Experimental Hematology & Oncology最新文献

{"title":"IHCH9033, a novel class I HDAC inhibitor, synergizes with FLT3 inhibitor and rescues quizartinib resistance in FLT3-ITD AML via enhancing DNA damage response.","authors":"Mingyue Yao, Wenzhong Yan, Yafang Wang, Yu Zhao, Xiaowei Xu, Yujun Chen, Chengcheng Yu, Yingnian Li, Hualiang Jiang, Jie Shen, Jianjun Cheng, Chengying Xie","doi":"10.1186/s40164-025-00605-y","DOIUrl":"10.1186/s40164-025-00605-y","url":null,"abstract":"<p><strong>Background: </strong>Despite initial success with FLT3 inhibitors (FLT3is), outcomes for FLT3-ITD acute myeloid leukemia (AML) patients remain unsatisfactory, underscoring the need for more effective treatment options. Epigenetic modifications, such as histone acetylation, contribute to AML's onset and persistence, advocating the potential for epigenetic therapies. However, the poor specificity of pan-histone deacetylase inhibitors (HDACis) leads to undesirable adverse effects, prompting the need for isoform-specific HDACis. This study aims to explore the antileukemic activities and mechanisms of IHCH9033, a novel class I HDACi, alone or combined with FLT3i in FLT3-ITD AML.</p><p><strong>Methods: </strong>The viability of AML cell lines and primary AML cells treated with HDACis alone or in combination with FLT3i was detected by MTT or CCK8 assay. Flow cytometry was utilized to examine cell apoptosis, cell cycle progression and ROS production. RNA sequencing analysis, RT-qPCR, western blotting, and co-immunoprecipitation assays were employed to elucidate the molecule mechanisms. The in vivo anti-leukemia efficacy was tested in xenografted mice models derived from FLT3-ITD cell lines and primary AML patients.</p><p><strong>Results: </strong>Here, we identified IHCH9033, a novel selective class I HDACi, which exhibited an increased antitumor effect in FLT3-ITD AML through effectively eliminating leukemia burden and overcoming resistance to FLT3i. Mechanically, IHCH9033 selectively inhibited DNA repair in FLT3-ITD AML cells, leading to the accumulation of DNA damage that eventually resulted in cell cycle arrest and apoptosis. Additionally, IHCH9033 induced HSP90 acetylation, FLT3 ubiquitination, and proteasomal degradation of FLT3, thereby inhibiting FLT3 downstream signaling. Notably, IHCH9033 maintained its potency in both FLT3i-resistant AML cell lines and primary-resistant patient samples, and exerted strong synergy with the FLT3i quizartinib, leading to tumor regression in FLT3-ITD/TKD AML xenografts. In patient-derived xenografts, the treatment with IHCH9033, both alone and in combination, led to nearly complete eradication of the AML burden, without significant adverse effects.</p><p><strong>Conclusions: </strong>Our study shows that IHCH9033, a novel class I HDACi with a desirable pharmacological profile, is a promising drug candidate for FLT3-ITD AML, and suggests a strategy of combining class I HDACis and FLT3is in AML clinical trials to increase efficacy and overcome resistance, thus potentially providing a curative treatment option.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"15"},"PeriodicalIF":9.4,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829435/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425385","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineered oncolytic virus coated with anti-PD-1 and alendronate for ameliorating intratumoral T cell hypofunction.","authors":"Yufu Zhu, Xuefeng Zhang, Jiaqi Jin, Xiaoqian Wang, Yang Liu, Jian Gao, Diancheng Hang, Lin Fang, Hengzhu Zhang, Hongmei Liu","doi":"10.1186/s40164-025-00611-0","DOIUrl":"10.1186/s40164-025-00611-0","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma is a highly aggressive and devastating primary brain tumor that is resistant to conventional therapies. Oncolytic viruses represent a promising therapeutic approach for glioblastoma by selectively lysing tumor cells and eliciting an anti-tumor immune response. However, the clinical efficacy of oncolytic viruses is often hindered by challenges such as short persistence, host antiviral immune responses, and T cell dysfunction.</p><p><strong>Methods: </strong>We have developed a novel therapeutic strategy by \"dressing\" oncolytic viruses with anti-PD-1 antibodies and alendronate (PD-1/Al@OV) to prevent premature clearance of the oncolytic viruses and enhance T cell function, thereby improving immunotherapy outcomes against glioma.</p><p><strong>Results: </strong>We found that in the high reactive oxygen species environment of the tumor, PD-1/Al@OV disassembled to release oncolytic viruses, anti-PD-1, and alendronate. The released anti-PD-1 blocked the PD-1/PD-L1 pathway, activating T cells; the alendronate eliminated tumor-associated macrophages, increasing the concentration of oncolytic viruses; and the oncolytic viruses directly lysed cancer cells, enhancing intratumoral T cell infiltration.</p><p><strong>Conclusion: </strong>This approach effectively improved the immunosuppressive microenvironment of glioblastoma and achieved a robust anti-tumor effect. Consequently, this study presents a novel strategy for immune combination therapy and the improvement of the glioblastoma immune microenvironment, thereby offering new prospects for the clinical application of oncolytic viruses.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"16"},"PeriodicalIF":9.4,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct response to IL-1β blockade in liver- and lung-specific metastasis mouse models of pancreatic cancer with heterogeneous tumor microenvironments.","authors":"Sophia Y Chen, Heng-Chung Kung, Birginia Espinoza, India Washington, Kai Chen, Kaiyi Mu, Haley Zlomke, Michael Loycano, Rulin Wang, William R Burns, Juan Fu, Lei Zheng","doi":"10.1186/s40164-025-00607-w","DOIUrl":"10.1186/s40164-025-00607-w","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is characterized by a heterogeneous tumor microenvironment (TME). The mechanism by which this heterogeneity confers resistance against immunotherapy remains unclear. Interleukin- 1β (IL-1β) is a proinflammatory cytokine that regulates heterogeneous cancer associated fibroblast (CAF) phenotype and promotes an immunosuppressive TME. Anti-IL-1β monoclonal antibody significantly enhanced the anti-tumor activity of anti-PD-1 in a preclinical model of PDAC. However, clinical trials have shown limited activity of the anti-IL-1β and anti-PD-1 combination. Therefore, we hypothesize that anti-tumor immune response to the combination of anti-IL-1β and anti-PD-1 antibodies is context-dependent and would be affected by the TME heterogeneity in PDAC.</p><p><strong>Methods: </strong>Liver- and lung-specific metastasis mouse models of PDAC were used to investigate the antitumor activity of anti-IL-1β and anti-PD-1 antibodies alone or in combination by ultrasound examination and survival analysis. Their effects on the TME heterogeneity were assessed by flow cytometry and single nuclear RNA sequencing.</p><p><strong>Results: </strong>The combination of anti-IL-1β and anti-PD-1 antibodies does not slow primary tumor growth but prolongs overall survival and reduces lung metastasis rates in a PDAC orthotopic murine model with lung metastasis tropism. In contrast, combination therapy slows primary tumor growth and prolongs survival, but does not reduce liver metastasis rates in a PDAC murine orthotopic model with liver metastasis tropism. Flow cytometry analysis showed that the combination of anti-IL-1β and anti-PD-1 antibodies restores T cell activation negated by the monotherapies. Mechanistically, in the PDAC model with lung metastasis tropism, but not in the model with liver metastasis tropism, combination treatment reverses an increased trend of immunosuppressive myeloid cells as a result of monotherapy. Single-nuclear RNA sequencing analysis of both organ-specific tumor models demonstrated that anti-IL-1β treatment altered infiltration and function of CAF and immune cells differently. Furthermore, anti-IL-1β treatment modulated cytokine/chemokine ligand-receptor-receptor interactions in the models with different organ-specific metastasis distinctly.</p><p><strong>Conclusion: </strong>This study reveals the differential responses of organ-specific metastasis mouse models of PDAC with distinct TMEs to anti-IL-1β and anti-PD-1 treatments, suggesting that treatment response is context-dependent and affected by TME heterogeneity.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"13"},"PeriodicalIF":9.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAR-macrophages targets CD26 to eliminate chronic myeloid leukemia stem cells.","authors":"Jiang Guoyun, Qin Yuefeng, Huang Zhenglan, Yuan Zuowei, Zhou Hongyan, Yuan Ying, Feng Wenli","doi":"10.1186/s40164-025-00608-9","DOIUrl":"10.1186/s40164-025-00608-9","url":null,"abstract":"<p><strong>Background: </strong>Chronic myeloid leukemia stem cells (CML-LSCs), which exhibit resistance to tyrosine kinase inhibitors (TKIs), are the leading cause of treatment failure and recurrence in chronic myeloid leukemia (CML). This highlights the urgent need for novel therapies aimed at eliminating these CML-LSCs. Chimeric antigen receptor macrophages (CAR-M) not only perform phagocytosis on target cells but also function as antigen-presenting cells, thereby activating the anti-tumor immune response.CD26 (dipeptidyl peptidase 4, DPP IV) is abundantly expressed in CML-LSCs and functions as a tumor-specific antigen (TSA) in CAR-M treatment. The purpose of this study is to evaluate CAR-M's efficacy in targeting CD26-positive CML cells and to develop a novel strategy for CML treatment.</p><p><strong>Methods: </strong>CD26 CAR-M was constructed using mouse-derived macrophage Raw264.7 cells. CD26 was overexpressed in CML cell lines BP210 and BP210-T315I. The targeting phagocytosis of CAR-M was verified using confocal microscopy and flow cytometry. X-ray was used to eliminate the tumorigenicity of CAR-M, and the safety of CAR-M was verified through CCK-8, clone formation assays, and animal experiments. To assess the anti-leukemia ability of CAR-M in the CML mouse model, the survival, peripheral blood white blood cell counts, and CML cell infiltration in the liver, spleen, and bone marrow (BM) were measured. Additionally, CD26 CAR-THP1 was constructed, and its phagocytic ability against CD26-positive cells NCI-H2452 was confirmed by confocal microscopy.</p><p><strong>Results: </strong>We successfully constructed CD26 CAR-M and validated its targeted phagocytosis of CD26-positive CML cells both in vitro and in vivo. The data indicate that CAR-M has higher phagocytic efficiency in CD26-positive CML cells than in CD26-negative cells. CAR-M-treated CML mice demonstrated extended survival and reduced CML invasion. In addition, CAR-THP1 demonstrated targeted phagocytosis of NCI-H2452 cells that normally express CD26.</p><p><strong>Conclusion: </strong>This study demonstrates that CD26 CAR-M effectively targets and phagocytizes CD26-positive CML cells, implying that targeting CD26 with CAR-M could be a viable method for eradicating CML-LSCs. Furthermore, our discoveries illuminate the potential application of CAR-M in treating hematological malignancies.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"14"},"PeriodicalIF":9.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143413535","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting secretory autophagy in solid cancers: mechanisms, immune regulation and clinical insights.","authors":"Xinyu Li, Haiying Zhao","doi":"10.1186/s40164-025-00603-0","DOIUrl":"10.1186/s40164-025-00603-0","url":null,"abstract":"<p><p>Secretory autophagy is a classical form of unconventional secretion that integrates autophagy with the secretory process, relying on highly conserved autophagy-related molecules and playing a critical role in tumor progression and treatment resistance. Traditional autophagy is responsible for degrading intracellular substances by fusing autophagosomes with lysosomes. However, secretory autophagy uses autophagy signaling to mediate the secretion of specific substances and regulate the tumor microenvironment (TME). Cytoplasmic substances are preferentially secreted rather than directed toward lysosomal degradation, involving various selective mechanisms. Moreover, substances released by secretory autophagy convey biological signals to the TME, inducing immune dysregulation and contributing to drug resistance. Therefore, elucidating the mechanisms underlying secretory autophagy is essential for improving clinical treatments. This review systematically summarizes current knowledge of secretory autophagy, from initiation to secretion, considering inter-tumor heterogeneity, explores its role across different tumor types. Furthermore, it proposes future research directions and highlights unresolved clinical challenges.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"12"},"PeriodicalIF":9.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Applications of liposomes and lipid nanoparticles in cancer therapy: current advances and prospects.","authors":"Zhe Cheng, Huichao Huang, Meilong Yin, Huaizheng Liu","doi":"10.1186/s40164-025-00602-1","DOIUrl":"10.1186/s40164-025-00602-1","url":null,"abstract":"<p><p>Liposomes and lipid nanoparticles are common lipid-based drug delivery systems and play important roles in cancer treatment and vaccine manufacture. Although significant progress has been made with these lipid-based nanocarriers in recent years, efficient clinical translation of active targeted liposomal nanocarriers remains extremely challenging. In this review, we focus on targeted liposomes, stimuli-responsive strategy and combined therapy in cancer treatment. We also summarize advances of liposome and lipid nanoparticle applications in nucleic acid delivery and tumor vaccination. In addition, we discuss limitations and challenges in the clinical translation of these lipid nanomaterials and make recommendations for the future research in cancer therapy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"11"},"PeriodicalIF":9.4,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A non-conditioned bone marrow transplantation mouse model to study clonal hematopoiesis and myeloid malignancies.","authors":"Sofia Bentivegna, Marwa Almosailleakh, Lin-Pierre Zhao, Mikkel Bruhn Schuster, Sébastien Benquet, Alexander Balhuizen, Helga Fibiger Munch-Petersen, Lene Dissing Sjö, Mads Hald Andersen, Nicolas Dulphy, Bo Porse, Kirsten Grønbæk","doi":"10.1186/s40164-025-00598-8","DOIUrl":"10.1186/s40164-025-00598-8","url":null,"abstract":"<p><p>Clonal hematopoiesis of indeterminate potential (CHIP) is a condition where blood or bone marrow cells carry mutations associated with hematological malignancies. Individuals with CHIP have an increased risk of developing hematological malignancies, atherosclerotic cardiovascular disease, and all-cause mortality. Bone marrow transplantation (BMT) of cells carrying CHIP mutations into irradiated mice are useful procedures to investigate the dynamics of clonal expansion and potential therapeutic strategies, but myeloablative conditioning can induce confounding effects. We established a non-conditioned BMT model using C57BL/6J-Kit^W-41J/J (W⁴¹) recipient mice to overcome the unwanted effects of irradiation. Conditional Tet2 deletion using tamoxifen was used to obtain Tet2^-/- cells from donor mice. Total BM Tet2^-/- cells were transplanted into W⁴¹ recipients, and longitudinal and terminal analyses at 10 months post-BMT were performed. We showed that W⁴¹ mice can be used for BMT procedures without myeloablative pre-conditioning. The transplantation of Tet2^-/- BM cells led to a progressive expansion of the donor cells in W⁴¹ recipients. By modulating the numbers of Tet2^-/- cells transplanted, recipient mice developed features of clonal hematopoiesis or myeloid malignancies. In conclusion, our model is an alternative to conventional irradiation-based transplantation models to study mechanisms underlying malignant hematopoiesis without confounding effects derived from pre-conditioning regimen.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"10"},"PeriodicalIF":9.4,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11781034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EZH2 inhibition induces pyroptosis via RHA-mediated S100A9 overexpression in myelodysplastic syndromes.","authors":"Qi Zhang, Yingwan Luo, Li Ye, Yuxia Wang, Lu Wang, Wenli Yang, Wei Lang, Shuanghong Zhu, Lingxu Jiang, Weimei Jin, Chen Mei, Xinping Zhou, Yanling Ren, Liya Ma, Gaixiang Xu, Bowatte Gedara Lakmal Vimukthi Bandara Bowattage, Hongyan Tong, Jie Sun","doi":"10.1186/s40164-025-00600-3","DOIUrl":"10.1186/s40164-025-00600-3","url":null,"abstract":"<p><p>Myelodysplastic Syndromes (MDS) represent a group of heterogeneous myeloid clonal diseases derived from aberrant hematopoietic stem/progenitor cells. Enhancer of zeste homolog 2 (EZH2) is an important regulator in gene expression through methyltransferase-dependent or methyltransferase-independent mechanisms. Herein, we found EZH2 inhibition led to MDS cell pyroptosis through RNA Helicase A (RHA) down-regulation induced overexpression of S100A9, a key regulator of inflammasome activation and pyroptosis. Moreover, EZH2 inhibitor reduced tumor burden and prolonged the survival of the mice transplanted with MDS cells. In summary, our results uncovered a novel pyroptosis pathway induced by EZH2 inhibition and provided a rationale for EZH2 inhibitor treatment in MDS.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"9"},"PeriodicalIF":9.4,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Telomeres, telomerase, and cancer: mechanisms, biomarkers, and therapeutics.","authors":"Songting Shou, Ayidana Maolan, Di Zhang, Xiaochen Jiang, Fudong Liu, Yi Li, Xiyuan Zhang, En Geer, Zhenqing Pu, Baojin Hua, Qiujun Guo, Xing Zhang, Bo Pang","doi":"10.1186/s40164-025-00597-9","DOIUrl":"10.1186/s40164-025-00597-9","url":null,"abstract":"<p><p>Telomeres and telomerase play crucial roles in the initiation and progression of cancer. As biomarkers, they aid in distinguishing benign from malignant tissues. Despite the promising therapeutic potential of targeting telomeres and telomerase for therapy, translating this concept from the laboratory to the clinic remains challenging. Many candidate drugs remain in the experimental stage, with only a few advancing to clinical trials. This review explores the relationship between telomeres, telomerase, and cancer, synthesizing their roles as biomarkers and reviewing the outcomes of completed trials. We propose that changes in telomere length and telomerase activity can be used to stratify cancer stages. Furthermore, we suggest that differential expression of telomere and telomerase components at the subcellular level holds promise as a biomarker. From a therapeutic standpoint, combining telomerase-targeted therapies with drugs that mitigate the adverse effects of telomerase inhibition may offer a viable strategy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"8"},"PeriodicalIF":9.4,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural basis of FpGalNase and its combination with FpGalNAcDeAc for efficient A-to-O blood group conversion.","authors":"Meiling Zhou, Kaishan Luo, Chao Su, Yan Sun, Zuyan Huang, Shuo Ma, Xun Gao, Jiwei Wang, Chen Zhang, Pengcheng Han, Guoqiu Wu","doi":"10.1186/s40164-025-00599-7","DOIUrl":"10.1186/s40164-025-00599-7","url":null,"abstract":"<p><p>Transfusion safety and blood typing continue to present significant challenges in clinical practice, including risks of incorrect blood transfusions and blood shortages. One promising solution is the enzymatic conversion of all red blood cell (RBC) types into universal O-type RBCs. However, the major obstacle to this strategy is the relatively low catalytic efficiency of the enzymes involved. In this study, we investigated two enzymes from Flavonifractor plautii, N-acetylgalactosamine deacetylase (FpGalNAcDeAc) and galactosaminidase (FpGalNase), which demonstrate synergistic activity in efficiently converting A-type RBCs to O-type. We optimized treatment conditions, achieving over 99% conversion in just five minutes using phosphate buffer saline and a 16 nM enzyme concentration. Additionally, we engineered two fusion proteins, FpGalNAcDeAc-FpGalNase and FpGalNase-FpGalNAcDeAc, which showed a 28-fold increase in catalytic efficiency compared to the enzyme mixture. Using cryo-electron microscopy, we resolved the full-length structure of FpGalNase, identifying critical active site residues involved in its catalytic mechanism. This study provides essential structural and biochemical insights for clinical applications in blood group conversion, offering a promising approach for producing universal O-type RBCs.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"7"},"PeriodicalIF":9.4,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762096/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}