Pub Date : 2026-03-19DOI: 10.1182/blood.2025028642
Gabriel S Salzman, Ann Mullally
Abstract: The discovery of calreticulin (CALR) mutations in patients with myeloproliferative neoplasms (MPNs) has paved the way for the elucidation of a unique disease mechanism that is particularly well suited to targeting by biologics. All MPN-associated pathogenic CALR mutations are characterized by a frameshift, resulting in translation of the same neoantigen peptide. This neoantigen directly activates the thrombopoietin receptor, leading to uncontrolled neoplastic cell proliferation. Current therapeutic approaches for MPNs are focused primarily on blood count control. Furthermore, current approaches are neither disease modifying nor clonally selective. However, because the mutant CALR neoantigen peptide is functional and not expressed in normal physiology, it is an ideal drug target. Here, we review the structure and function of mutant CALR, including the subtle yet clinically and therapeutically relevant differences between the 2 most commonly occurring types of mutation. We also review the current therapeutic landscape for CALR-mutated MPNs, highlighting the areas in which current approaches are inadequate. Finally, we review ongoing clinical and preclinical experimental approaches for targeting mutant CALR in MPNs in a clonally selective manner using monoclonal antibodies, bispecific antibodies, cancer vaccination, chimeric antigen receptor T cells, and antibody-drug conjugates. Taken together, we expect that ongoing developments in mutant CALR-targeted therapeutics will lead to promising novel strategies for long-term disease control.
{"title":"Novel strategies targeting mutant calreticulin in essential thrombocythemia and myelofibrosis.","authors":"Gabriel S Salzman, Ann Mullally","doi":"10.1182/blood.2025028642","DOIUrl":"10.1182/blood.2025028642","url":null,"abstract":"<p><strong>Abstract: </strong>The discovery of calreticulin (CALR) mutations in patients with myeloproliferative neoplasms (MPNs) has paved the way for the elucidation of a unique disease mechanism that is particularly well suited to targeting by biologics. All MPN-associated pathogenic CALR mutations are characterized by a frameshift, resulting in translation of the same neoantigen peptide. This neoantigen directly activates the thrombopoietin receptor, leading to uncontrolled neoplastic cell proliferation. Current therapeutic approaches for MPNs are focused primarily on blood count control. Furthermore, current approaches are neither disease modifying nor clonally selective. However, because the mutant CALR neoantigen peptide is functional and not expressed in normal physiology, it is an ideal drug target. Here, we review the structure and function of mutant CALR, including the subtle yet clinically and therapeutically relevant differences between the 2 most commonly occurring types of mutation. We also review the current therapeutic landscape for CALR-mutated MPNs, highlighting the areas in which current approaches are inadequate. Finally, we review ongoing clinical and preclinical experimental approaches for targeting mutant CALR in MPNs in a clonally selective manner using monoclonal antibodies, bispecific antibodies, cancer vaccination, chimeric antigen receptor T cells, and antibody-drug conjugates. Taken together, we expect that ongoing developments in mutant CALR-targeted therapeutics will lead to promising novel strategies for long-term disease control.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1267-1277"},"PeriodicalIF":23.1,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144942477","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}
Pub Date : 2026-03-19DOI: 10.1182/blood.2025032669
Jaclyn Rosenzweig,Lisa Giulino-Roth
{"title":"How can we safely eliminate RT in pediatric HL?","authors":"Jaclyn Rosenzweig,Lisa Giulino-Roth","doi":"10.1182/blood.2025032669","DOIUrl":"https://doi.org/10.1182/blood.2025032669","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"312 1","pages":"1243-1244"},"PeriodicalIF":20.3,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147483524","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}
Pub Date : 2026-03-18DOI: 10.1182/blood.2025031201
Hongzhi Miao,Tao Wu,Trupta Purohit,Dong Chen,Szymon Klossowski,Dmitry Borkin,Bradley Clegg,Joshua Martin Ray,SeRa Park,Rhiannon Stevens,EunGi Kim,Katarzyna Kempinska,Yi Wang,Miao He,Bo Wen,Joshua W Goldman,Jennifer E Agrusa,Chao Ding,Maria Luisa Sulis,Duxin Sun,Rajen Mody,Annette S Kim,Pingda Ren,Lian-Sheng Li,Yi Liu,Francis Burrows,Linda Kessler,Tomasz Cierpicki,Jolanta Grembecka
The protein-protein interaction between menin and KMT2A (histone lysine methyltransferase 2A) plays a critical role in acute leukemia with KMT2A rearrangements, nucleophosmin 1 (NPM1) mutations and nucleoporin 98 rearrangements, and represents an emerging opportunity for therapeutic intervention. Here, we report development and comprehensive evaluation of the activity of ziftomenib as an orally bioavailable, highly potent and selective small molecule inhibitor of the menin-KMT2A interaction. In leukemia cells and primary patient samples with the menin-KMT2A dependency, ziftomenib profoundly inhibited proliferation, reduced clonogenic potential and induced differentiation, which was associated with strong downregulation of the menin-KMT2A target genes, including MEIS1, HOXA9 and HOXB2. In xenografts and patient-derived xenograft models of KMT2A-rearranged leukemia, ziftomenib induced leukemia regression or reduced leukemia burden, accompanied by a pronounced reduction of the menin-KMT2A target genes. We next assessed ziftomenib against four MEN1 (gene encoding menin) mutants (T349M, M327I, G331R, G331D) associated with clinical resistance to another menin inhibitor revumenib. Ziftomenib retained anti-leukemic activity against T349M mutant cells and demonstrated low-nanomolar potency (GI50≤25 nM) against G331R cells, despite several-fold reduced potency relative to MEN1 wild-type cells, whereas M327I and G331D mutants were resistant. The crystal structures of ziftomenib in complex with menin wild-type, T349M or G331R mutants revealed a similar binding mode of ziftomenib to these menin variants, rationalizing potent inhibitory activity towards these mutants. Ziftomenib has recently received FDA approval for adult patients with NPM1-mutated acute myeloid leukemia and continues to be evaluated clinically in leukemias with NPM1 or KMT2A alterations, both as monotherapy and in combinations.
{"title":"Discovery and preclinical activity of the menin-KMT2A inhibitor ziftomenib in acute leukemia models.","authors":"Hongzhi Miao,Tao Wu,Trupta Purohit,Dong Chen,Szymon Klossowski,Dmitry Borkin,Bradley Clegg,Joshua Martin Ray,SeRa Park,Rhiannon Stevens,EunGi Kim,Katarzyna Kempinska,Yi Wang,Miao He,Bo Wen,Joshua W Goldman,Jennifer E Agrusa,Chao Ding,Maria Luisa Sulis,Duxin Sun,Rajen Mody,Annette S Kim,Pingda Ren,Lian-Sheng Li,Yi Liu,Francis Burrows,Linda Kessler,Tomasz Cierpicki,Jolanta Grembecka","doi":"10.1182/blood.2025031201","DOIUrl":"https://doi.org/10.1182/blood.2025031201","url":null,"abstract":"The protein-protein interaction between menin and KMT2A (histone lysine methyltransferase 2A) plays a critical role in acute leukemia with KMT2A rearrangements, nucleophosmin 1 (NPM1) mutations and nucleoporin 98 rearrangements, and represents an emerging opportunity for therapeutic intervention. Here, we report development and comprehensive evaluation of the activity of ziftomenib as an orally bioavailable, highly potent and selective small molecule inhibitor of the menin-KMT2A interaction. In leukemia cells and primary patient samples with the menin-KMT2A dependency, ziftomenib profoundly inhibited proliferation, reduced clonogenic potential and induced differentiation, which was associated with strong downregulation of the menin-KMT2A target genes, including MEIS1, HOXA9 and HOXB2. In xenografts and patient-derived xenograft models of KMT2A-rearranged leukemia, ziftomenib induced leukemia regression or reduced leukemia burden, accompanied by a pronounced reduction of the menin-KMT2A target genes. We next assessed ziftomenib against four MEN1 (gene encoding menin) mutants (T349M, M327I, G331R, G331D) associated with clinical resistance to another menin inhibitor revumenib. Ziftomenib retained anti-leukemic activity against T349M mutant cells and demonstrated low-nanomolar potency (GI50≤25 nM) against G331R cells, despite several-fold reduced potency relative to MEN1 wild-type cells, whereas M327I and G331D mutants were resistant. The crystal structures of ziftomenib in complex with menin wild-type, T349M or G331R mutants revealed a similar binding mode of ziftomenib to these menin variants, rationalizing potent inhibitory activity towards these mutants. Ziftomenib has recently received FDA approval for adult patients with NPM1-mutated acute myeloid leukemia and continues to be evaluated clinically in leukemias with NPM1 or KMT2A alterations, both as monotherapy and in combinations.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"89 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478528","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}
The optimal graft-versus-host disease (GvHD) prophylaxis strategy in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) remains controversial. In this open-label, phase Ⅲ study, patients aged 14-70 years with acute myeloid leukemia or myelodysplastic syndromes with excess blasts Ⅰ or Ⅱ were randomized (2:1:1) to receive low-dose ATG (5 mg/kg)/PTCy (50 mg/kg), standard-dose ATG (total dose 10 mg/kg), or a PTCy (total dose 100 mg/kg)-based regimen for GvHD prophylaxis. The co-primary endpoints were the cumulative incidence (CI) of grade Ⅱ-Ⅳ acute GvHD (aGvHD) by day 100 and GvHD/relapse-free survival (GRFS) at 1 year post-transplant. A total of 407 patients were randomized to receive ATG/PTCy (185 patients), ATG (113 patients), or PTCy (109 patients) regimen for GvHD prophylaxis. By day +100, the CI of grade Ⅱ-Ⅳ aGvHD did not differ significantly among the three groups (P=0.210). Although the overall incidence of chronic GvHD (cGvHD) was comparable across all groups (P=0.110), the 2-year CI of moderate-to-severe cGvHD was numerically lower in the ATG/PTCy (17.4%) and ATG (17.3%) groups compared to the PTCy group (28.3%), without reaching statistical significance (P=0.095). No significant differences were observed in survival outcomes among the three groups. Notably, the cumulative incidence of neutrophil and platelet recovery was significantly higher in the ATG/PTCy group compared to the other groups (P<0.001). This trial suggested that the three GvHD prophylaxis strategies presented similar efficacy in preventing grade II-IV aGvHD and yielded comparable survival. This trial was registered at www.clinicaltrials.gov as NCT03608059.
{"title":"Randomized trial of GvHD Prophylaxis in Haploidentical PBSC Transplantation: ATG, PTCy, and Low-Dose Combination Therapy.","authors":"Jun Yang,Yannan Jia,Xiaoxia Hu,Fang Zhou,Xiong Ni,Jiangbo Wan,Yi Ding,Mei Kang,Xiaolin Yu,Chuanhe Jiang,Luxiang Wang,Liping Wan,Yu Cai,Chongmei Huang,Huiying Qiu,Xueying Ding,Yin Tong,Baoxia Dong,Kun Zhou,Xianmin Song","doi":"10.1182/blood.2025032569","DOIUrl":"https://doi.org/10.1182/blood.2025032569","url":null,"abstract":"The optimal graft-versus-host disease (GvHD) prophylaxis strategy in haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) remains controversial. In this open-label, phase Ⅲ study, patients aged 14-70 years with acute myeloid leukemia or myelodysplastic syndromes with excess blasts Ⅰ or Ⅱ were randomized (2:1:1) to receive low-dose ATG (5 mg/kg)/PTCy (50 mg/kg), standard-dose ATG (total dose 10 mg/kg), or a PTCy (total dose 100 mg/kg)-based regimen for GvHD prophylaxis. The co-primary endpoints were the cumulative incidence (CI) of grade Ⅱ-Ⅳ acute GvHD (aGvHD) by day 100 and GvHD/relapse-free survival (GRFS) at 1 year post-transplant. A total of 407 patients were randomized to receive ATG/PTCy (185 patients), ATG (113 patients), or PTCy (109 patients) regimen for GvHD prophylaxis. By day +100, the CI of grade Ⅱ-Ⅳ aGvHD did not differ significantly among the three groups (P=0.210). Although the overall incidence of chronic GvHD (cGvHD) was comparable across all groups (P=0.110), the 2-year CI of moderate-to-severe cGvHD was numerically lower in the ATG/PTCy (17.4%) and ATG (17.3%) groups compared to the PTCy group (28.3%), without reaching statistical significance (P=0.095). No significant differences were observed in survival outcomes among the three groups. Notably, the cumulative incidence of neutrophil and platelet recovery was significantly higher in the ATG/PTCy group compared to the other groups (P<0.001). This trial suggested that the three GvHD prophylaxis strategies presented similar efficacy in preventing grade II-IV aGvHD and yielded comparable survival. This trial was registered at www.clinicaltrials.gov as NCT03608059.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"7 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478529","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}
Pub Date : 2026-03-18DOI: 10.1182/blood.2025031806
Sonja Astrid Wagner,Marlene Panzer,Elke Pertler,Stefan Redl,Martina Saretto,Benedikt Schaefer,Lorenz Michael Pammer,Laura Obholzer,Maria Rosina Troppmair,Michael W Hess,Willi Salvenmoser,Gerald Degenhart,Marisa Grossgut,Heribert Talasz,Klaus Faserl,Bettina Sarg,Roland Haubner,Markus A Hartmann,Stéphane Blouin,Verena Petzer,Petra Gronich-Wondrak,Andreas Kronbichler,Claudia Manzl,Bernhard Glodny,Herbert Tilg,Andre Franke,Myles Wolf,Michel V Hadjihannas,Heinz Zoller
Modern intravenous (IV) iron formulations allow treatment of iron deficiency anemia (IDA) with one or two infusions. Ferric carboxymaltose (FCM) is a widely used IV iron, which causes hypophosphatemia in the majority of patients. Osteomalacia and fractures are increasingly recognized after repeated infusions of FCM. It is unknown why ferric derisomaltose (FDI) rarely causes hypophosphatemia. In this study, we compare the effects of FCM and FDI on fracture risk and investigate potential underlying mechanisms explaining different effects on bone- and mineral-metabolism. For this aim, fracture rate and osteomalacia were assessed in a cohort of 357 patients treated with either drug, which reported a significantly higher rate of incident osteomalacia or fracture after FCM. These findings were validated in over 20,000 patients from the TriNetX database, where FCM-treatment was independently associated with a higher fracture risk compared with FDI. The underlying mechanisms were investigated in a mouse model of IDA treated with FCM or FDI, an osteocyte model and biochemically. FCM caused lower expression of collagen and ossification genes, associated with significantly higher bone iron concentrations than FDI. Electron microscopy showed iron-loaded vesicles in osteoblasts and early osteocytes. FCM but not FDI inhibited binding of dentin matrix protein 1 to [alpha]V[beta]3-integrin on osteocytes. This is a potential mechanism for reduced bone formation and higher levels of intact fibroblast-growth factor-23 after FCM. Our data report that IDA and FCM treatment can directly impair bone formation and increase fracture risk.
{"title":"Ferric Carboxymaltose Increases Fracture Risk in Patients and Reduces Bone Formation in Mice with Iron Deficiency Anemia.","authors":"Sonja Astrid Wagner,Marlene Panzer,Elke Pertler,Stefan Redl,Martina Saretto,Benedikt Schaefer,Lorenz Michael Pammer,Laura Obholzer,Maria Rosina Troppmair,Michael W Hess,Willi Salvenmoser,Gerald Degenhart,Marisa Grossgut,Heribert Talasz,Klaus Faserl,Bettina Sarg,Roland Haubner,Markus A Hartmann,Stéphane Blouin,Verena Petzer,Petra Gronich-Wondrak,Andreas Kronbichler,Claudia Manzl,Bernhard Glodny,Herbert Tilg,Andre Franke,Myles Wolf,Michel V Hadjihannas,Heinz Zoller","doi":"10.1182/blood.2025031806","DOIUrl":"https://doi.org/10.1182/blood.2025031806","url":null,"abstract":"Modern intravenous (IV) iron formulations allow treatment of iron deficiency anemia (IDA) with one or two infusions. Ferric carboxymaltose (FCM) is a widely used IV iron, which causes hypophosphatemia in the majority of patients. Osteomalacia and fractures are increasingly recognized after repeated infusions of FCM. It is unknown why ferric derisomaltose (FDI) rarely causes hypophosphatemia. In this study, we compare the effects of FCM and FDI on fracture risk and investigate potential underlying mechanisms explaining different effects on bone- and mineral-metabolism. For this aim, fracture rate and osteomalacia were assessed in a cohort of 357 patients treated with either drug, which reported a significantly higher rate of incident osteomalacia or fracture after FCM. These findings were validated in over 20,000 patients from the TriNetX database, where FCM-treatment was independently associated with a higher fracture risk compared with FDI. The underlying mechanisms were investigated in a mouse model of IDA treated with FCM or FDI, an osteocyte model and biochemically. FCM caused lower expression of collagen and ossification genes, associated with significantly higher bone iron concentrations than FDI. Electron microscopy showed iron-loaded vesicles in osteoblasts and early osteocytes. FCM but not FDI inhibited binding of dentin matrix protein 1 to [alpha]V[beta]3-integrin on osteocytes. This is a potential mechanism for reduced bone formation and higher levels of intact fibroblast-growth factor-23 after FCM. Our data report that IDA and FCM treatment can directly impair bone formation and increase fracture risk.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"10 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478526","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}
Pub Date : 2026-03-18DOI: 10.1182/blood.2025031924
Markus Meyerhöfer,Yawen Zhou,Aaron Gallego-Crespo,Viral Shah,Malte Andreas Behrendt,Maria Saura-Pañella,Björn Häupl,Oleksandr Todoriuk,Monika Hartmann,Matthias Klein,Catherine Wölfel,Patricia S Hähnel,Christian S Michel,Sabine Muth,Thomas Kindler,Tobias Bopp,Hansjörg Schild,Sarah J Horton,Markus P Radsak,Matthias Theobald,George S Vassiliou,Brian Jp Huntly,Michael Wm Kühn,Falk Butter,Thomas Oellerich,Daniel Sasca
The lysine acetyltransferase (KAT) activity of p300/CREBBP has traditionally been linked to transcriptional activation. This has been attributed largely to acetylation of histone residues such as H3K27ac, a defining hallmark of active regulatory elements. Here we show that, in acute myeloid leukemia (AML), inhibition of p300/CREBBP catalysis can paradoxically increase transcription. We combined time-resolved dynamics of nascent and total transcription with chromatin binding dynamics of p300/CREBBP and their associated TFs/co-regulators (inferred from chromatin pull-down proteomics, acetyl-proteomics and motif enrichment) to uncover mechanisms of transcriptional rewiring after p300/CREBBP catalytic inhibition. In parallel, we dissected the functional contribution of individual p300/CREBBP acetyl-interactome members to KAT inhibition using genome-wide CRISPR-Cas9 dropout and focused Perturb-seq screens. Together, these approaches revealed that KAT inhibition paradoxically retains p300/CREBBP and promotes cooperative TF assembly and increased H3K27 acetylation at a subset of regulatory elements. The effect was most pronounced at IRF motif-enriched loci, including interferon-stimulated genes (ISGs), where KAT inhibition triggered p300/CREBBP accumulation and enhanced combinatorial TF binding, enabling recruitment of the ISG activator STAT1. Consequently, ISG loci were converted into transcriptionally active states that induced cell-cycle arrest, differentiation and apoptosis. Therapeutically, combining KAT inhibition with interferon-alpha augmented ISG expression, synergistically drove AML cell death in vitro and significantly extended survival in both AML xenografts and murine models. These findings refine our understanding of p300/CREBBP KAT activity, demonstrating that cooperative TF assembly can reconfigure p300/CREBBP-containing complexes under catalytic inhibition to induce transcription, with translational implications for reprogramming interferon-driven programs through catalytic inhibition in AML and beyond.
{"title":"Inhibition of p300/CREBBP catalytic activity drives context-dependent transcriptional activation in AML.","authors":"Markus Meyerhöfer,Yawen Zhou,Aaron Gallego-Crespo,Viral Shah,Malte Andreas Behrendt,Maria Saura-Pañella,Björn Häupl,Oleksandr Todoriuk,Monika Hartmann,Matthias Klein,Catherine Wölfel,Patricia S Hähnel,Christian S Michel,Sabine Muth,Thomas Kindler,Tobias Bopp,Hansjörg Schild,Sarah J Horton,Markus P Radsak,Matthias Theobald,George S Vassiliou,Brian Jp Huntly,Michael Wm Kühn,Falk Butter,Thomas Oellerich,Daniel Sasca","doi":"10.1182/blood.2025031924","DOIUrl":"https://doi.org/10.1182/blood.2025031924","url":null,"abstract":"The lysine acetyltransferase (KAT) activity of p300/CREBBP has traditionally been linked to transcriptional activation. This has been attributed largely to acetylation of histone residues such as H3K27ac, a defining hallmark of active regulatory elements. Here we show that, in acute myeloid leukemia (AML), inhibition of p300/CREBBP catalysis can paradoxically increase transcription. We combined time-resolved dynamics of nascent and total transcription with chromatin binding dynamics of p300/CREBBP and their associated TFs/co-regulators (inferred from chromatin pull-down proteomics, acetyl-proteomics and motif enrichment) to uncover mechanisms of transcriptional rewiring after p300/CREBBP catalytic inhibition. In parallel, we dissected the functional contribution of individual p300/CREBBP acetyl-interactome members to KAT inhibition using genome-wide CRISPR-Cas9 dropout and focused Perturb-seq screens. Together, these approaches revealed that KAT inhibition paradoxically retains p300/CREBBP and promotes cooperative TF assembly and increased H3K27 acetylation at a subset of regulatory elements. The effect was most pronounced at IRF motif-enriched loci, including interferon-stimulated genes (ISGs), where KAT inhibition triggered p300/CREBBP accumulation and enhanced combinatorial TF binding, enabling recruitment of the ISG activator STAT1. Consequently, ISG loci were converted into transcriptionally active states that induced cell-cycle arrest, differentiation and apoptosis. Therapeutically, combining KAT inhibition with interferon-alpha augmented ISG expression, synergistically drove AML cell death in vitro and significantly extended survival in both AML xenografts and murine models. These findings refine our understanding of p300/CREBBP KAT activity, demonstrating that cooperative TF assembly can reconfigure p300/CREBBP-containing complexes under catalytic inhibition to induce transcription, with translational implications for reprogramming interferon-driven programs through catalytic inhibition in AML and beyond.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"6 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147478527","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}
Pub Date : 2026-03-17DOI: 10.1182/blood.2026033112
Hanny Al-Samkari,Cassi Friday,Raj S Kasthuri,James Gossage,Charles Griffin Murphy,Peter Hountras,Karen L Smith,Kristi Jackson Kirkland,Vivek Iyer,Vikas Prasad,Vaibhav Ahluwalia,Josanna Rodriguez-Lopez,Alison S Witkin,Miles Conrad,Steven Hetts,Michael Ohliger,Murali Chakinala,Bryan A Sisk,Melissa A Beasley,Paul Kirkpatrick,Jonathan Lindquist,John T Battaile,An Lu,Joseph Parambil,Keith R McCrae,Vladimir Sheynzon,Kevin Whitehead,Cassidy Sion,Justin P McWilliams,Lucas Russell Cusumano,Scott Trerotola,Theodore G Drivas,Mark Chesnutt,Claire Kaufman,Melissa Ann Dickey,Danielle Boyce,Nolie Krock,Crystal Cottrill,Tania Competiello,Hara Levy,Marianne S Clancy,Katharine Henderson,Jeffrey Pollak
Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vasculopathy afflicting 1 in 5000 individuals, is the second-most-common inherited bleeding disorder worldwide. Despite this prevalence, comprehensive data on disease manifestations and complications remain limited. To address this gap, the U.S. Congress allocated funding leading to the Comprehensive HHT Outcomes Registry of the United States (CHORUS; NCT06259292), a prospective, 15-center longitudinal registry enrolling unselected patients with confirmed HHT. In this initial report, we describe findings from the first 600 participants, with a median (range) age of 53 (0-88) years and 60% female. Despite most participants developing typical HHT manifestations by age 13, the majority (63%) were not diagnosed until mid-to-late adulthood. Recurrent spontaneous epistaxis occurred in 95% of participants, chronic gastrointestinal bleeding in 30%, and heavy menstrual bleeding in 35% of post-menarche females, together resulting in moderate-to-severe mucosal bleeding in 76%. Iron deficiency and/or anemia were diagnosed in 68%, with 41% requiring intravenous iron and 25% requiring red cell transfusions. Serious complications of solid-organ arteriovenous malformations were frequent, including intracranial hemorrhage (3%), pulmonary hemorrhage (2%), venous thromboembolism (7%), arterial thromboembolism (11%), heart failure (7%), and pulmonary hypertension (7%). This data from CHORUS, the first national registry of its kind, provides reliable, real-world estimates of the incidence, prevalence and severity of numerous HHT manifestations and complications. HHT has a high burden of moderate-to-severe bleeding, anemia, thrombosis, and major neurologic and cardiopulmonary complications. There is a mean interval between first symptoms and diagnosis of over two decades, during which substantial serious, preventable HHT morbidity, including early intracranial hemorrhage, may occur.
{"title":"Clinical Spectrum of Hereditary Hemorrhagic Telangiectasia: Data from the Comprehensive HHT Outcomes Registry of the US (CHORUS).","authors":"Hanny Al-Samkari,Cassi Friday,Raj S Kasthuri,James Gossage,Charles Griffin Murphy,Peter Hountras,Karen L Smith,Kristi Jackson Kirkland,Vivek Iyer,Vikas Prasad,Vaibhav Ahluwalia,Josanna Rodriguez-Lopez,Alison S Witkin,Miles Conrad,Steven Hetts,Michael Ohliger,Murali Chakinala,Bryan A Sisk,Melissa A Beasley,Paul Kirkpatrick,Jonathan Lindquist,John T Battaile,An Lu,Joseph Parambil,Keith R McCrae,Vladimir Sheynzon,Kevin Whitehead,Cassidy Sion,Justin P McWilliams,Lucas Russell Cusumano,Scott Trerotola,Theodore G Drivas,Mark Chesnutt,Claire Kaufman,Melissa Ann Dickey,Danielle Boyce,Nolie Krock,Crystal Cottrill,Tania Competiello,Hara Levy,Marianne S Clancy,Katharine Henderson,Jeffrey Pollak","doi":"10.1182/blood.2026033112","DOIUrl":"https://doi.org/10.1182/blood.2026033112","url":null,"abstract":"Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vasculopathy afflicting 1 in 5000 individuals, is the second-most-common inherited bleeding disorder worldwide. Despite this prevalence, comprehensive data on disease manifestations and complications remain limited. To address this gap, the U.S. Congress allocated funding leading to the Comprehensive HHT Outcomes Registry of the United States (CHORUS; NCT06259292), a prospective, 15-center longitudinal registry enrolling unselected patients with confirmed HHT. In this initial report, we describe findings from the first 600 participants, with a median (range) age of 53 (0-88) years and 60% female. Despite most participants developing typical HHT manifestations by age 13, the majority (63%) were not diagnosed until mid-to-late adulthood. Recurrent spontaneous epistaxis occurred in 95% of participants, chronic gastrointestinal bleeding in 30%, and heavy menstrual bleeding in 35% of post-menarche females, together resulting in moderate-to-severe mucosal bleeding in 76%. Iron deficiency and/or anemia were diagnosed in 68%, with 41% requiring intravenous iron and 25% requiring red cell transfusions. Serious complications of solid-organ arteriovenous malformations were frequent, including intracranial hemorrhage (3%), pulmonary hemorrhage (2%), venous thromboembolism (7%), arterial thromboembolism (11%), heart failure (7%), and pulmonary hypertension (7%). This data from CHORUS, the first national registry of its kind, provides reliable, real-world estimates of the incidence, prevalence and severity of numerous HHT manifestations and complications. HHT has a high burden of moderate-to-severe bleeding, anemia, thrombosis, and major neurologic and cardiopulmonary complications. There is a mean interval between first symptoms and diagnosis of over two decades, during which substantial serious, preventable HHT morbidity, including early intracranial hemorrhage, may occur.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"50 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471357","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}
Pub Date : 2026-03-17DOI: 10.1182/blood.2025031826
Alpa Trivedi,Byron Y Miyazawa,Haoqian Zhang,Longhui Qiu,Daniel Potter,Austin William Edwards,Lindsay Vivona,Maximillian Lin,Callie Keane,Huimin Geng,Simon J Cleary,Alison Nair,Michael M Fitzpatrick,Mark R Looney,Shibani Pati
Traumatic Brain Injury (TBI) is the leading cause of death in children and adults aged 18-44. Despite its high prevalence and devastating consequences, there are currently few effective therapies that target the acute, life-threatening complications of TBI - particularly cerebral edema and intracranial hemorrhage (ICH). The blood-brain barrier (BBB) and regulation of vascular stability following injury are emerging as critical therapeutic targets. In this study, we evaluate the therapeutic potential of a first-in-class, freeze-dried platelet-derived biologic (FDPlts) in a murine model of TBI. FDPlt transfusion significantly reduces post-TBI ICH and restores cerebral vascular perfusion. Additionally, FDPlts attenuate BBB permeability, suppress intravascular leukocytosis, and mitigate neuroinflammation evidenced by decreased microglial activation, astrocyte reactivity, and macrophage infiltration. Transcriptomic profiling of cortical and hippocampal tissues reveals that FDPlts downregulate gene networks associated with inflammation and fibrosis, suggesting a role for FDPlts in the modulation of post-injury repair. Mechanistically, FDPlts are enriched in Angiopoietin-1, a key bioactive protein that signals through the Tie2 receptor pathway, a central regulator of endothelial stability. Inhibition of Tie2 exacerbates BBB permeability after TBI, an effect attenuated by FDPlt administration; implicating Ang-1 as a key mediator of FDPlts mediated BBB protection in TBI. The BBB plays a vital role in maintaining cerebral homeostasis, and its breakdown after TBI initiates harmful cascades of edema, inflammation, and neuronal injury. Our findings demonstrate, for the first time, that a dried, platelet-derived biologic can promote vascular repair and neuroprotection in TBI.
{"title":"A Dried Platelet-Derived Biologic for Blood-Brain Barrier Repair and Hemorrhage Control Following TBI in Mice.","authors":"Alpa Trivedi,Byron Y Miyazawa,Haoqian Zhang,Longhui Qiu,Daniel Potter,Austin William Edwards,Lindsay Vivona,Maximillian Lin,Callie Keane,Huimin Geng,Simon J Cleary,Alison Nair,Michael M Fitzpatrick,Mark R Looney,Shibani Pati","doi":"10.1182/blood.2025031826","DOIUrl":"https://doi.org/10.1182/blood.2025031826","url":null,"abstract":"Traumatic Brain Injury (TBI) is the leading cause of death in children and adults aged 18-44. Despite its high prevalence and devastating consequences, there are currently few effective therapies that target the acute, life-threatening complications of TBI - particularly cerebral edema and intracranial hemorrhage (ICH). The blood-brain barrier (BBB) and regulation of vascular stability following injury are emerging as critical therapeutic targets. In this study, we evaluate the therapeutic potential of a first-in-class, freeze-dried platelet-derived biologic (FDPlts) in a murine model of TBI. FDPlt transfusion significantly reduces post-TBI ICH and restores cerebral vascular perfusion. Additionally, FDPlts attenuate BBB permeability, suppress intravascular leukocytosis, and mitigate neuroinflammation evidenced by decreased microglial activation, astrocyte reactivity, and macrophage infiltration. Transcriptomic profiling of cortical and hippocampal tissues reveals that FDPlts downregulate gene networks associated with inflammation and fibrosis, suggesting a role for FDPlts in the modulation of post-injury repair. Mechanistically, FDPlts are enriched in Angiopoietin-1, a key bioactive protein that signals through the Tie2 receptor pathway, a central regulator of endothelial stability. Inhibition of Tie2 exacerbates BBB permeability after TBI, an effect attenuated by FDPlt administration; implicating Ang-1 as a key mediator of FDPlts mediated BBB protection in TBI. The BBB plays a vital role in maintaining cerebral homeostasis, and its breakdown after TBI initiates harmful cascades of edema, inflammation, and neuronal injury. Our findings demonstrate, for the first time, that a dried, platelet-derived biologic can promote vascular repair and neuroprotection in TBI.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"1 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471358","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}
Pub Date : 2026-03-17DOI: 10.1182/blood.2025031869
Leon D Kaulen,Lakshmi Nayak,Philipp Karschnia,Imke Kraai,Daniela Raffaela Galluzzo,Fleur A de Groot,Matthew Witterholt,Laura Donovan,Sita Bhella,Luis P Kuschel,Christopher P Fox,Sabine Seidel,James Paterson,Benjamin Richter,Karan S Dixit,Thomas Zeyen,Juan Pablo Alderuccio,Silvia Montoto,Outi Kuittinen,Benjamin-Leon Traub,Sofia Doubrovinskaia,Hannah Rohdjess,Katharina Mueller,Roelien Enting,Jeroen de Bresser,Hanne Kuitunen,Fabio M Iwamoto,Alvaro J Alencar,Ulrich Herrlinger,Michael Platten,Kate Cwynarski,Joe S Mendez,Patrick Roth,Louisa von Baumgarten,Anca Prica,Govind Bhagat,Kathryn Lurain,David Schiff,Joost Sp Vermaat,Joachim Baehring,Marcel Nijland,Jörg Dietrich,Tracy T Batchelor,Wolfgang Wick
Immunodeficiency-associated primary CNS lymphoma (ID-PCNSL) represents a clinicopathologically distinct PCNSL subtype, for which large studies and prognostic models are lacking. To address this gap, the International PCNSL Collaborative Group conducted an international retrospective multi-center study, integrating clinical, radiological, and pathological data from 308 ID-PCNSL, diagnosed at 23 participating sites in 7 countries. Pre-existing immunodeficiency included administration of immunosuppressants for transplantation (41.2%) or autoimmunity (36.7%), and HIV infection (21.7%). All tumors were diffuse large B-cell lymphomas, with Epstein-Barr virus (EBV) detected in 79.2%. Immune reconstitution together with rituximab-methotrexate-(RM)-based chemotherapy was associated with highest response rates and prolonged progression-free survival, irrespective of immunodeficiency subtype and EBV status. Survival outcomes were highly variable with a 54-month median overall survival. Multivariable Cox regression identified age (per year increment HR: 1.05 (95%-CI:1.02-1.07); p < 0.001), Karnofsky Performance status (KPS) < 70 (HR: 3.10 (95%-CI:1.67-5.87); p < 0.001), EBV positivity (HR: 3.26 (95%-CI:1.47-7.33); p = 0.004) as prognostic factors for OS. A prognostic score was developed based on the sum of these adverse variables (age > 60 years, KPS < 70, EBV positivity). Stratification by this score yielded median survival times of 135, 29, and 3 months in patients with up to one, two and three unfavorable markers (p < 0.0001). It allowed improved prognostic stratification of ID-PCNSL as compared to the well-established MSKCC and IELSG models developed for immunocompetent PCNSL. Collectively, this large international cohort defines clinicobiologic features of ID-PCNSL and introduces an easily applicable prognostic system with potential to guide future management.
{"title":"Immunodeficiency-associated primary CNS lymphomas: An International Primary CNS Lymphoma Collaborative Group (IPCG) Study.","authors":"Leon D Kaulen,Lakshmi Nayak,Philipp Karschnia,Imke Kraai,Daniela Raffaela Galluzzo,Fleur A de Groot,Matthew Witterholt,Laura Donovan,Sita Bhella,Luis P Kuschel,Christopher P Fox,Sabine Seidel,James Paterson,Benjamin Richter,Karan S Dixit,Thomas Zeyen,Juan Pablo Alderuccio,Silvia Montoto,Outi Kuittinen,Benjamin-Leon Traub,Sofia Doubrovinskaia,Hannah Rohdjess,Katharina Mueller,Roelien Enting,Jeroen de Bresser,Hanne Kuitunen,Fabio M Iwamoto,Alvaro J Alencar,Ulrich Herrlinger,Michael Platten,Kate Cwynarski,Joe S Mendez,Patrick Roth,Louisa von Baumgarten,Anca Prica,Govind Bhagat,Kathryn Lurain,David Schiff,Joost Sp Vermaat,Joachim Baehring,Marcel Nijland,Jörg Dietrich,Tracy T Batchelor,Wolfgang Wick","doi":"10.1182/blood.2025031869","DOIUrl":"https://doi.org/10.1182/blood.2025031869","url":null,"abstract":"Immunodeficiency-associated primary CNS lymphoma (ID-PCNSL) represents a clinicopathologically distinct PCNSL subtype, for which large studies and prognostic models are lacking. To address this gap, the International PCNSL Collaborative Group conducted an international retrospective multi-center study, integrating clinical, radiological, and pathological data from 308 ID-PCNSL, diagnosed at 23 participating sites in 7 countries. Pre-existing immunodeficiency included administration of immunosuppressants for transplantation (41.2%) or autoimmunity (36.7%), and HIV infection (21.7%). All tumors were diffuse large B-cell lymphomas, with Epstein-Barr virus (EBV) detected in 79.2%. Immune reconstitution together with rituximab-methotrexate-(RM)-based chemotherapy was associated with highest response rates and prolonged progression-free survival, irrespective of immunodeficiency subtype and EBV status. Survival outcomes were highly variable with a 54-month median overall survival. Multivariable Cox regression identified age (per year increment HR: 1.05 (95%-CI:1.02-1.07); p < 0.001), Karnofsky Performance status (KPS) < 70 (HR: 3.10 (95%-CI:1.67-5.87); p < 0.001), EBV positivity (HR: 3.26 (95%-CI:1.47-7.33); p = 0.004) as prognostic factors for OS. A prognostic score was developed based on the sum of these adverse variables (age > 60 years, KPS < 70, EBV positivity). Stratification by this score yielded median survival times of 135, 29, and 3 months in patients with up to one, two and three unfavorable markers (p < 0.0001). It allowed improved prognostic stratification of ID-PCNSL as compared to the well-established MSKCC and IELSG models developed for immunocompetent PCNSL. Collectively, this large international cohort defines clinicobiologic features of ID-PCNSL and introduces an easily applicable prognostic system with potential to guide future management.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"8 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147471371","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}
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