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HLA-haploidentical stem cell transplantation for chronic granulomatous disease: an EBMT-IEWP retrospective study.
IF 21 1区 医学
Blood Pub Date : 2025-03-16 DOI: 10.1182/blood.2024026915
Quentin Riller, Mathias M Hauri-Hohl, Su Han Lum, Jeroen Knippenberg, Tiarlan Sirait, Alexandra Laberko, Khalid Halahleh, Hasan Hashem, Musa Karakukcu, Henrik Sengeloev, Fulvio Porta, Benedicte Bruno, Marco Zecca, Serap Aksoylar, Vincent Barlogis, Catharina Schuetz, Jochen Buechner, Maura Faraci, Claudia Wehr, Wolfgang Holter, Karin M Mellgren, Franco Locatelli, Antonio Pérez-Martínez, Felipe Suarez, Despina Moshous, Andrew R Gennery, Dmitry Balashov, Michael H Albert, Mary A Slatter, Tayfun Güngör, Bénédicte Neven
{"title":"HLA-haploidentical stem cell transplantation for chronic granulomatous disease: an EBMT-IEWP retrospective study.","authors":"Quentin Riller, Mathias M Hauri-Hohl, Su Han Lum, Jeroen Knippenberg, Tiarlan Sirait, Alexandra Laberko, Khalid Halahleh, Hasan Hashem, Musa Karakukcu, Henrik Sengeloev, Fulvio Porta, Benedicte Bruno, Marco Zecca, Serap Aksoylar, Vincent Barlogis, Catharina Schuetz, Jochen Buechner, Maura Faraci, Claudia Wehr, Wolfgang Holter, Karin M Mellgren, Franco Locatelli, Antonio Pérez-Martínez, Felipe Suarez, Despina Moshous, Andrew R Gennery, Dmitry Balashov, Michael H Albert, Mary A Slatter, Tayfun Güngör, Bénédicte Neven","doi":"10.1182/blood.2024026915","DOIUrl":"https://doi.org/10.1182/blood.2024026915","url":null,"abstract":"<p><p>Chronic granulomatous disease (CGD) is an inborn error of immunity characterized by defective NADPH oxidase function, leading to impaired microbial killing, recurrent infections and granulomatous inflammation. Allogenic hematopoietic stem cell transplantation (HSCT) is a curative treatment for CGD, particularly effective when a fully HLA-matched donor is available. However, the place of HLA-haploidentical HSCT remains less established. This retrospective, multicenter study analyzed outcomes of 64 CGD patients (53 males, 46 with X-linked CGD) who underwent a first HSCT with HLA-haploidentical family donors either with in vitro TCRαβ/CD19 depletion or in vivo depletion using post-transplant cyclophosphamide (PTCY). The mean age at transplant was 5.8 years (0-33 years). Patients exhibited a high disease burden prior to HSCT, with 45% experiencing infections in the 6 months prior to HSCT and 67% exhibiting inflammation. Outcomes in the entire cohort showed a 3-year overall survival (OS), event-free survival (EFS) and GvHD grade III to IV-free, event-free survival (GEFS) of 75.9%, of 70.2%, and of 56.1% respectively and were not impacted by the type of depletion or age. The cumulative incidence (CI) of primary graft failure was 20.6%. The CI of grade II to IV acute GvHD was higher in the PTCY group (p=0.04) whereas the CI of GVH grade III to IV was not. These results indicate that HLA-haploidentical HSCT is a feasible transplant option for CGD patients lacking HLA-matched donors. Further refinement of transplant protocols is necessary to mitigate graft failure and acute GvHD, ultimately improving access and outcomes for this life-saving therapy.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Ruxolitinib combined with dexamethasone for adult patients with newly diagnosed hemophagocytic lymphohistiocytosis in China.
IF 21 1区 医学
Blood Pub Date : 2025-03-16 DOI: 10.1182/blood.2024026139
De Zhou, Xianbo Huang, Lixia Zhu, Xuelian Hu, Xiudi Yang, Mixue Xie, Xin Huang, Fang Yu, Juying Wei, Liya Ma, Jingjing Zhu, Shuqi Zhao, Wanzhuo Xie, Hongyan Tong, Jie Jin, Xiujin Ye
{"title":"Ruxolitinib combined with dexamethasone for adult patients with newly diagnosed hemophagocytic lymphohistiocytosis in China.","authors":"De Zhou, Xianbo Huang, Lixia Zhu, Xuelian Hu, Xiudi Yang, Mixue Xie, Xin Huang, Fang Yu, Juying Wei, Liya Ma, Jingjing Zhu, Shuqi Zhao, Wanzhuo Xie, Hongyan Tong, Jie Jin, Xiujin Ye","doi":"10.1182/blood.2024026139","DOIUrl":"https://doi.org/10.1182/blood.2024026139","url":null,"abstract":"<p><p>Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome, and the overall survival of adult patients is poor. Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, has shown promise in treating HLH and exerts synergistic effects when combined with dexamethasone. Our pilot study preliminarily demonstrated that the combination of ruxolitinib and dexamethasone (the Ru-D regimen) had a high response rate and led to favorable short-term survival outcomes in adult HLH patients. In this prospective phase 2 clinical trial, we propose the Ru-D regimen as a first-line treatment for adults newly diagnosed with HLH with unknown triggers (chictr.org.cn identifier: ChiCTR2100049996). A total of 28 Chinese patients were enrolled, and the median follow-up time was 25.1 months (range, 0.87-34.0). The 2-month OS rate (the primary endpoint) was 85.7%, which exceeded our expected 2-month OS rate of 75%. The 6-month and 2-year OS rates were 67.9% (19/28) and 53.6% (15/28), respectively. The median OS of lymphoma-associated HLH (LAHS) patients was 5.8 months, and most of these patients had NK/T-cell lymphoma. In contrast, the 2-year OS rate of non-LAHS patients was 75%. The overall response rate (ORR) was 85.7% (24/28); 17.9% (5/28) of patients achieved a complete response (CR) during the Ru-D regimen. Overall, the Ru-D regimen was well tolerated in HLH patients. This study demonstrates the efficacy and safety of the Ru-D regimen in adults newly diagnosed with HLH with unknown triggers and warrants a phase 3 randomized controlled study.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Safety and efficacy of rilzabrutinib vs placebo in adults with immune thrombocytopenia: the phase 3 LUNA3 study.
IF 21 1区 医学
Blood Pub Date : 2025-03-16 DOI: 10.1182/blood.2024027336
David J Kuter, Waleed Ghanima, Nichola Cooper, Howard Allen Liebman, Lei Zhang, Yu Hu, Yoshitaka Miyakawa, Wojciech Homenda, Luisa Elena Elena Morales Galindo, Ana Lisa Basquiera, Chuen Wen Tan, Guray Saydam, Marie Luise Hütter-Krönke, Chatree Chai-Adisaksopha, David Gomez-Almaguer, Huy Tran, Ho-Jin Shin, Ademar Dantas da Cunha Junior, Zsolt Lazar, Cristina Pascual-Izquierdo, Ilya Kirgner, Elisa Lucchini, Ganna Kuzmina, Michael Fillitz, Sylvain Audia, Minakshi Taparia, Matias Cordoba, Remco Diab, Mengjie Yao, Imene Gouia, Michelle Lee, Ahmed Abd Almalik Daak
{"title":"Safety and efficacy of rilzabrutinib vs placebo in adults with immune thrombocytopenia: the phase 3 LUNA3 study.","authors":"David J Kuter, Waleed Ghanima, Nichola Cooper, Howard Allen Liebman, Lei Zhang, Yu Hu, Yoshitaka Miyakawa, Wojciech Homenda, Luisa Elena Elena Morales Galindo, Ana Lisa Basquiera, Chuen Wen Tan, Guray Saydam, Marie Luise Hütter-Krönke, Chatree Chai-Adisaksopha, David Gomez-Almaguer, Huy Tran, Ho-Jin Shin, Ademar Dantas da Cunha Junior, Zsolt Lazar, Cristina Pascual-Izquierdo, Ilya Kirgner, Elisa Lucchini, Ganna Kuzmina, Michael Fillitz, Sylvain Audia, Minakshi Taparia, Matias Cordoba, Remco Diab, Mengjie Yao, Imene Gouia, Michelle Lee, Ahmed Abd Almalik Daak","doi":"10.1182/blood.2024027336","DOIUrl":"https://doi.org/10.1182/blood.2024027336","url":null,"abstract":"<p><p>Rilzabrutinib is a covalent, reversible BTK inhibitor with multiple mechanisms targeting key immune thrombocytopenia (ITP) disease pathophysiology. The phase 3 LUNA3 study in previously treated adults with persistent/chronic ITP evaluated oral rilzabrutinib 400 mg bid (n=133) vs placebo (n=69) for 24 weeks. At baseline overall, median age was 47 years (range, 18-80), 63% female, 7.7 year (range, 0.3-52.2) median duration of ITP, and 28% were splenectomized. Overall (N=202), 85 (64%) rilzabrutinib and 22 (32%) placebo patients achieved platelet response (≥50×109/L or 30×109/L-<50×109/L and doubled from baseline) during the first 12 weeks and were eligible to complete the double-blind period. The primary endpoint durable platelet response (platelet count ≥50×109/L for ≥two-thirds of ≥8 of the last 12 of 24 weeks without rescue therapy) was observed in 31 (23%) rilzabrutinib vs 0 placebo patients (P<0.0001). All secondary efficacy endpoints were significantly superior for rilzabrutinib (P<0.05). Median time to first platelet response was 15 d in rilzabrutinib responders. Rilzabrutinib significantly reduced rescue therapy use by 52% (P=0.0007) and improved week 25 bleeding scores (P=0.0006). Improved physical fatigue was sustained from week 13 (P=0.01) through 25 (P=0.0003). Treatment-related adverse events were mainly grade 1-2. One rilzabrutinib patient with multiple risk factors had serious treatment-related grade 3 peripheral embolism (lower left leg) and another died from unrelated pneumonia. Rilzabrutinib-- in ITP patients who failed multiple previous therapies (splenectomy, TPO-RA, rituximab and/or fostamatinib) resulted in rapid and durable platelet response, reduced rescue medication use and bleeding, significantly improved physical fatigue, and showed favorable safety. NCT04562766; EudraCT 2020-002063-60.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Impact of HLA Alloimmunization in Gene-Modified Autologous Stem Cell Transplant For Transfusion-Dependent Thalassemia.
IF 21 1区 医学
Blood Pub Date : 2025-03-16 DOI: 10.1182/blood.2024027034
Nora M Gibson, Eugene Khandros, Caitlin W Elgarten, Elizabeth Worster, Dimitrios S Monos, Alexis A Thompson, Janet L Kwiatkowski, Timothy Olson
{"title":"Impact of HLA Alloimmunization in Gene-Modified Autologous Stem Cell Transplant For Transfusion-Dependent Thalassemia.","authors":"Nora M Gibson, Eugene Khandros, Caitlin W Elgarten, Elizabeth Worster, Dimitrios S Monos, Alexis A Thompson, Janet L Kwiatkowski, Timothy Olson","doi":"10.1182/blood.2024027034","DOIUrl":"https://doi.org/10.1182/blood.2024027034","url":null,"abstract":"<p><p>We report our single center experience demonstrating that HLA Class I alloimmunization predicts longer time to platelet engraftment, increased bleeding complications and higher transfusion requirements in patients undergoing gene-modified hematopoietic stem cell transplant for transfusion-dependent beta thalassemia.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Lymphoid Malignancies in patients with Shwachman-Diamond Syndrome.
IF 21 1区 医学
Blood Pub Date : 2025-03-16 DOI: 10.1182/blood.2024026507
Helen D Reed, Hyunwoo Do, Edie A Weller, Marian H Harris, Christopher R Reilly, Harrison K Tsai, Jason E Farrar, Bonnie W Lau, Lauren Pommert, Christopher J Gamper, Ian Atkinson, Katherine Coyne, Margret Joos, Sara Katherine Loveless, Sarah K Steltz, Leah Cheng, Maggie Malsch, Kasiani C Myers, Akiko Shimamura
{"title":"Lymphoid Malignancies in patients with Shwachman-Diamond Syndrome.","authors":"Helen D Reed, Hyunwoo Do, Edie A Weller, Marian H Harris, Christopher R Reilly, Harrison K Tsai, Jason E Farrar, Bonnie W Lau, Lauren Pommert, Christopher J Gamper, Ian Atkinson, Katherine Coyne, Margret Joos, Sara Katherine Loveless, Sarah K Steltz, Leah Cheng, Maggie Malsch, Kasiani C Myers, Akiko Shimamura","doi":"10.1182/blood.2024026507","DOIUrl":"https://doi.org/10.1182/blood.2024026507","url":null,"abstract":"<p><p>This study identified an increased risk of lymphoid malignancy in Shwachman-Diamond syndrome with an observed risk 38-fold higher than expected based on population data. Increased toxicity was observed with standard therapies in patients with SDS.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Azacitidine and venetoclax for HR-MDS: election results pending.
IF 21 1区 医学
Blood Pub Date : 2025-03-13 DOI: 10.1182/blood.2024027567
Sangeetha Venugopal, Mikkael A Sekeres
{"title":"Azacitidine and venetoclax for HR-MDS: election results pending.","authors":"Sangeetha Venugopal, Mikkael A Sekeres","doi":"10.1182/blood.2024027567","DOIUrl":"https://doi.org/10.1182/blood.2024027567","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 11","pages":"1099-1100"},"PeriodicalIF":21.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Heat-insoluble cryoglobulin in peripheral blood.
IF 21 1区 医学
Blood Pub Date : 2025-03-13 DOI: 10.1182/blood.2024027775
Keyliz Peraza Cruces, Katalin Marianna Kovacs
{"title":"Heat-insoluble cryoglobulin in peripheral blood.","authors":"Keyliz Peraza Cruces, Katalin Marianna Kovacs","doi":"10.1182/blood.2024027775","DOIUrl":"https://doi.org/10.1182/blood.2024027775","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 11","pages":"1225"},"PeriodicalIF":21.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Why is InO's divine veil not protective against resistance?
IF 21 1区 医学
Blood Pub Date : 2025-03-13 DOI: 10.1182/blood.2024027572
Philippe Rousselot
{"title":"Why is InO's divine veil not protective against resistance?","authors":"Philippe Rousselot","doi":"10.1182/blood.2024027572","DOIUrl":"https://doi.org/10.1182/blood.2024027572","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 11","pages":"1106-1107"},"PeriodicalIF":21.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Development of ALL-Hematotox: predicting post-CAR T-cell hematotoxicity in B-cell acute lymphoblastic leukemia. 开发 ALL-Hematotox (ALL-HT):预测B细胞急性淋巴细胞白血病的CAR T细胞后血液毒性。
IF 21 1区 医学
Blood Pub Date : 2025-03-13 DOI: 10.1182/blood.2024025910
Monica S Nair, Sara K Silbert, Kai Rejeski, Karilynn A Wilson, Adam J Lamble, Yannis Valtis, Bonnie Yates, Alexa Morales Arana, Roni Shouval, Kevin Curran, Rebecca A Gardner, Haneen Shalabi, Colleen Annesley, Jae H Park, Marion Subklewe, Nirali N Shah
{"title":"Development of ALL-Hematotox: predicting post-CAR T-cell hematotoxicity in B-cell acute lymphoblastic leukemia.","authors":"Monica S Nair, Sara K Silbert, Kai Rejeski, Karilynn A Wilson, Adam J Lamble, Yannis Valtis, Bonnie Yates, Alexa Morales Arana, Roni Shouval, Kevin Curran, Rebecca A Gardner, Haneen Shalabi, Colleen Annesley, Jae H Park, Marion Subklewe, Nirali N Shah","doi":"10.1182/blood.2024025910","DOIUrl":"10.1182/blood.2024025910","url":null,"abstract":"<p><p>Immune effector cell-associated hematotoxicity (ICAHT) is a major B-cell targeted chimeric antigen receptor (CAR) T-cell related toxicity. Although ICAHT incidence and severity is documented in large B-cell lymphoma (LBCL), mantle cell lymphoma (MCL), and multiple myeloma (MM), ICAHT has not been described in B-cell acute lymphoblastic leukemia (B-ALL). Similarly, the CAR-HEMATOTOX (CAR-HT) model, designed to predict severe prolonged neutropenia (≥14 days of absolute neutrophil count [ANC] <500/μL), has been validated in LBCL, MCL, and MM, but not in B-ALL. As B-ALL bone marrow (BM) infiltration can impact cytopenias, we sought to describe ICAHT and assess CAR-HT for predicting hematotoxicity in B-ALL. In a cohort of 156 children and young adults with relapsed/refractory B-ALL, the median duration of severe neutropenia (ANC <500/μL) was 13 days (95% confidence interval, 10-16 days), with 83 (53%) experiencing grade ≥3 ICAHT. Applying CAR-HT, nearly 90% were classified as high risk, demonstrating limited discriminative power and prompting further development. Using the association identified between BM disease burden and postinfusion neutropenia (r = 0.64, P < .0001), we developed the ALL-Hematotox (ALL-HT) score, which substitutes BM disease burden for ferritin in CAR-HT. The ALL-HT score associated with severe prolonged neutropenia (area under the curve = 0.84, P < .0001), and appropriately discriminated high-risk patients (47%) who had more cumulative days of neutropenia (26 vs 4 days; P < .0001), fewer rates of complete response (88% vs 98%; P = .03), and shorter median overall survival (9.8 vs 24 months; log-rank P = .0002). ALL-HT was also validated in 2 independent cohorts. The ALL-HT score refines a widely accepted predictive model of postinfusion hematotoxicity, which is applicable in B-ALL.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1136-1148"},"PeriodicalIF":21.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142674796","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}
引用次数: 0
Selenoprotein-mediated redox regulation shapes the cell fate of HSCs and mature lineages. 硒蛋白介导的氧化还原调控塑造造血干细胞和成熟谱系的细胞命运。
IF 21 1区 医学
Blood Pub Date : 2025-03-13 DOI: 10.1182/blood.2024025402
Yumi Aoyama, Hiromi Yamazaki, Koutarou Nishimura, Masaki Nomura, Tsukasa Shigehiro, Takafumi Suzuki, Weijia Zang, Yota Tatara, Hiromi Ito, Yasutaka Hayashi, Yui Koike, Miki Fukumoto, Atsushi Tanaka, Yifan Zhang, Wataru Saika, Chihiro Hasegawa, Shuya Kasai, Yingyi Kong, Yohei Minakuchi, Ken Itoh, Masayuki Yamamoto, Shinya Toyokuni, Atsushi Toyoda, Tomokatsu Ikawa, Akifumi Takaori-Kondo, Daichi Inoue
{"title":"Selenoprotein-mediated redox regulation shapes the cell fate of HSCs and mature lineages.","authors":"Yumi Aoyama, Hiromi Yamazaki, Koutarou Nishimura, Masaki Nomura, Tsukasa Shigehiro, Takafumi Suzuki, Weijia Zang, Yota Tatara, Hiromi Ito, Yasutaka Hayashi, Yui Koike, Miki Fukumoto, Atsushi Tanaka, Yifan Zhang, Wataru Saika, Chihiro Hasegawa, Shuya Kasai, Yingyi Kong, Yohei Minakuchi, Ken Itoh, Masayuki Yamamoto, Shinya Toyokuni, Atsushi Toyoda, Tomokatsu Ikawa, Akifumi Takaori-Kondo, Daichi Inoue","doi":"10.1182/blood.2024025402","DOIUrl":"10.1182/blood.2024025402","url":null,"abstract":"<p><strong>Abstract: </strong>The maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. Motivated by our observation of messenger RNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs) and previous findings of increased lipid peroxidation in aged hematopoiesis, we used selenocysteine transfer RNA (tRNASec) gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis. This revealed insights into the protective roles of selenoproteins in preserving HSC stemness and B-lineage maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs' self-renewal capacity, recapitulating certain aspects of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and pre-B cells. Although Trsp KO activated an antioxidant response transcription factor NRF2, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in pre-B cells of Trsp KO mice, and KO pro-B/pre-B cells displayed differentiation potential toward functional CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B-to-myeloid switch. Given the similarities between the KO model and aged wild-type mice, including ferroptosis vulnerability, impaired HSC self-renewal and B-lineage maturation, and characteristic lineage switch, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and suggest the preventive potential of selenoproteins against aging-related alterations.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1149-1163"},"PeriodicalIF":21.0,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11923430/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142944611","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}
引用次数: 0
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