1. Maternal Tmprss6 is required for hepcidin suppression and fetal health.
作者: Katherine Louise Fielding.;Cavan Bennett.;Anne Pettikiriarachchi.;Naomi Jones.;Rebecca Harding.;Alistair R D McLean.;Louise M Randall.;Ute Schaeper.;Alberto Martinez.;Ricardo Ataide.;Sant-Rayn Pasricha.
来源: Blood. 2025年
The antenatal role of the hepcidin-regulating protease Tmprss6 has never been elucidated as knockout dams are infertile. Utilising an in vivo knockdown approach, we confirm Tmprsss6 is critical for hepcidin suppression in pregnancy, and Tmprss6 inhibition drives deleterious fetal outcomes.
2. Dissection of single-cell landscapes for the development of chimeric antigen receptor T cells in Hodgkin lymphoma.
作者: Adrian Gottschlich.;Ruth Grünmeier.;Gordon Victor Hoffmann.;Sayantan Nandi.;Vladyslav Kavaka.;Philipp Jie Müller.;Jakob Jobst.;Arman Oner.;Rainer Kaiser.;Jan Gärtig.;Ignazio Piseddu.;Stephanie Frenz-Wiessner.;Savannah D Fairley.;Heiko Schulz.;Veronika Igl.;Thomas Alexander Janert.;Lea Di Fina.;Maité Mulkers.;Moritz Thomas.;Daria Briukhovetska.;Donjetë Simnica.;Emanuele Carlini.;Christina Angeliki Tsiverioti.;Marcel P Trefny.;Theo Lorenzini.;Florian Märkl.;Pedro Mesquita.;Ruben Brabenec.;Thaddäus Strzalkowski.;Sophia Stock.;Stefanos Michaelides.;Johannes Hellmuth.;Martin Thelen.;Sarah Reinke.;Wolfram Klapper.;Pascal Francois Gelebart.;Leo Nicolai.;Carsten Marr.;Eduardo Beltrán.;Remco T A Megens.;Christoph Klein.;Fanny Baran-Marszak.;Andreas Rosenwald.;Michael von Bergwelt-Baildon.;Paul J Bröckelmann.;Stefan Endres.;Sebastian Kobold.
来源: Blood. 2025年145卷14期1536-1552页
The success of targeted therapies for hematological malignancies has heralded their potential as both salvage treatment and early treatment lines, reducing the need for high-dose, intensive, and often toxic chemotherapeutic regimens. For young patients with classic Hodgkin lymphoma (cHL), immunotherapies provide the possibility to lessen long-term, treatment-related toxicities. However, suitable therapeutic targets are lacking. By integrating single-cell dissection of the tumor landscape and an in-depth, single-cell-based off-tumor antigen prediction, we identify CD86 as a promising therapeutic target in cHL. CD86 is highly expressed on Hodgkin and Reed-Sternberg cancer cells and cHL-specific tumor-associated macrophages. We reveal CD86-CTLA-4 as a key suppressive pathway in cHL, driving T-cell exhaustion. Cellular therapies targeting CD86 had extraordinary efficacy in vitro and in vivo and were safe in immunocompetent mouse models without compromising bacterial host defense in sepsis models. Our results prove the potential value of anti-CD86 immunotherapies for treating cHL.
3. Reducing clinical trial eligibility barriers for patients with MDS: an icMDS position statement.
作者: Uma Borate.;Kelly Pugh.;Allyson Waller.;Rina Li Welkie.;Ying Huang.;Jan Philipp Bewersdorf.;Maximilian Stahl.;Amy E DeZern.;Uwe Platzbecker.;Mikkael A Sekeres.;Andrew H Wei.;Rena J Buckstein.;Gail J Roboz.;Michael R Savona.;Sanam Loghavi.;Robert P Hasserjian.;Pierre Fenaux.;David A Sallman.;Christopher S Hourigan.;Matteo Giovanni Della Porta.;Stephen Nimer.;Richard F Little.;Valeria Santini.;Fabio Efficace.;Justin Taylor.;Guillermo Garcia-Manero.;Olatoyosi Odenike.;Tae Kon Kim.;Stephanie Halene.;Rami S Komrokji.;Elizabeth A Griffiths.;Peter L Greenberg.;Mina L Xu.;Zhuoer Xie.;Rafael Bejar.;Guillermo F Sanz.;Mrinal M Patnaik.;Maria Figueroa.;Hetty E Carraway.;Omar Abdel-Wahab.;Daniel Starczynowski.;Eric Padron.;Jacqueline Boultwood.;Steven Gore.;Naval G Daver.;Jane E Churpek.;Ravindra Majeti.;John M Bennett.;Alan F List.;Andrew M Brunner.;Amer M Zeidan.
来源: Blood. 2025年145卷13期1369-1381页
Excessively restrictive inclusion and exclusion criteria in clinical trials are one of many barriers to clinical trial enrollment for patients with myelodysplastic syndromes/neoplasms (MDSs). Many organizations are developing efforts to increase clinical trial eligibility; yet, several recent publications focused on patients with MDS suggest that many patients with this disease may be excluded from clinical trials unnecessarily. Clinical trial eligibility should reflect the phase of the study and risks of the agent being studied. Phase 3 trials should be less restrictive than early-phase trials to represent the real-world population as closely as possible. We hypothesize that many clinical trials, particularly phase 3 trials, have unnecessarily restrictive eligibility criteria. This study aims to evaluate the most common eligibility criteria according to phase of trial and to determine whether criteria correspond with drug safety signals. We identified MDS clinical trials registered on ClinicalTrials.gov from 1 January 2000 to 1 September 2023 and analyzed the eligibility criteria of 191 therapeutic MDS trials. We found that categorical inclusion and exclusion criteria are remarkably similar in representation across trial phases. Additionally, only 13% of trials are concordant with drug safety signals, suggesting that the eligibility criteria are often arbitrary. On behalf of the icMDS (International Consortium for Myelodysplastic Syndromes), an association of international MDS experts, we provide a position statement on restrictive eligibility criteria for MDS clinical trials that should be avoided with the aim of removing barriers to clinical trial enrollment.
4. NGS-based IG/TR rearrangement profiling in acute lymphoblastic leukemia: age dependence of immunogenetic maturation.
作者: Michaela Kotrova.;Constantin Proske.;Nikos Darzentas.;Anna Laqua.;Britta Kehden.;Jan Christian Kässens.;Sonja Bendig.;Saskia Kohlscheen.;Monika Szczepanowski.;Wiebke Wessels.;Željko Antić.;Christiane Pott.;Matthias Ritgen.;Jacques J M van Dongen.;Nicola Gökbuget.;Guranda Chitadze.;Anke Bergmann.;Lorenz Bastian.;Claudia D Baldus.;Gunnar Cario.;Martin Schrappe.;Stefan Schwartz.;Julia Alten.;Rolf Koehler.;Monika Brüggemann.
来源: Blood. 2025年
We comprehensively profiled the landscape of immunoglobulin (IG) and T-cell receptor (TR) rearrangements at diagnosis in 1212 acute lymphoblastic leukemia (ALL) patients (573 children, 639 adults) diagnosed in Germany between 2017 and 2022.Our findings indicate that immunogenetic maturity in ALL patients is age-dependent, with younger patients exhibiting more mature profiles. In fact, 68.7% of pediatric B-ALL and 85.7% T-ALL patients carried IGK, or complete TRB and/or TRD rearrangements, respectively; compared to 39.0% and 67.3% in adults (B-ALL: p<2.2e-16, T-ALL: p=6.7e-03). Additionally, children carried more IG/TR markers compared to adults (mean 6/patient versus 4/patient, respectively; p=2.5e-38). Only 0.5% of pediatric patients lacked markers, contrasted with 6.7% of adults.IGH clonal evolution was most pronounced among pro-B ALL cases (60.9%), with the V-to-DJ mechanism driving pro-B evolution (78.6%), while V-replacement dominated other immunophenotypes. Additionally, we observed that the presence of expanded accompanying T-cell clones of unknown significance in B-ALL patients increased with age.This next-generation sequencing (NGS)-based study offers an unprecedented characterization of IG/TR rearrangement patterns across ALL subtypes and age groups. It highlights the higher immunogenetic maturity in children, which may be explained by the infection-driven abnormal activity of the IG/TR recombination machinery in pediatric ALL.
5. Clonal hematopoiesis is clonally unrelated to multiple myeloma and is associated with specific microenvironmental changes.
作者: Marta Lionetti.;Margherita Scopetti.;Antonio Matera.;Akihiro Maeda.;Alessio Marella.;Francesca Lazzaroni.;Giancarlo Castellano.;Sonia Fabris.;Stefania Pioggia.;Silvia Lonati.;Alfredo Marchetti.;Alessandra Cattaneo.;Marta Tornese.;Antonino Neri.;Claudia Leoni.;Loredana Pettine.;Valentina Traini.;Ilaria Silvestris.;Marzia Barbieri.;Giuseppina Fabbiano.;Domenica Ronchetti.;Elisa Taiana.;Claudio De Magistris.;Matteo Claudio Da Via'.;Francesco Passamonti.;Niccolò Bolli.
来源: Blood. 2025年
Multiple myeloma (MM) initiation is dictated by genomic events. However, its progression from asymptomatic stages to an aggressive disease that ultimately fails to respond to treatments is also dependent on changes of the tumor microenvironment (TME). Clonal hematopoiesis of indeterminate potential (CHIP) is a prevalent clonal condition of the hematopoietic stem cell whose presence is causally linked to a more inflamed microenvironment. Here, we show in 106 patients with MM that CHIP is frequently co-existing with MM at diagnosis, associates with a more advanced R-ISS stage, higher age and shows a non-significant trend towards lower median hemoglobin. In our cohort the two conditions do not share a clonal origin. Single cell RNA-sequencing in 16 MM patients highlights significant TME changes when CHIP is present: decreased naïve T cells, a pro-inflammatory TME, decreased antigen-presenting function by dendritic cells and expression of exhaustion markers in CD8 cells. Inferred interactions between cell types in CHIP-positive TME suggested that especially monocytes, T cells and clonal plasma cells may have a prominent role in mediating inflammation, immune evasion and pro-survival signals in favor of MM cells. Altogether, our data show that, in the presence of CHIP, the TME of MM at diagnosis is significantly disrupted in line with what usually seen in more advanced disease, with potential translational implications. Our data highlight the relevance of this association and prompt for further studies on the modifier role of CHIP in the MM TME.
6. Enhanced α2-3 linked sialylation determines the extended half-life of CHO-rVWF.
作者: Ciara Byrne.;Soracha Ward.;Jamie M O'Sullivan.;Alain Chan Kwo Chion.;Patricia Lopes.;Bogdan Baci.;Caoimhe Dowd.;Darragh Jordan.;Ross Ian Baker.;Roger Preston.;Marco Monopoli.;Peter L Turecek.;Maximilianos Kotsias.;Jack Cheeseman.;Alan Moran.;Richard A Gardner.;Daniel I R Spencer.;Ferdows Atiq.;James S O'Donnell.
来源: Blood. 2025年
The half-life of recombinant VWF (rVWF) expressed in CHO cells (CHO-rVWF; Vonicog alfa, VonvendiÒ / VeyvondiÒ) is significantly longer than plasma-derived (pd) VWF concentrates. This finding is intriguing since CHO cells do not generate α2-6 sialylation, which constitutes the majority of human pdVWF sialylation. We hypothesized that glycan differences might regulate the longer half-life of CHO-rVWF. In lectin plate binding assays and liquid chromatography mass spectrometry analysis, we confirmed that CHO-rVWF lacked α2-6 linked sialylation. Conversely, however, α2-3 linked sialylation was significantly increased on CHO-rVWF, which also had reduced exposed β-Gal compared to pdVWF. Consistent with human data, CHO-rVWF clearance was significantly (p<0.001) reduced in VWF-/- mice compared to pdVWF. However, clearance of asialo-pdVWF and asialo-CHO-rVWF were identical. In keeping with the in vivo half-life prolongation, CHO-rVWF binding to murine macrophages (p=0.012) and HepG2 cells (p=0.001) was significantly decreased compared to pdVWF. Furthermore, CHO-rVWF binding to purified MGL and ASGPR receptors was also significantly reduced. In contrast to pdVWF, in vivo studies in MGL1-/- mice and Asgr1-/- mice demonstrated that neither MGL nor ASGPR play significant roles in regulating CHO-rVWF clearance. Together, our findings demonstrate that enhanced α2-3 linked sialylation on CHO-rVWF is responsible for its extended in vivo half-life.
7. Safety and efficacy of rilzabrutinib vs placebo in adults with immune thrombocytopenia: the phase 3 LUNA3 study.
作者: David J Kuter.;Waleed Ghanima.;Nichola Cooper.;Howard Allen Liebman.;Lei Zhang.;Yu Hu.;Yoshitaka Miyakawa.;Wojciech Homenda.;Luisa Elena Elena Morales Galindo.;Ana Lisa Basquiera.;Chuen Wen Tan.;Guray Saydam.;Marie Luise Hütter-Krönke.;Chatree Chai-Adisaksopha.;David Gomez-Almaguer.;Huy Tran.;Ho-Jin Shin.;Ademar Dantas da Cunha Junior.;Zsolt Lazar.;Cristina Pascual-Izquierdo.;Ilya Kirgner.;Elisa Lucchini.;Ganna Kuzmina.;Michael Fillitz.;Sylvain Audia.;Minakshi Taparia.;Matias Cordoba.;Remco Diab.;Mengjie Yao.;Imene Gouia.;Michelle Lee.;Ahmed Abd Almalik Daak.
来源: Blood. 2025年
Rilzabrutinib is a covalent, reversible BTK inhibitor with multiple mechanisms targeting key immune thrombocytopenia (ITP) disease pathophysiology. The phase 3 LUNA3 study in previously treated adults with persistent/chronic ITP evaluated oral rilzabrutinib 400 mg bid (n=133) vs placebo (n=69) for 24 weeks. At baseline overall, median age was 47 years (range, 18-80), 63% female, 7.7 year (range, 0.3-52.2) median duration of ITP, and 28% were splenectomized. Overall (N=202), 85 (64%) rilzabrutinib and 22 (32%) placebo patients achieved platelet response (≥50×109/L or 30×109/L-<50×109/L and doubled from baseline) during the first 12 weeks and were eligible to complete the double-blind period. The primary endpoint durable platelet response (platelet count ≥50×109/L for ≥two-thirds of ≥8 of the last 12 of 24 weeks without rescue therapy) was observed in 31 (23%) rilzabrutinib vs 0 placebo patients (P<0.0001). All secondary efficacy endpoints were significantly superior for rilzabrutinib (P<0.05). Median time to first platelet response was 15 d in rilzabrutinib responders. Rilzabrutinib significantly reduced rescue therapy use by 52% (P=0.0007) and improved week 25 bleeding scores (P=0.0006). Improved physical fatigue was sustained from week 13 (P=0.01) through 25 (P=0.0003). Treatment-related adverse events were mainly grade 1-2. One rilzabrutinib patient with multiple risk factors had serious treatment-related grade 3 peripheral embolism (lower left leg) and another died from unrelated pneumonia. Rilzabrutinib-- in ITP patients who failed multiple previous therapies (splenectomy, TPO-RA, rituximab and/or fostamatinib) resulted in rapid and durable platelet response, reduced rescue medication use and bleeding, significantly improved physical fatigue, and showed favorable safety. NCT04562766; EudraCT 2020-002063-60.
8. Blunted CD40-responsive enhancer activation in CREBBP-mutant lymphomas can be restored by enforced CD4 T-cell engagement.
作者: Haopeng Yang.;Wenchao Zhang.;Vida Ravanmehr.;Guiling Cui.;Kevin Bowman.;Ruidong Chen.;Jared Henderson.;Shyanne Ruby Lockman.;Estela Rojas.;Ashley Lauren Wilson.;Sydney Parsons.;Ariel Mechaly.;Leslie Regad.;Ahmed Haouz.;Christopher R Flowers.;Sattva S Neelapu.;Loretta J Nastoupil.;Richard Eric Davis.;Qing Deng.;Fernando Rodrigues Lima.;Michael R Green.
来源: Blood. 2025年
The CREBBP lysine acetyltransferase (KAT) is frequently mutated in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) and has been studied using gene knock-out (KO) in murine and human cells. However, the majority of CREBBP mutations encode amino acid substitutions within the catalytic KAT domain (CREBBP KAT-PM) that retain an inactive protein and have not been extensively characterized. Using CRISPR gene editing and extensive epigenomic characterization of lymphoma cell-lines, we found that CREBBP KAT-PM lead to unloading of CREBBP from chromatin, loss of enhancer acetylation and prevention of EP300 compensation. These enhancers were enriched for those that are dynamically loaded by CREBBP in the normal centroblast-to-centrocyte transition in the germinal center, including enhancers activated in response to CD40 signaling, leading to blunted molecular response to CD40 ligand in lymphoma cells. We provide evidence that CREBBP KAT-PM inhibits EP300 function by binding limiting quantities nuclear transcription factor, thereby preventing its compensatory activity. This effect can be experimentally overcome by expressing saturating quantities of transcription factor, or biologically attenuated by strong stimulation of CD40 signaling that increases nuclear transcription factor abundance. Importantly, epigenetic responses to CD40 signaling can be induced by enforcing CD4 T-cell engagement using a bispecific antibody, leading to CD40-dependent restoration of antigen presentation machinery in CREBBP KAT-PM cells and cell death. We therefore provide a mechanistic basis for enhancer deregulation by CREBBP KAT-PM and highlight enforced CD4 T-cell engagement as a potential approach for overcoming these effects.
9. Beyond genotype: challenges in predicting disease risk for carriers of biallelic perforin variants.
作者: Oliver Wegehaupt.;Oleg Borisov.;Elena Sieni.;Florian Oyen.;Jasmin Mann.;Maria Luisa Coniglio.;Aurora Chinnici.;Francesco Pegoraro.;Linda Beneforti.;Kimberly C Gilmour.;Despina Moshous.;Geneviève de Saint Basile.;Wenying Zhang.;Rebecca A Marsh.;Carmela De Fusco.;Katharina Wustrau.;Fabio Timeus.;Concetta Micalizzi.;Eberhard Gunsilius.;Laine Hosking.;Sharon Choo.;Sujal Ghosh.;Anna Köttgen.;Kai Lehmberg.;Stephan Ehl.
来源: Blood. 2025年
Genetic screening for severe congenital immuno-hematological diseases offers potential for early intervention, particularly through preemptive allogeneic stem cell transplantation (HSCT). However, the clinical value of such screening depends on precise prognostic predictions based on genotype-phenotype correlations and/or functional confirmation. We investigated familial hemophagocytic lymphohistiocytosis type 2 (FHL2), caused by PRF1 variants. Specifically we evaluated the clinical significance of the frequent PRF1 A91V variant, if present in trans with a predicted loss-of-function (pLOF) PRF1 variant, defined as "disease mutation" listed in the Human Gene Mutation Database. We combined clinical and functional data from our HLH-network registry with UK Biobank data to evaluate disease penetrance and clinical outcomes. Among 52 A91V/pLOF individuals in the registry, 39 (72%) showed FHL2-related manifestations with mean onset at 20 years. Four patients had recurrent disease, 15 were transplanted, and 14 died. Among 14 A91V/pLOF individuals identified by family screening (mean 29 years), however, only one was symptomatic. Moreover, among 21 A91V/pLOF carriers identified in 200,000 UK Biobank participants, 12 with genotypes identical to symptomatic registry patients, none had developed HLH by age 73. Premature stop pLOF alleles appeared more penetrant than missense variants, but functional data including perforin expression or cytotoxicity failed to predict disease manifestation. Our combined registry and population-based approach reveals significant variability in disease penetrance and severity among PRF1 A91V/pLOF carriers, with no clear association between genotype, functional data and clinical outcomes. This complexity illustrates the challenges of genetic screening and highlights the need for careful clinical decision-making regarding preemptive HSCT in asymptomatic carriers.
10. Impact of HLA alloimmunization in gene-modified autologous stem cell transplant for transfusion-dependent thalassemia.
作者: Nora M Gibson.;Eugene Khandros.;Caitlin W Elgarten.;Elizabeth Worster.;Dimitrios S Monos.;Alexis A Thompson.;Janet L Kwiatkowski.;Timothy S Olson.
来源: Blood. 2025年145卷22期2666-2670页
We report our single-center experience demonstrating that HLA class I alloimmunization predicts longer time to platelet engraftment, increased bleeding complications, and higher transfusion requirements in patients undergoing gene-modified hematopoietic stem cell transplant for transfusion-dependent β thalassemia.
11. Single-cell panleukemia signatures of HSPC-like blasts predict drug response and clinical outcome.
作者: Changya Chen.;Jason Xu.;Jonathan H Sussman.;Tiffaney L Vincent.;Joseph S Tumulty.;Satoshi Yoshimura.;Fatemeh Alikarami.;Wenbao Yu.;Yang-Yang Ding.;Chia-Hui Chen.;Elizabeth Y Li.;Austin Yang.;Xiaohuan Qin.;Shovik Bandyopadhyay.;Jacqueline Jiahui Peng.;Petri Pölönen.;Haley Newman.;Brent Wood.;Jianzhong Hu.;Rawan Shraim.;Andrew D Hughes.;Caroline Diorio.;Lahari Uppuluri.;Gongping Shi.;Theresa Ryan.;Tori Fuller.;Mignon L Loh.;Elizabeth A Raetz.;Stephen P Hunger.;Stanley B Pounds.;Charles G Mullighan.;David Frank.;Jun J Yang.;Kathrin Maria Bernt.;David Trent Teachey.;Kai Tan.
来源: Blood. 2025年
The critical role of leukemic initiating cells as a therapy-resistant population in myeloid leukemia is well established, however, the molecular signatures of such cells in acute lymphoblastic leukemia remain underexplored. Moreover, their role in therapy response and patient prognosis is yet to be systematically investigated across various types of acute leukemia. We employed single-cell multiomics to analyze diagnostic specimens from 96 pediatric patients with acute lymphoblastic, myeloid, and lineage ambiguous leukemias. Through the integration of single-cell multiomics with extensive bulk RNA-Seq and clinical datasets, we uncovered a prevalent, chemotherapy-resistant subpopulation that resembles hematopoietic stem and progenitor cells (HSPC-like) and is associated with poor clinical outcomes across all subtypes investigated. We identified a core transcriptional regulatory network (TRN) in HSPC-like blasts that is combinatorically controlled by HOXA/AP1/CEBPA. This TRN signature can predict chemotherapy response and long-term clinical outcomes. We identified shared potential therapeutic targets against HSPC-like blasts, including FLT3, BCL2, and the PI3K pathway. Our study provides a framework for linking intra-tumoral heterogeneity with therapy response, patient outcome and discovery of new therapeutic targets for pediatric acute leukemias.
12. Clonal hematopoiesis landscape in frequent blood donors.
作者: Darja Karpova.;Hector Huerga Encabo.;Elisa Donato.;Silvia Calderazzo.;Michael Scherer.;Miriam Llorian-Sopena.;Aino-Maija Leppä.;Roberto Würth.;Patrick Stelmach.;Despoina Papazoglou.;Alessandra Ferrelli.;Steven Ngo.;Iuliia Kotova.;Sabine Harenkamp.;Kai Zimmer.;Dominik Wolf.;Jasper Panten.;John Reed.;Adriana Przybylla.;Torsten Tonn.;Annette Kopp-Schneider.;Lars Velten.;John F DiPersio.;Terrence N Wong.;Dominique Bonnet.;Halvard Bonig.;Andreas Trumpp.
来源: Blood. 2025年145卷21期2411-2423页
Donor blood saves lives, yet the potential impact of recurrent large-volume phlebotomy on donor health and hematopoietic stem cells (HSCs) remains largely unexplored. In our study, we conducted a comprehensive screening of 217 older male volunteer donors with a history of extensive blood donation (>100 lifetime donations) to investigate the phenomenon of clonal hematopoiesis (CH). No significant difference in the overall incidence of CH was found in frequent donors (FDs) compared with sporadic donors (<10 lifetime donations; 212 donors). However, upon deeper analysis of mutations in DNMT3A, the most commonly affected gene in CH, we observed distinct mutational patterns between the FD and age/sex-matched control donor cohorts. Functional analysis of FD-enriched DNMT3A variants examined in CRISPR-edited human HSCs demonstrated their competitive outgrowth potential upon stimulation with erythropoietin (EPO), a hormone that increases in response to blood loss. In contrast, clones harboring leukemogenic DNMT3A R882 mutations increase upon stimulation with interferon gamma. Through concurrent mutational and immunophenotypic profiling of primary samples at single-cell resolution, a myeloid bias of premalignant R882 mutant HSCs was found, whereas no significant lineage bias was observed in HSCs harboring EPO-responsive DNMT3A variants. The latter exhibited preferential erythroid differentiation when persistent erythropoietic stress was applied to CRISPR-edited human HSC xenografts. Our data demonstrate a nuanced, ongoing Darwinian evolution at the somatic stem cell level, with EPO identified as a novel environmental factor that favors HSCs carrying certain DNMT3A mutations.
13. Decoding functional hematopoietic progenitor cells in the adult human lung.
作者: Catharina Conrad.;Mélia Magnen.;Jessica Tsui.;Harrison Wismer.;Mohammad Naser.;Urmila Venkataramani.;Bushra Samad.;Simon J Cleary.;Longhui Qiu.;Jennifer J Tian.;Marco De Giovanni.;Nicole Mende.;Andrew D Leavitt.;Emmanuelle Passegué.;Elisa Laurenti.;Alexis J Combes.;Mark R Looney.
来源: Blood. 2025年145卷18期1975-1986页
Although the bone marrow is the main site of blood cell production in adults, rare pools of hematopoietic stem and progenitor cells have been found in extramedullary organs. In mice, we have previously shown that the lung contains hematopoietic progenitor cells and is a site of platelet production. Here, in the adult human lung, we show that functional hematopoietic precursors reside in the extravascular spaces with a frequency similar to the bone marrow and are capable of proliferation and engraftment in mice. The gene signature of pulmonary and medullary CD34+ hematopoietic progenitors indicates greater baseline activation of immune-, megakaryocyte/platelet-, and erythroid-related pathways in lung progenitors. Spatial transcriptomics mapped blood progenitors in the lung to an alveolar interstitium niche with only a few cells identified in an intravascular location. In human blood samples collected for stem cell transplantation, CD34+ cells with a lung signature enriched the mobilized pool of hematopoietic stem cells. These results identify the lung as a pool for uniquely programmed blood stem and progenitor cells with the potential to support hematopoiesis in humans.
14. Aberrant single-cell phenotype and clinical implications of genotypically defined polyclonal plasma cells in myeloma.
作者: Matteo Claudio Da Viá.;Francesca Lazzaroni.;Antonio Matera.;Alessio Marella.;Akihiro Maeda.;Claudio De Magistris.;Loredana Pettine.;Antonio Giovanni Solimando.;Vanessa Desantis.;Giuseppe M Peretti.;Laura Mangiavini.;Riccardo Giorgino.;Sonia Fabris.;Stefania Pioggia.;Alfredo Marchetti.;Marzia Barbieri.;Silvia Lonati.;Alessandra Cattaneo.;Marta Tornese.;Margherita Scopetti.;Emanuele Calvi.;Nayyer Latifinavid.;Giancarlo Castellano.;Federica Torricelli.;Antonino Neri.;Cathelijne Fokkema.;Tom Cupedo.;Marta Lionetti.;Francesco Passamonti.;Niccolò Bolli.
来源: Blood. 2025年
Multiple Myeloma is driven by clonal plasma cell (cPC)-intrinsic factors and changes in the tumorigenic microenvironment (TME). To investigate if residual polyclonal PCs (pPCs) are disrupted, single-cell (sc) RNAseq and sc B-cell receptor analysis were applied in a cohort of 46 samples with PC dyscrasias and 21 healthy donors (HDs). Out of n=234,789 PCs, 64,432 were genotypically identified as pPCs with frequencies decreasing over different disease stages, from 23.66% in monoclonal gammopathy of undetermined significance (MGUS) to 3.23% in MMs (p=0.00012). Both cPCs and pPCs had a comparable expression of typical lineage markers (i.e. CD38, CD138), while others were more variable (CD27, ITGB7). Only cPCs overexpressed oncogenes (e.g. CCND1/2, NSD2), but CCND3 was often expressed in pPCs. BCMA was expressed on both p- and cPCs, while GPRC5D was mostly upregulated in cPCs with implications for on-target, off-tumor activity of targeted immunotherapies. In comparison with HDs, pPCs from patients showed upregulated autophagy and disrupted interaction with TME. Importantly, interferon related pathways where significantly enriched in pPCs from patients vs HDs (p-adjusted < 0.05) showing an inflamed phenotype affecting genotypically normal PCs. Function of pPCs was consequently impacted and correlated with immunoparesis, driven by disrupted cellular interactions with TME. Leveraging our scRNAseq data, we derived a "healthy PC signature" that could be applied to bulk transcriptomics from the CoMMpass dataset and predicted significantly better PFS and OS (log rank p < 0.05 for both). Our findings show that genotypic, single-cell identification of pPCs in PC dyscrasias has relevant pathogenic and clinical implications.
15. Magrolimab plus azacitidine vs physician's choice for untreated TP53-mutated acute myeloid leukemia: the ENHANCE-2 study.
作者: Joshua F Zeidner.;David A Sallman.;Christian Récher.;Naval G Daver.;Anskar Yh Leung.;Devendra K Hiwase.;Marion Subklewe.;Thomas Pabst.;Pau Montesinos.;Richard A Larson.;Lindsay Wilde.;Anoop K Enjeti.;Ichiro Kawashima.;Cristina Papayannidis.;Jenny O'Nions.;Lisa Johnson.;Mei Dong.;Julie Huang.;Taravat Bagheri.;Gal Hacohen-Kleiman.;Calvin Lee.;Paresh Vyas.
来源: Blood. 2025年
Patients with TP53-mutated acute myeloid leukemia (AML) have an extremely poor prognosis, necessitating new treatments. The global, randomized, phase 3 ENHANCE-2 trial evaluated the anti-CD47 monoclonal antibody magrolimab plus azacitidine (Magro/Aza) for previously untreated TP53-mutated AML. Patients determined inappropriate for intensive therapy were randomized to receive Magro/Aza or venetoclax plus azacitidine (Ven/Aza); those appropriate for intensive therapy were randomized to receive Magro/Aza or 7+3 induction chemotherapy. Primary endpoint was overall survival (OS) in the non-intensive arm. At interim analysis, non-intensive-arm OS hazard ratio (HR) between treatment groups was 1.191 (95% CI, 0.744-1.906), meeting the study's definition for futility and resulting in study termination. At final analysis, median OS was 4.4 vs 6.6 months (HR, 1.132; 95% CI, 0.783-1.637; P = .5070) in the non-intensive arm (n = 205) and 7.3 vs 11.1 months (HR, 1.434; 95% CI, 0.635-3.239; P = .3798) in the intensive arm (n = 52) between Magro/Aza and control groups, respectively. Incidences of grade ≥3 adverse events (AEs) were similar across Magro/Aza and control groups (non-intensive, n = 194: 96.9% and 95.9%; intensive, n = 50: 92.6% and 95.7%), including grade ≥3 anemia (non-intensive: 27.1% and 23.5%; intensive: 25.9% and 21.7%). Grade ≥3 infections were observed in 50.0% and 53.1% of patients in the non-intensive arm and 44.4% and 65.2% of intensive arm patients. ENHANCE-2 did not meet its primary endpoint of OS in TP53-mutated AML but provides important data informing future studies in this challenging population. This trial was registered at www.clinicaltrials.gov as #NCT04778397.
16. NOTCH1 dimeric signaling is essential for T-cell leukemogenesis and leukemia maintenance.
作者: Francesco Tamiro.;Costanzo Padovano.;Elisabetta De Santis.;Serena Di Iasio.;Francesca Delia Sansico.;Valentina Canistro.;Mattia Colucci.;Chiara Di Nunzio.;Gaja Bruno.;Kashish Doshi.;Angela Totaro.;Eric Gu.;Michele Santodirocco.;Andrew P Weng.;Vincenzo Giambra.
来源: Blood. 2025年
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by an expansion of T-cell progenitors and DNA mutations that lead to an overactive NOTCH1 signaling in over 50% of T-ALL cases. Using synthetic models of human T-ALL, we report that NOTCH1 dimeric signaling was crucial for the leukemogenesis of human hematopoietic stem/progenitor cells (HSPCs) from cord blood. We also identified a Notch-dimerization-dependent gene signature, including HES4 transcription factor, which induced proliferative advantage in human HSPCs as well as in Notch-dimerization-dependent patient-derived xenografts (PDXs) of T-ALL. Interestingly, in human T-ALL cells, HES4 enforced the expression of D133p53 isoform with the concomitant block of pro-apoptotic p53 target genes and the induction of BCL2L1 gene expression and anti-apoptotic Bcl-xL protein. Additionally, through an integrated experimental approach including genetically modified cell lines, RNA/Chip-sequencing and single cell RNA-sequencing (scRNA-Seq) profiles of primary T-ALL samples, we revealed cell subsets with Notch-dimerization-dependent gene signature, which indirectly correlated with pro-apoptotic genes as well as directly associated with cell markers of poor clinical outcome in primary T-ALL samples. Taken together, these findings highlight the crucial role of NOTCH1 dimeric signaling in human T-cell leukemogenesis and T-ALL maintenance suggesting that a possible benefit can be obtained from a therapeutic strategy targeting NOTCH1-dimer signaling or its downstream effectors.
17. The MURANO study: final analysis and retreatment/crossover substudy results of VenR for patients with relapsed/refractory CLL.
作者: Arnon P Kater.;Rosemary Anne Harrup.;Thomas J Kipps.;Barbara Eichhorst.;Carolyn Owen.;Sarit E Assouline.;Nicole Lamanna.;Tadeusz Robak.;Javier de la Serna.;Ulrich Jaeger.;Guillaume Cartron.;Marco Montillo.;Clemens Mellink.;Anton W Langerak.;Brenda Chyla.;Relja Popovic.;Yanwen Jiang.;Rosemary Millen.;Marcus Lefebure.;Maria Thadani-Mulero.;Michelle Boyer.;John F Seymour.
来源: Blood. 2025年
Fixed-duration venetoclax-rituximab (VenR) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) in the phase 3 MURANO trial (NCT02005471) resulted in superior progression-free survival (PFS) and overall survival (OS) vs bendamustine-rituximab (BR). We report the final analyses of MURANO (median 7 years follow-up). Patients were randomized to VenR (venetoclax 400 mg daily for 2 years plus monthly rituximab for 6 months; n = 194) or BR (6 months; n = 195). In a substudy, patients with progressive disease (PD) received VenR as retreatment or crossover from BR. At the final data cut (3 August 2022), median PFS with VenR was 54.7 vs 17.0 months with BR. Seven-year PFS with VenR was 23.0%. Seven-year OS was 69.6% and 51.0%, respectively. Among VenR-treated patients with undetectable (u) minimal residual disease (MRD) and no PD at end of treatment (EOT) (n = 83), median PFS from EOT was 52.5 vs 18.0 months in patients with MRD at EOT (n = 35; P < 0.0001). Fourteen patients had enduring uMRD. Three distinct mutations in BCL2 in four patients were identified. In the substudy, 25 patients were retreated with VenR and nine patients crossed over to VenR; median PFS was 23 and 27 months, and best overall response rate was 72% and 89%, respectively. At the end of combination treatment, following retreatment or crossover, eight and six patients achieved uMRD, respectively. No new safety findings were observed. Overall, these final MURANO analyses support consideration of fixed-duration VenR therapy for patients with relapsed/refractory CLL.
18. STING activation improves T-cell-engaging immunotherapy for acute myeloid leukemia.
作者: Andreas Linder.;Daniel Nixdorf.;Niklas Kuhl.;Ignazio Piseddu.;TengTeng Xu.;Anne V Holtermann.;Gunnar Kuut.;Rebekka Endres.;Nora Philipp.;Veit Bücklein.;Johann de Graaff.;Thomas Carell.;Sebastian Kobold.;Roman Kischel.;Veit Hornung.;Marion Subklewe.
来源: Blood. 2025年145卷19期2149-2160页
T-cell-recruiting bispecific antibodies (BsAbs) are in clinical development for relapsed/refractory acute myeloid leukemia (AML). Despite promising results, early clinical trials have failed to demonstrate durable responses. We investigated whether activation of the innate immune system through stimulator of interferon (IFN) genes (STING) can enhance target cell killing by a BsAb targeting CD33 (CD33 bispecific T-cell engager molecule; AMG 330). Indeed, we show that cytotoxicity against AML mediated by AMG 330 can be greatly enhanced when combined with the STING agonist 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) or diamidobenzimidazole (diABZI). We used in vitro cytotoxicity assays, immunoblotting, transcriptomic analyses, and extensive CRISPR-Cas9 knockout experiments to investigate the enhancing effect of a STING agonist on the cytotoxicity of AMG 330 against AML. Importantly, we validated our findings with primary AML cells and in a xenograft AML model. Mechanistically, in addition to direct cytotoxic effects of STING activation on AML cells, activated T cells render AML cells more susceptible to STING activation through their effector cytokines, IFN-γ and tumor necrosis factor, resulting in enhanced type I IFN production and induction of IFN-stimulated genes. This feeds back to the T cells, leading to a further increase in effector cytokines and an overall cytotoxic T-cell phenotype, contributing to the beneficial effect of cGAMP/diABZI in enhancing AMG 330-mediated lysis. We established a key role for IFN-γ in AMG 330-mediated cytotoxicity against AML cells and in rendering AML cells responsive to STING agonism. Here, we propose to improve the efficacy of CD33-targeting BsAbs by combining them with a STING agonist.
19. 17(R)-Resolvin D1 protects against sickle cell-related inflammatory cardiomyopathy in humanized mice.
作者: Enrica Federti.;Domenico Mattoscio.;Antonio Recchiuti.;Alessandro Matte.;Maria Monti.;Flora Cozzolino.;Manuela Iezzi.;Martina Ceci.;Alessandra Ghigo.;Emanuela Tolosano.;Angela Siciliano.;Jacopo Ceolan.;Veronica Riccardi.;Elisa Gremese.;Carlo Brugnara.;Lucia De Franceschi.
来源: Blood. 2025年145卷17期1915-1928页
Cardiovascular disease has been recognized as the main cause of death in adults with sickle cell disease (SCD). Although the exact mechanism linking SCD to cardiomyopathy remains elusive, a possible role of subclinical acute transient myocardial ischemia during acute sickle cell-related vaso-occlusive crises (VOCs) has been suggested. We approached SCD cardiomyopathy by integrated omics using humanized SS mice exposed to hypoxia/reoxygenation (H/R; 10 hours hypoxia followed by 3 hours reoxygenation) stress, mimicking acute VOCs. In sickle cell (SS) mice exposed to H/R, a neutrophil-driven cardiac hypertrophic response is initiated by cardiac proinflammatory pathways, intersecting proteins and micro RNA involved in profibrotic signaling. This response may be facilitated by local unresolved inflammation. We then examined the effect of 17(R)-resolvin D1 (17R-RvD1), a member of the specialized proresolving lipid mediator superfamily, administration on H/R-activated profibrotic and proangiogenic pathways. In SS mice, we found that 17R-RvD1 (1) modulates miRNAome; (2) prevents the activation of NF-κB p65; (3) protects against the H/R-induced activation of both platelet derived growth factor receptor and transforming growth factor (TGF)-β1/Smad2-3 canonical pathways; (4) reduces the expression of hypoxia-inducible factor-dependent proangiogenic signaling; and (5) decreases the H/R-induced proapoptotic cell signature. The protective role of 17R-RvD1 against H/R-induced maladaptive heart remodeling was supported by the reduction of galectin-3, procollagen C-proteinase enhancer-1, and endothelin-1 expression and perivascular fibrosis in SS mice at 3 days after H/R stress compared with vehicle-treated SS animals. Collectively, our data support the novel role of unresolved inflammation in pathologic heart remodeling in SCD mice in response to H/R stress. Our study provides new evidence for protective effects of 17R-RvD1 against SCD-related cardiovascular disease.
20. Venetoclax plus daunorubicin and cytarabine for newly diagnosed acute myeloid leukemia: results of a phase 1b study.
作者: Ioannis Mantzaris.;Mendel Goldfinger.;Matan Uriel.;Aditi Shastri.;Nishi Shah.;Kira Gritsman.;Noah S Kornblum.;Lauren Shapiro.;Roberto Alejandro Sica.;Anne Munoz.;Nicole Chambers.;Aradhika Dhawan.;Jhannine Alyssa Verceles.;Karen Fehn.;Balda Tirone.;Lamisha Shah.;Shaunmonique Clark.;Chenxin Zhang.;Mimi Kim.;Dennis L Cooper.;Amit Verma.;Marina Konopleva.;Eric J Feldman.
来源: Blood. 2025年145卷17期1870-1875页
Venetoclax (Ven), when combined with intensive chemotherapy, shows promise for untreated acute myeloid leukemia (AML), but its integration with the 7+3 regimen remains underexplored. In a phase 1b study, we assessed the safety and efficacy of Ven with daunorubicin and cytarabine in patients with newly diagnosed AML. A total of 34 patients (median age, 59 years; 62% non-White) received Ven at escalating durations (8, 11, or 14 days). Adverse events included febrile neutropenia (100%), sepsis (29%), and enterocolitis (23.5%), but there were no induction deaths. The median recovery times for neutrophils (>1.0 × 103/μL) and platelets (>100 × 103/μL) were less than 30 days. Composite complete remission was achieved in 85.3% of patients, and 86.2% were negative for measurable residual disease (MRD). Responses spanned all European Leukemia Net 2022 risk categories. With a median follow-up of 9.6 (2-20) months, the median duration of response, event-free survival, and overall survival were not reached. Ven (400 mg), when combined with 7+3 chemotherapy, was safe and effective in achieving MRD-negative remissions across all durations. Ven dose optimization is being explored in the expansion phase of this trial. Future multicenter studies should confirm our findings. This trial was registered at clinicaltrials.gov as #NCT05342584.
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