Blood最新文献

{"title":"Choice of a different donor reduces relapse risk after second allogeneic SCT for MDS","authors":"Giuliano Filippini Velazquez,Christoph Schmid,Luuk Gras,Laurien Greetje Antoinette Baaij,Linda Koster,Nicolaus Kröger,Jan Frederic Weller,Thomas Schroeder,Katja Sockel,Wolfgang Andreas Bethge,Elisa Sala,Linde M. Morsink,Johan A. Maertens,Jakob R Passweg,Uwe Platzbecker,Victoria Potter,Jan Vydra,Alexandros Spyridonidis,Francesco Onida,Christof Scheid,Carmelo Gurnari,Joanna Ewa Drozd-Sokolowska,Kavita Raj,Marie Robin,Donal P McLornan","doi":"10.1182/blood.2026033876","DOIUrl":"https://doi.org/10.1182/blood.2026033876","url":null,"abstract":"Myelodysplastic neoplasms (MDS) relapsing after allogeneic stem cell transplantation (alloSCT) have a poor prognosis. A second alloSCT (alloSCT2) can offer durable remission, however, earlier studies reported <20% long-term survival. Here we summarize contemporary outcome and risk factors after alloSCT2 (2012-2023), particularly focusing on donor change (DoC). We included 313 adults undergoing alloSCT2 for MDS relapse. Donors for alloSCT2 were matched- related/unrelated/haploidentical in 19%/62%/19%, with DoC reported in 71%. Two-year overall-/progression-free survival (OS/PFS), cumulative relapse incidence (RI) and non-relapse mortality (NRM) from alloSCT2 were 45%/33%/37%/30%. Outcome improved over time (2y-OS/PFS: 51%/39% in years 2018-2023). In multivariable analyses, DoC was associated with lower risk of relapse (HR=0.56, 95%-CI: 0.36-0.89), a finding never observed after alloSCT2 for acute leukemia. Additionally, adverse cytogenetics were correlated with relapse risk (HR=1.93, 95%-CI: 1.18-3.17). Risk of NRM decreased in more recent years (HR=0.88, per year later) and in patients with Karnofsky performance score (KPS) ≥90 at alloSCT2 (HR=0.59). Concerning survival, remission after alloSCT1 ≥12 months (HR=0.62/0.67) and KPS ≥90 (HR=0.68/0.69) were associated with better OS/PFS. In summary, we report improved outcomes of alloSCT2 in MDS in more recent years and demonstrate superior disease control by DoC, although a trend toward increased NRM precluded a significant survival benefit.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"21 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088471","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":"EVIDENCE OF CLL DEVELOPMENT FROM HEMATOPOIETIC PROGENITOR CELLS IN HUMANS","authors":"Francesca Gandini,Chiara Lenzi,Elisavet Vlachonikola,Lorenza Pecciarini,Anna Talarico,Andrea Demarchi,Lydia Scarfò,Michela Frenquelli,Kostas Stamatopoulos,Massimo Pini,Paolo Ghia","doi":"10.1182/blood.2026034234","DOIUrl":"https://doi.org/10.1182/blood.2026034234","url":null,"abstract":"Two siblings developed CLL after allogeneic transplantation from one to the other. Despite sharing the same precursors, the CLL clones displayed distinct IG gene rearrangements and genomic aberrations. Shared MED12 and NOTCH1 mutations suggest NOTCH pathway involvement in disease predisposition.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"15 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088470","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":"A multicenter phase II study of glofitamab plus polatuzumab-R-CHP for patients with diffuse large B-cell lymphoma","authors":"Jennifer L. Crombie,Robert Redd,Clare Phinney,Megan Forsyth,Juniper Mai,Sandra Re,Ann S. LaCasce,Oreofe O. Odejide,Erin M. Parry,David A. Qualls,Christine E. Ryan,Reid W Merryman,David C. Fisher,Austin I. Kim,Caron A. Jacobson,Eric D. Jacobsen,Jennifer R. Brown,Inhye E. Ahn,Matthew S. Davids,Gottfried von Keudell,Alvaro J Alencar,Michele Stanchina,Russ A. Kuker,Craig H. Moskowitz,Philippe Armand,Juan Pablo Alderuccio","doi":"10.1182/blood.2026034588","DOIUrl":"https://doi.org/10.1182/blood.2026034588","url":null,"abstract":"In this phase II trial, we evaluated the addition of the CD3xCD20 bispecific antibody, glofitamab (glofit) to polatuzumab, rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) and an international prognostic index (IPI) ³ 2. Patients received two cycles of pola-R-CHP (one cycle of R-CHOP allowed). Glofitamab was added to pola-R-CHP during cycles 3 through 6 and used as monotherapy for cycles 7 and 8. The primary objective was the best complete response (CR) rate. A total of 41 patients enrolled. The median age was 61 years (range 35-86), and 59% were male. IPI scores were 2 (39%), 3 (41%), and 4 (20%), and 86% of patients had stage III/IV disease. Most patients had DLBCL, NOS (78%) and 12% had high grade B-cell lymphoma with translocations in MYC and BCL-2 and/or BCL-6. The best CR rate was 95% (39/41) (95% CI: 83-99) and both patients with a partial response at the end of therapy converted to CR without intervention. With a median follow-up of 23.9 months, the median progression-free survival (PFS) has not been reached and the 24-month PFS was 95% (95% CI: 89-100). Four (10%) patients developed cytokine release syndrome (CRS) (all grade 1), and no immune effector cell-associated neurotoxicity syndrome (ICANS) was reported. Glofit-pola-R-CHP resulted in high rates of CR and preliminary evidence of durable responses and the schedule, with delayed incorporation of glofit, resulted in low rates of CRS and no neurotoxicity. These data support further evaluation of this regimen. NCT05800366","PeriodicalId":9102,"journal":{"name":"Blood","volume":"1 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088472","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":"Telomere length in chronic lymphocytic leukemia treated with venetoclax-based regimen in GAIA/CLL13 and CLL2-GIVe trials","authors":"Billy Michael Chelliah Jebaraj,Eugen Tausch,Deyan Yordanov Yosifov,Christof Schneider,Moritz Fürstenau,Can Zhang,Sandra Robrecht,Caspar da Cunha-Bang,Mark-David Levin,Philipp B. Staber,Henriette Huber,Tamar Tadmor,Patrick Thornton,Michael Gregor,Anna-Maria Fink,Kirsten Fischer,Karl-Anton Kreuzer,Matthias Ritgen,Michael J Hallek,Arnon P Kater,Carsten Utoft Niemann,Barbara F. Eichhorst,Stephan Stilgenbauer","doi":"10.1182/blood.2025032302","DOIUrl":"https://doi.org/10.1182/blood.2025032302","url":null,"abstract":"Telomere length is a prognostic factor in chronic lymphocytic leukemia (CLL), yet its relevance under targeted therapies remains unclear. Here, we analyzed telomere length using qPCR in 917 samples from treatment-naïve CLL patients without TP53 aberrations enrolled in the GAIA/CLL13 trial comparing venetoclax-based combinations with rituximab (RV), obinutuzumab (GV), or obinutuzumab plus ibrutinib (GIV) versus chemoimmunotherapy (CIT). For CLL with TP53 aberrations, samples from 41 treatment-naïve patients receiving GIV in the CLL2-GIVe trial were analyzed. The median telomere lengths in GAIA/CLL13 and CLL2-GIVe were 4.0 kb (1.2-15.2) and 2.8 kb (1.4-14.0), respectively. A prognostic cutoff of 4.17 kb, based on GAIA/CLL13, was used for dichotomization into short and long telomeres. Within GAIA/CLL13, short telomeres significantly correlated with adverse clinical features including advanced Binet stage, high ECOG, high serum ß2-microglobulin and thymidine kinase levels, high lymphocyte count and large lymph nodes (all P<0.01). Among genetic features, short telomeres significantly associated with unmutated IGHV, del(11q), mutations in NOTCH1, SF3B1, XPO1, RPS15, EGR2 and NFKBIE, and karyotypic complexity (all P<0.01). Short telomeres were associated with shorter progression-free survival (PFS) within CIT, RV, GV, GIV in GAIA/CLL13 (all P<0.01) and in CLL2-GIVe (dichotomized by median; P=0.04), and impacted overall survival only in the CIT arm (P=0.024). Multivariable analysis suggested telomere length as an independent prognostic factor for PFS in the overall GAIA/CLL13 cohort. These findings propose telomere length as a prognostic marker for PFS in CLL patients receiving venetoclax-based first-line therapy and could be of relevance for risk stratification in the modern treatment era. NCT02950051","PeriodicalId":9102,"journal":{"name":"Blood","volume":"24 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088473","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":"Mosunetuzumab and Polatuzumab Vedotin as First-line Treatment for Large B Cell Lymphoma in Older Unfit or Frail Patients","authors":"Adam J. Olszewski,Herbert A. Eradat,Abraham Avigdor,Netanel A. Horowitz,Matthew S. McKinney,Seung Tae Lee,Juan Miguel Bergua Burgues,Antonia Rodriguez Izquierdo,Mariana Bastos-Oreiro,Chezi Ganzel,Tae Min Kim,Youngwoo Jeon,Michał Taszner,Mayur S. Narkhede,Won Seog Kim,Ho-Jin Shin,Dariusz Woszczyk,Neta Goldschmidt,Avrita Singh,Michael C. Wei,Jue Wang,Connie Lee Batlevi,Wahib Ead,Martin Janousek,Gila Sellam,Wojciech Jurczak","doi":"10.1182/blood.2026035116","DOIUrl":"https://doi.org/10.1182/blood.2026035116","url":null,"abstract":"Older or medically unfit patients with diffuse large B-cell lymphoma (DLBCL) frequently cannot tolerate standard anthracycline-based immunochemotherapy, creating a persistent unmet clinical need. We conducted a multicenter, international, open-label phase I/II trial evaluating an immunotherapy-based first-line approach using subcutaneous mosunetuzumab in combination with polatuzumab vedotin in previously untreated patients classified as unfit or frail by simplified geriatric assessment (sGA). Participants received six cycles of polatuzumab vedotin with step-up-dosing of subcutaneous mosunetuzumab, followed by mosunetuzumab monotherapy for a planned total of eight cycles. The primary endpoint was objective response rate (ORR) at end of treatment, assessed by independent review using PET-CT Lugano 2014 criteria. Among participants treated at full dose (n=101), the median age was 81 years with 58% classified as unfit and 41% as frail by sGA. The ORR at the end of treatment was 61.4% (95% CI, 51.1-70.9), with a complete response (CR) rate of 56.4%. The best observed ORR and CR rates on therapy were 80.2% and 66.3%, respectively. With a median follow-up of 36.5 months, median investigator-assessed duration of response and overall survival were not reached; estimated 2-year progression-free and overall survival were 52.2% and 62.4%, respectively. Cytokine release syndrome occurred in 30.6% of participants and was predominantly grade 1. Infection-related mortality was observed, largely during the COVID-19 pandemic and among participants classified as frail. This geriatric assessment-guided treatment demonstrated durable efficacy and may represent a potential first-line treatment option for carefully selected unfit or frail patients with newly diagnosed DLBCL. Trial registration: #NCT03677154.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"75 2 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088474","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":"Diagnosis and Management of Chronic Lymphocytic Leukemia with TP53 Loss of Function in the Novel Agent Era","authors":"Constantine S. Tam,John F. Seymour,Piers Blombery","doi":"10.1182/blood.2026033293","DOIUrl":"https://doi.org/10.1182/blood.2026033293","url":null,"abstract":"TP53 loss-of-function (TP53-LoF) remains the single most important prognostic factor in chronic lymphocytic leukemia (CLL). Comprehensive assessment for TP53-LoF requires testing for both gene deletion and mutation. Historically, patients with TP53-LoF CLL have had poor outcomes and experienced short survival when treated with chemoimmunotherapy. In the novel agent era, multiple studies have demonstrated the effectiveness of continuous covalent BTK inhibitor (cBTKi) therapy, especially in the frontline setting, with a median progression-free survival (PFS) of approximately 7 years. Continuous cBTKi is therefore the de-facto standard for current management of TP53-LoF CLL. In contrast, fixed-duration regimens combining venetoclax with either obinutuzumab or cBTKi have shown slower response kinetics with longer time to undetectable minimal residual disease (uMRD) status, and reduced PFS, in patients with TP53-LoF CLL. Although early data from fixed-duration regimen studies indicate that most patients respond to retreatment, specific data for the TP53-LoF subset have not been reported. Therefore, the application of fixed-duration regimens for treatment of TP53-LoF CLL requires careful deliberation on the risks vs benefits of long-term cBTKi therapy, and acceptance of the uncertainty around the lack of granular retreatment outcomes. Multiple fixed-duration studies have shown that uMRD is a key endpoint in patients with TP53-LoF CLL. In this respect, clinical trials examining consolidation strategies in patients with detectable MRD, or in those with high-risk genomics, may be especially impactful in patients with TP53-LoF CLL.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"15 9 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088477","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":"Genomic drivers of leukemia and blinatumomab response in adult acute lymphoblastic leukemia - the ECOG-ACRIN E1910 study","authors":"Xiaoming Zhong,Kathryn G Roberts,Huimei Wei,Zhuoxin Sun,Lindsey E. Montefiori,Amit Kumar,Ilaria Iacobucci,Pradyumna Baviskar,Qingsong Gao,Petri Pölönen,Shondra M Pruett-Miller,Rori M Schreiber,Ti-Cheng Chang,Wenchao Zhang,Shaohua Lei,Evadnie Rampersaud,Yiping Fan,Gang Wu,Ryan J Mattison,Yanming Zhang,Janis Racevskis,Hillard M Lazarus,Jacob M. Rowe,Daniel A. Arber,Matthew J Wieduwilt,Yasser Abou Mourad,Paul J. Shami,Maria R Baer,Adam S Asch,Kristen M O'Dwyer,Aric Hall,Michaela Liedtke,Julie Bergeron,Brent L. Wood,Keith W. Pratz,Shira Naomi Dinner,Noelle V Frey,Steven D Gore,Bhavana Bhatnagar,Ehab L Atallah,Geoffrey L. Uy,Deepa Jeyakumar,Tara L. Lin,Cheryl L Willman,Nikolai A. Podoltsev,Daniel J DeAngelo,Shejal Patel,Michelle Ann Elliott,Anjali S. Advani,Dimitrios Tzachanis,Pankit Vachhani,Rupali Roy Bhave,Elad Sharon,Richard F. Little,Harry P. Erba,Richard M Stone,Martin S. Tallman,Jun J Yang,Selina M Luger,Elizabeth Paietta,Mark R. Litzow,Charles G. Mullighan","doi":"10.1182/blood.2026033793","DOIUrl":"https://doi.org/10.1182/blood.2026033793","url":null,"abstract":"The bispecific CD19/CD3 T-cell engaging antibody blinatumomab is efficacious in front-line therapy in B-cell acute lymphoblastic leukemia (B-ALL) but the biological determinants of response and resistance are incompletely understood. To examine the genomic determinants of outcome, we analyzed genomic and clinical data of 569 adults registered to the ECOG-ACRIN E1910 study of blinatumomab in BCR::ABL1-negative B-ALL (ClinicalTrials.gov NCT02003222). We identified 23 molecular subtypes including the high-risk subtypes BCR::ABL1 (20%), BCR::ABL1-like (18%), low hypodiploid (14%) and KMT2A-R (12%), and 267 putative driver genes. We identified a subtype characterized by CEBPA overexpression or elevated CEBPB expression due to chromosomal translocation-mediated enhancer hijacking, or insertions downstream of CEBPA that generate neoenhancers. Attainment of MRD-negativity patients after induction and intensification chemotherapy was more common in PAX5alt, TCF3::PBX1 and ZNF384-R B-ALL, and less common in BCR::ABL1-like and KMT2A-R B-ALL. Integration of genomic and clinical data suggested that the addition of blinatumomab to chemotherapy was associated with improved relapse-free and overall survival for several B-ALL subtypes, including hyperdiploid, PAX5alt, PAX5 P80R, BCR::ABL1-like JAK-STAT and KMT2A-R B-ALL, although small sample sizes for several subtypes indicate that confirmation is required. Alteration of TP53 or mutations associated with myeloid clonal hematopoiesis of indeterminate potential (CHIP) were identified in 15.3% and 9.8% of patients, respectively. The presence of these mutations was associated with older age at diagnosis and inferior outcome to chemotherapy. In summary, we define the landscape of genomic alterations of adult B-ALL, and identify genomic subtypes that may influence the efficacy of blinatumomab when combined with chemotherapy.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"298 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088543","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":"Piezo 1 and Shear-induced Erythrocyte Transformation and Procoagulant Activity: Implication for LVAD-Induced Bleeding","authors":"Katie L. L Houck,Yi Wang,Mengchen Yang,Sam Joy Neuffer,Manal Alshamrani,Abdulrahman Alkhalifa,Sinan Tosun,Priyanka Prathipati,Jianning Zhang,Hognxia Fu,Moritz Stolla,Reheman Adili,Xiaoyun Fu,Angelo Nascimbene,Jingfei Dong","doi":"10.1182/blood.2026034903","DOIUrl":"https://doi.org/10.1182/blood.2026034903","url":null,"abstract":"Mucosal bleeding is a common complication in patients on left ventricular assist device (LVAD) support and often originates at sites of angiodysplasia. LVAD-induced bleeding has been attributed to the loss of large von Willebrand factor (VWF) multimers due to excessive proteolysis; however, this tentative mechanism is not fully supported by clinical and research observations. We have previously shown that phosphatidylserine (PS)-expressing extracellular membrane vesicles (EMVs) are associated with adverse events in LVAD patients. In this study, we used an unbiased proteomic approach to identify EMV-derived molecules associated with LVAD-induced hemostatic complications and studied their role in systemic coagulation dysregulation in vitro and in mouse model. Levels of hemopexin on red blood cell (RBC)-derived EMVs in samples collected 3 months post-LVAD differentiated between patients with bleeding, thrombosis, or uncomplicated assessed 6 months post-LVAD. Furthermore, we detected a subset of deformed RBCs in these patients that were smaller, denser, and less granular than normal RBCs and were prone to hemolysis. The proportion of deformed RBCs increased from 15.3% at baseline to 46.8% after LVAD implantation. These deformed RBCs extensively expressed PS, making them highly procoagulant in vitro and in mice. We found that the mechanosensitive ion channel Piezo1 mediated this RBC deformation and microvesiculation under high shear stress. We further demonstrated that hemolysis and RBC-mediated procoagulant activity contribute to the systemic consumptive coagulopathy that develops after LVAD implantation.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"14 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088476","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":"STAG2 mutations fine-tune the ALK-driven oncogenic program in ALK-positive anaplastic large cell lymphoma","authors":"Rosalie Borry,François Vilcot,Bruno Tesson,Josquin Moraly,Elisa Fabiole,Alexandre Boullé,Zakia Aid,Maria Emilia Puig Lombardi,Rania Sellami,Charlotte Degoutte,Alice Darchen,Layla Veleanu,Maxime Heintzé,Léonardo Panunzi,Marie As,Carine Giovannangeli,Nicolas Cagnard,Vahid Asnafi,Ludovic Lhermitte,Lucile Couronné,Didier Surdez,Kevin Muller,Eddy Pasquier,Marion Le Grand,Patrick Revy,Thomas Mercher,Laurence Lamant,Loelia Babin,Fabienne Meggetto,David Sibon,Erika Brunet","doi":"10.1182/blood.2025032902","DOIUrl":"https://doi.org/10.1182/blood.2025032902","url":null,"abstract":"ALK-positive Anaplastic Large Cell Lymphoma (ALK+ ALCL) is a rare yet aggressive T-cell lymphoma, most often characterized by the NPM1::ALK fusion. Because few somatic variants have been identified in ALK+ ALCL, we conducted paired whole-exome sequencing of patient tumors with matched normal tissue. Compared with previous studies, we identified a higher frequency of mutations in cohesin complex genes, mostly STAG2 variants (6/16) predicted to impair protein function. Immunohistochemistry confirmed loss of STAG2 in additional patient tumor samples. Using an original model of NPM1::ALK-driven lymphomagenesis that recapitulates early steps of ALK-driven transformation initiated in primary T lymphocytes, we demonstrated that STAG2 defect accelerates oncogenesis, enhancing early cell proliferation of ALK-positive cells. Single-cell RNA-seq revealed that STAG2 depletion accelerates the early acquisition of the major ALK+ ALCL hallmarks and concomitantly reduces the oncogene-induced senescence signature. Despite higher ALK expression and robust cell transformation, STAG2 depletion resulted in the attenuation of the global ALK+ ALCL transcriptional program. Importantly, STAG2 expression was found decreased upon NPM1::ALK induction, indicating intrinsic downregulation during transformation even without genomic mutations. We also successfully identified STAG2-low/ALK-high cells in both patient-derived tumors and PDX models. Functionally, STAG2-depleted cells exhibit increased cell adhesion and migration, alongside constitutive YAP1 activation and upregulation of adhesion molecule such as ALCAM and CD44 but also increased PD-L1. Overall, our findings reveal that STAG2 loss plays a key role during the earliest stages of ALK+ ALCL lymphomagenesis by promoting cell tolerance to NPM1::ALK expression and increasing permissiveness to malignant transformation while also impacting cell adhesion, migration.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"13 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088478","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":"TLR9-dependent migration identifies different Chronic Lymphocytic Leukemia signaling states under BTK inhibition.","authors":"Emma Kennedy,Lauren Stott,Iona Ashworth,Eleni Ladikou,John R Jones,Rosalynd Johnston,Aimilia Vareli,Valter Gattei,Antonella Zucchetto,Triantafillos Liloglou,Piers EM Patten,Sandrine Jayne,Martin JS Dyer,Sean F Girvan,David A Cairns,Fabio Simoes,Simon Mitchell,Chris Pepper,Andrea GS Pepper","doi":"10.1182/blood.2025032914","DOIUrl":"https://doi.org/10.1182/blood.2025032914","url":null,"abstract":"B-cell receptor (BCR) inhibitors have transformed chronic lymphocytic leukemia (CLL) therapy, yet many patients show incomplete responses or develop resistance in the absence of Bruton's tyrosine kinase (BTK) mutations. We investigated Toll-like receptor 9 (TLR9) signaling as a tumor-response mechanism to BCR blockade. Using 102 TLR9-stimulated patient samples, we identified two distinct migratory phenotypes: TLR9-induced migratory Responders (R), with enhanced migration, and TLR9-induced migratory Reverse-Responders (RR), with suppression of migration following TLR9 activation. Transcriptomic and protein analyses showed TLR9-stimulated R samples expressed higher IRAK4/IRAK1 and induced NF-kB p100, consistent with intact TLR9 signaling. In contrast, RR samples exhibited elevated basal BCR activity, and lower IRAK4/IRAK1 with rapid IRAK1 degradation, indicating suppressed TLR9 signaling. In-silico modeling and biochemical validation showed high basal BCR signaling suppresses TLR9 responsiveness, whereas low basal activity permits full TLR9 activation. Functionally, TLR9-induced migration persisted despite BTK inhibition (BTKi) in R but not RR samples, and was abrogated by TLR9 antagonism, consistent with signaling through a BTK-independent pathway in the R subgroup. CLL cells from BTKi-resistant patients expressed higher TLR9 and matched pre- and post-relapse samples showed decreased BCR and increased TLR-associated NF-kB signaling post-relapse. Clinically, in small exploratory","PeriodicalId":9102,"journal":{"name":"Blood","volume":"8 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088541","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}