Blood最新文献

{"title":"Targeting caseinolytic mitochondrial matrix peptidase, a novel contributor to the pathobiology of high-risk multiple myeloma.","authors":"Li Qin, Luz Yurany Moreno Rueda, Upasana Ray, Iqbal Mahmud, Lin Tan, Philip L Lorenzi, Suyu Liu, Heather Lin, David E Mery, Fenghuang Zhan, John D Shaughnessy, Qing Yi, Maria Jose Acevedo Calado, Hua Wang, Elisabet E Manasanch, Hans C Lee, Krina K Patel, Isere Kuiatse, David E Symer, Robert Z Orlowski","doi":"10.1182/blood.2024024781","DOIUrl":"10.1182/blood.2024024781","url":null,"abstract":"<p><strong>Abstract: </strong>Plasma cell dyscrasias encompass a spectrum from the precursors monoclonal gammopathy of undetermined significance and smoldering myeloma to symptomatic myeloma, but the genes that enable progression and confer poor prognosis are incompletely understood. Using single-cell transcriptomics, we identified the caseinolytic protease proteolytic subunit (CLPP), a key component of the mitochondrial caseinolytic protease (CLP) serine endopeptidase, as being overexpressed in CD138+ neoplastic vs normal and in symptomatic vs precursor plasma cells. Its high expression was associated with an adverse prognosis across multiple molecularly defined subgroups in the newly diagnosed and relapsed/refractory settings and with extramedullary disease. Pharmacologic CLPP inhibition and genetic suppression reduced organoid growth, cell viability, and cell cycle progression, and triggering an unfolded protein response and apoptosis. This occurred in association with mitochondrial transmembrane potential loss and caspase and proteasome activation in a reactive oxygen species-dependent manner. Downstream consequences included autophagy and mitophagy induction and reductions in oxidative phosphorylation and glycolysis with consequent compromise of mitochondrial and cytoplasmic adenosine triphosphate (ATP) production. CLP endopeptidase inhibition overcame conventional and novel drug resistance, induced apoptosis in primary samples, showed efficacy in vivo, and could be achieved with the clinically relevant agent inobrodib. Finally, regimens combining a CLPP and proteasome inhibitor showed enhanced efficacy, as did combinations with inhibitors of intermediary metabolism and autophagy. Taken together, our data indicate that CLPP is a key contributor to transformed plasma cells, a novel mediator of high-risk behavior, and a legitimate target for myeloma therapy whose inhibitors could be rationally combined with current therapeutics to improve outcomes.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2614-2629"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163742/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254465","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 TIM-3-Fc decoy secreted by engineered T cells improves CD19 CAR T-cell therapy in B-cell acute lymphoblastic leukemia.","authors":"Aïda Falgàs, Rodrigo Lázaro-Gorines, Samanta Romina Zanetti, Laura Rubio-Pérez, Alba Martínez-Moreno, Meritxell Vinyoles, Mercedes Guerrero-Murillo, Narcís Fernández-Fuentes, Heleia Roca-Ho, Néstor Tirado, Carla Panisello, Talia Velasco-Hernandez, Andrea Mayado, Alba Pérez-Pons, Eulalia Genescà, Josep-Maria Ribera, Jordi Ribera, Mireia Camos, Manuel Ramírez-Orellana, Eduardo Anguita, Paola Ballerini, José Luis Fuster, Manel Juan, Europa Azucena González-Navarro, Franco Locatelli, Ronald W Stam, Sergi Querol, Pablo Velasco, Valentín Ortiz-Maldonado, Nuria Martínez-Cibrián, Julio Delgado, Alberto Orfao, Luis Álvarez-Vallina, Clara Bueno, Pablo Menéndez","doi":"10.1182/blood.2024025440","DOIUrl":"10.1182/blood.2024025440","url":null,"abstract":"<p><strong>Abstract: </strong>Relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging disease with dismal prognosis. Despite the revolutionary impact of CD19-directed chimeric antigen receptor (CAR19) T-cell therapy, >50% of patients relapse within a year. Both leukemia cell-intrinsic factors favoring immune escape and poor CAR T-cell persistence contribute to clinical failure. Moreover, the expression of immune checkpoint receptors (ICRs) and their ligands within the bone marrow (BM) microenvironment may contribute to leukemia progression and therapy resistance. Here, we characterized the expression of ICRs and their ligands in leukemic blasts, T cells, and mesenchymal stromal cells (MSCs) from B-ALL BM samples at diagnosis and relapse, comparing them with age-matched healthy BM controls. Our findings reveal a significantly upregulated expression of TIM-3 in T cells and its ligand, galectin-9, in both blasts and MSCs throughout disease progression. The expression of galectin-9 in B-ALL blasts and TIM-3 in CAR19 T cells negatively correlates with clinical outcome. Furthermore, we demonstrate that galectin-9 impairs CAR19 T-cell homeostasis and cytotoxicity. Notably, an engineered TIM-3-Fc decoy receptor, delivered either by primary T cells coadministered with CAR19 T cells or via a bicistronic all-in-one CAR19-TIM-3-Fc construct, improved the antileukemia efficacy and persistence of CAR19 T cells in B-ALL xenograft models. Mechanistically, CAR19-TIM-3-Fc T-cell treatment promotes the in vivo expansion of transduced and bystander effector and memory T cells, as determined by spectral flow cytometry. Collectively, these TIM-3-Fc decoy-armored CAR19 T cells offer a promising therapeutic strategy for patients with R/R B-ALL.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2599-2613"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639611","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}

{"title":"Exploring the ABO-VTE connection.","authors":"Noel Chan, Jack Hirsh","doi":"10.1182/blood.2025028652","DOIUrl":"https://doi.org/10.1182/blood.2025028652","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 22","pages":"2544-2545"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172599","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}

{"title":"Are you ready for it? VEN-HMA for younger patients with AML.","authors":"Tara L Lin","doi":"10.1182/blood.2025028825","DOIUrl":"https://doi.org/10.1182/blood.2025028825","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 22","pages":"2543-2544"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172530","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}

{"title":"HLA antibodies delay platelet recovery after gene therapy.","authors":"Ashish O Gupta, Akshay Sharma","doi":"10.1182/blood.2025028995","DOIUrl":"https://doi.org/10.1182/blood.2025028995","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 22","pages":"2546-2547"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172645","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}

{"title":"Primary myelofibrosis involving lymph nodes with the same mutational profile in bone marrow.","authors":"Yanna Ding, Kikkeri N Naresh","doi":"10.1182/blood.2025028556","DOIUrl":"https://doi.org/10.1182/blood.2025028556","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 22","pages":"2672"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172667","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}

{"title":"One hundred thirty-four germ line PU.1 variants and the agammaglobulinemic patients carrying them.","authors":"Ainsley V C Knox, Lauren Y Cominsky, Di Sun, Emylette Cruz Cabrera, Brian E Nolan, Edann Ofray, Elisa Benetti, Camilla Visconti, Federica Barzaghi, Sergio D Rosenzweig, Monica G Lawrence, Kathleen E Sullivan, Samuel Yoon, Suzanna Rachimi, Nurcicek Padem, Erin Conboy, Maja Stojanovic, Gordana Petrovic, Srdjan Pasic, Joseph Church, Ronald M Ferdman, Fabio Candotti, Tiphaine Arlabosse, Katerina Theodoropoulou, Cullen M Dutmer, László Maródi, Gabriella Szücs, Arnon Broides, Amit Nahum, Jacov Levy, Kaisa Kettunen, Ravindra Daddali, Mikko Seppänen, Markku Vänttinen, Timi Martelius, Juha Grönholm, Matilde Peri, Chiara Azzari, Silvia Ricci, Samar Ojaimi, Emily S J Edwards, Menno C van Zelm, Jinqiao Sun, Hassan Abolhassani, Qiang Pan-Hammarström, Hakon Hakonarson, Daniel Mayr, Kaan Boztug, Bertrand Boisson, Jean-Laurent Casanova, Carole Le Coz, Gregory M K Poon, Neil Romberg","doi":"10.1182/blood.2024026683","DOIUrl":"10.1182/blood.2024026683","url":null,"abstract":"<p><strong>Abstract: </strong>Leukopoiesis is lethally arrested in mice lacking the master transcriptional regulator PU.1. Depending on the animal model, subtotal PU.1 loss either induces acute myeloid leukemia or arrests early B-cell and dendritic-cell development. Although humans with absolute PU.1 deficiency have not been reported, a small cadre of congenital agammaglobulinemia patients with sporadic, inborn PU.1 haploinsufficiency was recently described. To better estimate the penetrance, clinical complications, immunophenotypic features, and malignancy risks of PU.1-mutated agammaglobulinemia (PU.MA), a collection of 134 novel or rare PU.1 variants from publicly available databases, institutional cohorts, previously published reports, and unsolved agammaglobulinemia cases were functionally analyzed. In total, 25 loss-of-function (LOF) variants were identified in 33 heterozygous carriers from 21 kindreds across 13 nations. Of individuals harboring LOF PU.1 variants, 22 were agammaglobulinemic, 5 displayed antibody deficiencies, and 6 were unaffected, indicating an estimated disease penetrance of 81.8% with variable expressivity. In a cluster of patients, disease onset was delayed, sometimes into adulthood. All LOF variants conveyed effects via haploinsufficiency, either by destabilizing PU.1, impeding nuclear localization, or directly interfering with transcription. PU.MA patient immunophenotypes consistently demonstrated B-cell, conventional dendritic-cell, and plasmacytoid dendritic-cell deficiencies. Associated infectious and noninfectious symptoms hewed closely to X-linked agammaglobulinemia and not monogenic dendritic-cell deficiencies. No carriers of LOF PU.1 variants experienced hematologic malignancies. Collectively, in vitro and clinical data indicate heterozygous LOF PU.1 variants undermine humoral immunity but do not convey strong leukemic risks.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2549-2560"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031927","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":"\"Scotty, we need more power!\"","authors":"Kelvin Lee","doi":"10.1182/blood.2025028349","DOIUrl":"https://doi.org/10.1182/blood.2025028349","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 22","pages":"2540-2541"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172517","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}

{"title":"Ibrutinib lead-in followed by venetoclax plus ibrutinib for relapsed/refractory chronic lymphocytic leukemia: the SAKK 34/17 trial.","authors":"Adalgisa Condoluci, Ilaria Romano, Daniel Dietrich, Katia Pini, Georg Stüssi, Gisela Müller, Nathan Cantoni, Richard Cathomas, Ulrich Mey, Anouk Widmer, Thorsten Zenz, Michael Gregor, Dominik Heim, Martin Andres, Rudolf Benz, Davide Rossi","doi":"10.1182/blood.2024026879","DOIUrl":"10.1182/blood.2024026879","url":null,"abstract":"<p><strong>Abstract: </strong>The combination of ibrutinib plus venetoclax (IV) in chronic lymphocytic leukemia (CLL) treatment leverages their complementary mechanisms of action. Studies investigating IV typically begin with a short initial course of ibrutinib, followed by venetoclax introduction for a limited duration, typically 12 months. The Swiss Group for Clinical Cancer Research (SAKK) 34/17 study is a single-arm, multicenter, phase 2 trial evaluating the effectiveness of a modified IV schedule in patients with relapsed/refractory (R/R) CLL. No prior exposure to BTK or BCL2 inhibitors was allowed. The lead-in phase with ibrutinib was extended to 6 months to reduce the tumor burden and related tumor lysis syndrome (TLS) risk. Additionally, the treatment phase with IV is prolonged to a minimum of 24 months to enhance the undetectable minimal residual disease (uMRD; 10-4) rate. The primary end point was the rate of complete response or complete response with incomplete bone marrow recovery (CR/CRi) with uMRD in both bone marrow (BM) and peripheral blood (PB). Secondary end points included assessing the proportion of patients transitioning to a low-risk category for TLS after receiving ibrutinib lead-in. Of the 30 enrolled patients with R/R CLL, 40.0% achieved uMRD CR/CRi by intention-to-treat analysis, and 53.3% showed uMRD in the BM and PB. After the lead-in period with ibrutinib, 57.1% of patients achieved a low risk of TLS. At cycle 31, the progression-free survival rate was 89.9%. These results contribute to the increasing body of evidence supporting the idea that a longer IV duration is beneficial for enhancing therapeutic effectiveness. This trial was registered at www.clinicaltrials.gov as #NCT03708003.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2587-2598"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514593","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}

{"title":"Precision medicine for high-risk gene fusions in pediatric AML: a focus on KMT2A, NUP98, and GLIS2 rearrangements.","authors":"Grace Egan, Sarah K Tasian","doi":"10.1182/blood.2024026598","DOIUrl":"10.1182/blood.2024026598","url":null,"abstract":"<p><strong>Abstract: </strong>Robust genetic characterization of pediatric acute myeloid leukemia (AML) has demonstrated that fusion oncogenes are highly prevalent drivers of AML leukemogenesis in young children. Identification of fusion oncogenes associated with adverse outcomes has facilitated risk stratification of patients, although successful development of precision medicine approaches for most fusion-driven AML subtypes have been historically challenging. This knowledge gap has been in part due to difficulties in targeting structural alterations involving transcription factors and in identification of a therapeutic window for selective inhibition of the oncofusion without deleterious effects upon essential wild-type proteins. Herein, we discuss the current molecular landscape and functional characterization of 3 of the most lethal childhood AML fusion-oncogene driven subtypes harboring KMT2A, NUP98, or CBFA2T3::GLIS2 rearrangements. We further review early-phase clinical trial data of novel targeted inhibitors and immunotherapies that have demonstrated initial success specifically for children with these poor-prognosis genetic subtypes of AML and provide appreciable optimism to improve clinical outcomes in the future.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2574-2586"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982217","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}