Blood最新文献

{"title":"Fetal context conveys heritable protection against MLL-rearranged AML that depends on MLL3.","authors":"Jonny Mendoza-Castrejon, Wei Yang, Elisabeth D Denby, Helen C Wang, Emily B Casey, Rohini Muthukumar, Riddhi M Patel, Jihye Yoon, Yanan Li, J Michael White, Ran Chen, Luis Francisco Zirnberger Batista, Jeffrey A Magee","doi":"10.1182/blood.2025029686","DOIUrl":"10.1182/blood.2025029686","url":null,"abstract":"<p><p>MLL rearrangements (MLLr) are the most common cause of congenital and infant leukemias. MLLr arise prior to birth and can transform fetal/neonatal progenitors with the help of only a few additional cooperating mutations. Despite the low threshold for transformation, infant leukemias are rare, and congenital leukemias, which arise before birth, are even less common. These observations raise the question of whether mechanisms exist to suppress leukemic transformation during fetal life, thereby protecting the developing fetus from malignancy during a period of rapid hematopoietic progenitor expansion. To test this possibility, we used a mouse model of temporally controlled MLL::ENL expression to show that fetal MLL::ENL exposure establishes a heritable, leukemia-resistant state within hematopoietic progenitors that persists after birth. When we induced MLL::ENL expression prior to birth and transplanted hematopoietic stem and progenitor cells, very few recipient mice developed acute myeloid leukemia (AML) despite robust engraftment. When we induced MLL::ENL expression shortly after birth, all recipient mice developed a highly penetrant AML. Fetal MLL::ENL expression imposed a negative selective pressure on hematopoietic progenitors before birth followed by loss of self-renewal gene expression and enhanced myeloid differentiation after birth that precluded transformation. These changes did not occur when MLL::ENL expression initiated shortly after birth. The fetal barrier to transformation was enforced by the histone methyltransferase MLL3, and it could be overcome by cooperating mutations, such as NrasG12D. Heritable fetal protection against leukemic transformation may contribute to the low incidence of congenital and infant leukemias in humans.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.1,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145205546","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":"Mechanisms of immune escape and extramedullary tropism in leukemia cutis.","authors":"Livius Penter,Katie Maurer,Nicoletta Cieri,Wesley Lu,Haoxiang Lyu,Mischa Selig,Maria Joosten,Jana Ihlow,Shuqiang Li,Kenneth J Livak,Lars Bullinger,Jerome Ritz,Pavan Bachireddy,Matthew S Davids,Jacqueline S Garcia,Robert J Soiffer,Catherine J Wu","doi":"10.1182/blood.2025029121","DOIUrl":"https://doi.org/10.1182/blood.2025029121","url":null,"abstract":"The mechanisms that lead to extramedullary tropism of acute myeloid leukemia (eAML) remain obscure and no specific therapeutic approaches for this entity exist. As the long-term survival of eAML is poor, a deeper understanding of the immune microenvironment and leukemia phenotypes underlying this entity is warranted. Here, we performed bulk and single-cell transcriptome profiling of 23 eAML biopsies from 10 patients with isolated extramedullary disease in skin and subcutaneous tissue. Unlike normal healthy skin, we found leukemia cutis to be heavily immune-infiltrated; in cases of extramedullary relapse following allogeneic stem cell transplantation, >90% of T/NK cells were donor-derived. eAML-associated T cells expressed a clear signature of T cell exhaustion, dissimilar to leukemia-associated immune populations in bone marrow relapse (n=7), but related to acute and chronic skin inflammation. Further, HLA class II was down-regulated in 4 of 7 leukemia cutis specimens, consistent with an immune escape phenotype in cases of eAML. Extramedullary and bone marrow-resident leukemia cells differed with regard to the expression of 8 homing receptor molecules (ICAM1 (encoding CD54), PECAM1 (CD31), ITGA4, ITGA6, ITGAL, ITGB4, ITGA5, and ITGAV). Serial samples obtained from one leukemia cutis case throughout consecutive immune checkpoint blockade with ipilimumab followed by nivolumab showed a consistently high degree of overlap between local and circulating T cell receptor (TCR) sequences, suggesting that only a minority of eAML-associated T cells are leukemia-specific. Our analysis reveals eAML to associate with complex changes in leukemia and T cell gene expression profiles that suggest multiple potential avenues for therapeutic targeting.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"6 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194458","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":"Genome-wide analysis defines genetic determinants of MPN subtypes and identifies a sex-specific association at CDH22/CD40.","authors":"William J Tapper,Ahmed A Z Dawoud,Joannah Score,Andrew J Chase,E Joanna Baxter,Joanne Ewing,Louise Wallis,Paola Guglielmelli,Dolors Colomer,Beatriz Bellosillo,Monste Gomez,Juan Carlos Hernandez-Boluda,Carlos Besses,Francisco Cervantes,Steffen Koschmieder,Anthony R Green,Andreas Reiter,Alessandro M Vannucchi,Claire N Harrison,Nicholas C P Cross","doi":"10.1182/blood.2025028489","DOIUrl":"https://doi.org/10.1182/blood.2025028489","url":null,"abstract":"To identify genetic variants that influence myeloproliferative neoplasm (MPN) phenotype, we undertook a two-stage case-only genome-wide association study using cohorts from the UK (including UK Biobank), Spain, Germany and Italy. MPN subtype [essential thrombocythemia (ET); polycythemia vera (PV)] were compared to each other, to healthy controls and stratified analyses was performed based on chromosome 9p aberrations, JAK2 V617F mutation burden and sex. The ET versus PV analysis identified known associations: (i) at HBS1L-MYB that increased ET risk (PMETA=7.93x10-6, OR=1.28) and reduced PV risk (PMETA=9.43x10-5, OR=0.81) and (ii) at GFI1B-GTF3C5 that predisposed to PV only (PMETA=1.43x10-9, OR=1.38). Two further linked intronic SNPs, rs2425786 and rs2425788, at CDH22/CD40 were significant in females only (PMETA=2.67x10-8) with predisposition to PV (PMETA=0.0006, OR=1.3) and reduction of ET risk (PMETA=7.82x10-5, OR=0.75). Associations with JAK2, TERT, ATM, TET2, PINT, GFI1B and SH2B3 were confirmed (PMETA<5x10-8) and nine further loci were replicated (PMETA<0.05). A polygenic risk score consisting of 48 SNPs from 31 loci demonstrated moderate discriminative performance for ET and PV (AUC=0.718) and was improved by optimization for disease subtype (AUCET=0.724 and AUCPV=0.755). Overall, our results reveal that multiple germline variants influence MPN phenotype with HBS1L-MYB and a novel sex-specific association with CDH22/CD40 being the strongest determinants.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"31 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194457","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":"The Biology of MZL subtypes: Challenge and Relevance of Classification.","authors":"Camille Laurent,Francesco Bertoni","doi":"10.1182/blood.2024028268","DOIUrl":"https://doi.org/10.1182/blood.2024028268","url":null,"abstract":"Marginal zone lymphomas (MZLs) are a heterogeneous group of low-grade B-cell neoplasms classified into different entities by the current lymphoma classifications. They share some features, but differ significantly in clinical presentation, associated inflammatory conditions, anatomical sites of involvement, and molecular alterations. Etiopathogenesis is strongly linked to chronic antigenic stimulation and specific infections or autoimmune disorders for extranodal disease. Genetic hallmarks include constitutive NF-κB activation, and common trisomies 3 and 18, alongside subtype-specific lesions such as translocations in extranodal MZL and recurrent KLF2/NOTCH2 mutations in both nodal and splenic MZL, and deletions involving chromosome 7q, predominantly observed in splenic MZL. Diagnosis can be challenging due to overlapping features with other lymphomas like follicular lymphoma and lymphoplasmacytic lymphoma; integrating morphology, immunophenotype, and molecular data is essential. Transformation to aggressive DLBCL occurs in 3-15% of cases and is associated with the accumulation of genetic lesions, particularly in cell cycle, NF-κB, and epigenetic regulators, with subtype-specific drivers like TNFAIP3, TP53, and CDKN2A/B alterations. The tumor microenvironment plays a critical but understudied role, influenced by chronic antigen stimulation and involving complex interactions with immune cells that can promote immune suppression and influence therapeutic response. Understanding the heterogeneity of MZLs across their classification, genetic landscapes, and interaction with the microenvironment is crucial for accurate diagnosis, prognosis, and the development of effective targeted therapies.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"91 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194459","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":"PROs vs clinician-reported adverse events in a large clinical trial: findings from the phase 3 POLARIX study.","authors":"Carrie Thompson,Marek Trněný,Franck Morschhauser,Gilles A Salles,Patrick M M Reagan,Mark Hertzberg,Huilai Zhang,Catherine Thieblemont,Bei Hu,Gustavo Fonseca,Won Seog Seog Kim,Maurizio Martelli,Amitkumar Mehta,Avrita Singh,Mark Yan,Jamie Hirata,Matthew Sugidono,Calvin Lee,Jeff P Sharman,Neha Mehta-Shah,Christopher R Flowers,Hervé Tilly,Neil Chua,Olivier Casasnovas,Fiona Miall,Tae Min Min Kim,Xavier Cheng-Hong Tsai,Sunita D Nasta,Seung Tae Lee,Jonathan W Friedberg","doi":"10.1182/blood.2025028848","DOIUrl":"https://doi.org/10.1182/blood.2025028848","url":null,"abstract":"Diffuse large B-cell lymphoma (DLBCL) poses a challenge in hematology given its varied symptoms, and the complex interplay between disease and treatment effects on health-related quality of life (HRQoL). The phase 3 POLARIX study (NCT03274492) demonstrated superior progression-free survival (PFS) and a similar safety profile with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin and prednisone (Pola-R-CHP) vs rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in patients with previously untreated DLBCL. Here, we evaluate HRQoL through patient-reported outcome (PRO) instruments to fully characterize the patient experience in the POLARIX study. Changes from baseline in HRQoL, lymphoma symptoms, and gastrointestinal (GI) symptoms were assessed, as well as incidence and severity of common symptoms by PROs vs clinician-reported adverse events (AEs). Baseline characteristics of PRO-evaluable patients (N = 874) were consistent. Comparison between PROs and clinician-reported AEs revealed a notable discordance; patients generally reported a higher incidence of symptoms than clinicians, emphasizing the need for patient-centric tools to accurately capture the patient experience. Both treatments exhibited rapid and sustained improvements in HRQoL and lymphoma symptoms, with the most substantial improvements seen in global health status/QoL, lymphoma symptoms, fatigue, role, emotional, and social functioning. GI symptoms (diarrhea, constipation, nausea, and vomiting) were generally similar between treatment arms and returned to baseline levels after treatment completion. These HRQoL data underscore the complementarity of PROs, as an adjunct to clinician-reported AEs, in evaluating the efficacy and tolerability of new treatments, including Pola-R-CHP, which may represent a new benchmark for patient-reported HRQoL in previously untreated DLBCL.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"87 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140272","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":"Silent TAM keeps quiet.","authors":"Jeffrey A Magee","doi":"10.1182/blood.2025030018","DOIUrl":"https://doi.org/10.1182/blood.2025030018","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"146 13","pages":"1528-1529"},"PeriodicalIF":23.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136457","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":"Karpova D, Huerga Encabo H, Donato E, et al. Clonal hematopoiesis landscape in frequent blood donors. Blood. 2025;145(21):2411-2423.","authors":"","doi":"10.1182/blood.2025031167","DOIUrl":"https://doi.org/10.1182/blood.2025031167","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"59 1","pages":"1630"},"PeriodicalIF":20.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134383","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":"Biallelic antigen escape is a mechanism of resistance to anti-CD38 antibodies in multiple myeloma.","authors":"Benjamin Diamond, Linda Baughn, Mansour Poorebrahim, Alexandra M Poos, Holly Lee, Marcella Kaddoura, J Erin Wiedmeier-Nutor, Michael Durante, Gregory Otteson, Dragan Jevremovic, Hongwei Tang, Stefan Fröhling, Marc A Baertsch, Marios Papadimitriou, Bachisio Ziccheddu, Tomas Jelinek, Cendrine Lemoine, Alexey Rak, Damian J Green, Ola Landgren, Paola Neri, Leif Bergsagel, Esteban Braggio, Shaji Kumar, Marc S Raab, Rafael Fonseca, Nizar Bahlis, Niels Weinhold, Francesco Maura","doi":"10.1182/blood.2024028107","DOIUrl":"10.1182/blood.2024028107","url":null,"abstract":"<p><strong>Abstract: </strong>Monoclonal antibodies targeting CD38 are a therapeutic mainstay in multiple myeloma (MM). Although they have contributed to improved outcomes, most patients still experience disease relapse, and little is known about tumor-intrinsic mechanisms of resistance to these drugs. Antigen escape has been implicated as a mechanism of tumor-cell evasion in immunotherapy. Yet, it is unknown whether MM cells can develop permanent resistance to anti-CD38 antibodies by acquiring genomic events leading to biallelic disruption of the CD38 gene locus. Here, we analyzed whole-genome and whole-exome sequencing data from patients 701 newly diagnosed MM, 67 patients at relapse with naivety to anti-CD38 antibodies, and 50 patients collected at relapse after anti-CD38 antibodies. We report a loss of CD38 in 10 of 50 patients (20%) after CD38 therapy, 3 of whom exhibited a loss of both copies. Two of these cases showed convergent evolution in which distinct subclones independently acquired similar advantageous variants. Functional studies on missense mutations involved in biallelic CD38 events revealed that 2 variants, L153H and C275Y, decreased binding affinity and antibody-dependent cellular cytotoxicity of the commercial antibodies daratumumab and isatuximab. However, a third mutation, R140G, conferred selective resistance to daratumumab, while retaining sensitivity to isatuximab. Clinically, patients with MM are often rechallenged with CD38 antibodies after disease progression and these data suggest that next-generation sequencing may play a role in subsequent treatment selection for a subset of patients.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1575-1585"},"PeriodicalIF":23.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12451653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265231","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":"Losing CD38 in myeloma.","authors":"Maximilian Merz","doi":"10.1182/blood.2025029889","DOIUrl":"https://doi.org/10.1182/blood.2025029889","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"146 13","pages":"1529-1530"},"PeriodicalIF":23.1,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145136451","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":"USP25-Mediated Talin-1 Stabilization in Platelets: A Novel Mechanism of Hyperreactivity and Thrombosis Risk During Aging.","authors":"Xuemei Jia,Shuoyi Jiang,Hong Cheng,Zhicheng Wang,Zhihan Chen,Weiguo Dong,Haoxuan Zhong,Qi Zhang,Xianmin Song,Si Zhang,Rong Xia","doi":"10.1182/blood.2023023352","DOIUrl":"https://doi.org/10.1182/blood.2023023352","url":null,"abstract":"Aging is a critical risk factor for platelet hyperreactivity and thrombosis, yet the mechanisms involved remain poorly understood. This study investigates the role of ubiquitination in platelet function during aging. We identified heightened platelet reactivity in aged mice and human donors. Proteomic analysis of ubiquitin (Ub)-modified proteins and western blot revealed a reduction in overall ubiquitination in aged platelets, correlated with increased expression of deubiquitinating enzymes (DUBs). Notably, USP25 was significantly upregulated in platelets from aged individuals. Functional assays indicated that USP25 deficiency impairs platelet function and delays arterial thrombus formation. Mechanistic investigations integrating ubiquitin-modified proteomics and mass spectrometry demonstrated that USP25 enhances platelet hyperreactivity by stabilizing talin-1 through deubiquitination, maintaining its levels across various tissues, including the liver and spleen. Additionally, AZ1, a USP25/28 inhibitor, effectively suppressed platelet functions in both aged human and mouse models, and decrease age-dependent platelet hyperreactivity and thrombus formation. Collectively, the findings delineate a remodeling of platelet ubiquitination during aging and establish USP25-mediated talin-1 stabilization as a key modulator of platelet hyperactivity in the elderly.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"86 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140271","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}