacy and safety of ruxolitinib, with or without intensive chemotherapy, in pediatric patients with hemophagocytic syndrome.Methods: Pediatric patients with newly diagnosed hemophagocytic lymphohistiocytosis treated with ruxolitinib between January 2021 and December 2024 were analyzed.Results: A total of 34 patients were included, with a median age of 45.6 months. The median ruxolitinib treatment duration was 62 days, with a median daily dosage of 0.63 mg/kg. Twenty-four patients received VP-16, while ten did not. Significant differences were observed in hemoglobin, sCD25, LDH, and ALT levels between the groups. The overall response rates at weeks 2, 4, and 8 were 73.5%, 76.4%, and 70.6% respectively. Platelets, ferritin, triglycerides, IL-6, IL-10, TNF-α, and liver function markers also changed significantly. The median follow-up was 502 days. Seven patients died, with a two-year overall survival rate of 78.3%, higher in the non-VP-16 group (90.0%) than the VP-16 group (73.2%). The two-year event-free survival rate was 63.2%, with 80.0% in the non-VP-16 group and 58.3% in the VP-16 group. Poor prognostic factors included high IL-6 levels, lack of response to initial ruxolitinib, and bone marrow hemophagocytic cells. The VP-16 dosage was reduced compared to HLH-1994, and no patients discontinued ruxolitinib due to side effects.Conclusion: Ruxolitinib is effective and safe for pediatric hemophagocytic syndrome, potentially reducing the need for etoposide. Its initial treatment response can serve as an important factor for prognostic analysis.

Background: Autologous hematopoietic stem cell transplantation (auto-HSCT) is standard for eligible multiple myeloma (MM) patients, yet outcomes are heterogeneous. Besides established markers like cytogenetics and ISS, the independent prognostic value of pretreatment hemoglobin (Hb), myeloma subtype, and induction regimen requires clarification. This study aimed to assess these factors to improve risk stratification.

Methods: We retrospectively analyzed 350 MM patients undergoing first auto-HSCT at Beijing Chao-Yang Hospital (2001-2019). The impact of baseline Hb (<10 vs. ≥10 g/dL), subtype (IgG vs. non-IgG), and induction regimen (bortezomib-based vs. others) on progression-free survival (PFS) and overall survival (OS) was evaluated using Kaplan-Meier and Cox regression.

Results: With a median follow-up of 58 months, median PFS and OS were 42 months (95% CI 36-48) and 98 months (95% CI 83-113), respectively. Multivariate analysis identified three independent predictors of superior PFS: Hb ≥10 g/dL (HR = 0.65, P = 0.012), IgG subtype (HR = 0.72, P = 0.018), and bortezomib-based induction (HR = 0.58, P = 0.004). Attaining CR/VGPR post-transplant also significantly prolonged PFS versus PR or less (median 55 vs. 37 months, P = 0.044).

Conclusion: Pretreatment hemoglobin, IgG subtype, and bortezomib-based induction are independent predictors of survival after auto-HSCT. Hb, a simple and widely available marker, adds prognostic value beyond ISS and cytogenetics. Integrating these factors into prognostic models can help tailor therapy and improve patient management.

Background: Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count (PLT). Bruton tyrosine kinase (BTK) is a therapeutic target in immune-mediated diseases. This study aimed to evaluate the effects of a BTK inhibitor, zanubrutinib (Zan), on refractory ITP.

Methods: Peripheral blood was collected from healthy controls (HC) and refractory ITP patients (n = 15), and peripheral blood mononuclear cell (PBMC) extraction was performed. The proportion of myeloid-derived suppressor cells (MDSCs) in PBMCs and Arg-1, iNOS, Fc gamma receptor (FcγR), GPIIb/IIIa, and GPIb/IX autoantibody levels were measured. ITP monocytes were separated into control (Con), Zan (Zan), dexamethasone (DXM), and combination (Zan + DXM) groups. Detection ophagocytosis and platelet activation by flow cytometry; FcγR expression by qRT-PCR and western blot; and IFN-γ, IL-4, IL-2, and IL-10 levels were determined by ELISA.

Results: PBMCs from the ITP group demonstrated lower MDSCs proportions and Arg-1 levels, but higher iNOS, FcγRIII, FcγRIIb, FcγRI, GPIIb/IIIa, and GPIb/IX autoantibody levels than those in the HC group. Following Zan intervention, ITP monocytes exhibited decreased phagocytosis, FcγRIIa, FcγRI protein, IFN-γ, IL-2, p-mTOR/mTOR levels, and increased FcγRIIb, PLTs, IL-4, PAC-1, and CD62p levels.

Conclusion: Zan may modulate FcγR toward FcγRIIb to inhibit platelet destruction, thereby improving refractory ITP.

Background: With the aging population, there is a growing need for treating multiple myeloma (MM) in elderly patients; however, real-world studies of them are quite limited.

Methods: We retrospectively analyzed 519 patients diagnosed between 1997 and 2020 in the Kansai Myeloma Forum database to evaluate the efficacy and safety of novel agents available for 80 years and older patients with MM. Patients were divided into groups according to the treatment year: up to 2010 (Group 1), 2011-2015 (Group 2), and 2016-2020 (Group 3).

Results: The median age and number of treatment lines were 83 years (range, 80-96) and 2, respectively. The median time to next treatment (TTNT) was 7.8 months. The TTNT for Group 3 was significantly shorter (3.8 months) than in other groups (p < 0.001). Median progression free survival and overall survival (OS) were 24.4 and 43.7 months, respectively, and did not differ significantly between 3 groups based on pairwise comparisons. In Group 3, the 1-year cumulative incidence of adverse events (AEs), progression or death, and planned treatment leading to treatment discontinuation was 37.7%, 29.4%, and 15.6%, respectively. In addition, the median time until discontinuation due to AEs has been shortened in recent years.

Conclusion: Our findings suggest that AEs threaten the continued treatment of very elderly patients receiving novel agents, with careful management needed to extend the TTNT.