HemaSphere最新文献

{"title":"Improved red blood cell storage quality of blood from donors carrying the hypermorphic PIMT I120 variant.","authors":"Shaun Bevers, Aaron V Issaian, Ariel Hay, Gregory R Keele, Monika Dzieciatkowska, Julie A Reisz, Zachary B Haiman, Travis Nemkov, Daniel Stephenson, Amy L Moore, Xutao Deng, Mars Stone, Kirk C Hansen, Steve Kleinman, Philip J Norris, Michael P Busch, Bernhard O Palsson, Nareg H Roubinian, John Janetzko, Beat Vӧgeli, Grier P Page, David N Jones, Morkos A Henen, Elan Z Eisenmesser, James C Zimring, Angelo D'Alessandro","doi":"10.1002/hem3.70361","DOIUrl":"10.1002/hem3.70361","url":null,"abstract":"<p><p>Protein-l-isoaspartate <i>O</i>-methyltransferase (PIMT), encoded by <i>PCMT1</i>, is a repair enzyme that corrects isoaspartyl lesions, preserving protein structure and function. While indispensable for neuronal integrity, its role in red blood cells (RBCs) and transfusion outcomes is incompletely understood. Here, we show that novel erythroid-specific <i>Pcmt1</i> knockout mice display profound remodeling of one-carbon metabolism, accumulation of repair intermediates, and destabilization of glycolytic and cytoskeletal proteins, yet maintain lower lipid peroxidation and normal post-transfusion recovery. Analysis of 13,091 blood donors from the Recipient Epidemiology and Donor Evaluation Study (REDS)-III Red Blood Cell Omics (RBC Omics) study revealed that common <i>PCMT1</i> variants associate with hemolysis phenotypes and regulate PIMT protein level, as gleaned by protein quantitative trait loci (pQTL) analyses. The nonsynonymous rs4816 (V120I) allele, enriched in donors of Asian or African ancestry, emerged as a beneficial variant: carriers exhibited lower osmotic hemolysis, altered peptide methylation flux, and higher PIMT protein levels. Recombinant expression confirmed that the I120 variant displays preserved global folding, but greater catalytic activity than the canonical V120 enzyme. Transfusion outcome data showed that <i>PCMT1</i> genotype influences hemoglobin increments and bilirubin responses in recipients. These findings identify PIMT as a novel determinant of RBC storage biology and establish rs4816 as a protective allele, with broader implications for donor diversity, transfusion efficacy, and proteome maintenance in aging.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":"e70361"},"PeriodicalIF":14.6,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13084699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole-genome sequencing of cell-free DNA for assessment of minimal residual disease in high-risk smoldering multiple myeloma.","authors":"Chrissy Baker, Elizabeth Hill, Dickran Kazandjian, Marios Papadimitriou, Michael Durante, Abhishek Pandey, Bachisio Ziccheddu, Tomas Jelinek, David Coffey, Brian Walker, Ryan Young, Kylee Maclachlan, Neha Korde, Nickoli Parkinson, Zoe R Goldstein, Alexi Runnels, William F Hooper, Dan Landau, Nicolas Robine, Francesco Maura, Ola Landgren, Benjamin Diamond","doi":"10.1002/hem3.70367","DOIUrl":"https://doi.org/10.1002/hem3.70367","url":null,"abstract":"<p><p>In multiple myeloma (MM), minimal residual disease (MRD) is an established endpoint for accelerated drug approval but is limited by a need for serial invasive bone marrow (BM) biopsies, which may under-sample spatial heterogeneity and result in false negativity. Furthermore, longitudinal (i.e., sustained) MRD negativity is emerging as a powerful tool for clinical decision-making. To these ends, reliable systemic MRD assessment is a growing need. Next-generation sequencing approaches for plasma cell-free (cf) DNA generally fail to achieve adequate detection limits in low tumor fraction (TF) settings (i.e., MRD), but tumor-informed approaches leveraging whole-genome sequencing (WGS) have thus far achieved the lowest limits of detection (LODs). We therefore performed a longitudinal analysis of MRD assessed by serial WGS of plasma cfDNA as compared to clinical standard flow-cytometric BM MRD in high-risk smoldering MM. 25 baseline tumor WGS served to inform detection of disease in 87 sequential plasma samples. The median LOD across patients was 1.2 × 10^-4 (range 9.0 × 10^-5 - 2.1 × 10^-4). TF was prognostic, and tumors with high-risk genomics had higher baseline TF (P = 0.002) and eventual disease progression (<i>n</i> = 7, P < 0.001). Furthermore, dynamic changes in serially tracked TF portended outcome. In comparison to BM flow, cfDNA WGS was concordant in 33/45 (73.3%) MRD samples with consistent capture of BM-positive cases, but added resolution to apparent false-negative BM samples. Overall, despite the deeper LOD of localized BM flow, cfDNA WGS can detect MRD when BM flow did not, adding dynamic and systemic/spatial resolution to standard hyper-local MRD assessment.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":"e70367"},"PeriodicalIF":14.6,"publicationDate":"2026-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13084702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147722578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lower efficacy of transfusion of red blood cells from donors with sickle cell trait.","authors":"Monika Dzieciatkowska, Daniel Stephenson, Ariel Hay, Xunde Wang, Gregory R Keele, Travis Nemkov, Xutao Deng, Mars Stone, Kirk C Hansen, Steve Kleinman, Philip J Norris, Michael P Busch, Grier P Page, Steven L Spitalnik, Nareg Roubinian, James C Zimring, Swee-Lay Thein, Angelo D'Alessandro","doi":"10.1002/hem3.70360","DOIUrl":"10.1002/hem3.70360","url":null,"abstract":"<p><p>Sickle cell trait (SCT), the heterozygous state for the hemoglobin S (HbS) mutation, affects roughly 1 in 13 African American individuals and is common among blood donors recruited for antigen-matched transfusions in sickle cell disease (SCD). While individuals with SCT are typically asymptomatic, it is unclear whether red blood cells (RBCs) from SCT donors have impaired storage quality and transfusion efficacy. Here, we integrate multi-omics to characterize RBCs from donors SCT and evaluate their performance post-transfusion. We first profiled RBCs from 174 HbAS and 248 HbAA volunteers, identifying elevated levels of metabolic markers of the storage lesion in SCT RBCs at baseline. We then interrogated the REDS RBC Omics dataset (>13,000 donors), identifying blood donors carrying the HbS E6V variants. SCT RBCs exhibited accelerated metabolic aging, oxidative stress, and proteostatic activation-phenotypes further exacerbated by storage duration and co-inheritance of G6PD deficiency. Functional assays confirmed decreased osmotic fragility and increased oxidative hemolysis in SCT RBCs by storage Day 42. Pre-clinically, stored RBCs from Townes mice carrying one allele of human sickle hemoglobin were characterized by a drop in post-transfusion recovery compared to mice expressing canonical human hemoglobin. Clinically, analysis of 6828 transfusion events revealed that SCT RBCs were associated with lower hemoglobin increments 24 h post-transfusion. These findings provide mechanistic and clinical evidence that SCT influences RBC quality and transfusion outcomes. Given the overrepresentation of SCT in donor pools serving patients with SCD, our study supports a more personalized approach to inventory management and transfusion strategies in high-risk populations.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":"e70360"},"PeriodicalIF":14.6,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13077787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147689885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning enhances risk stratification and treatment failure prediction in diffuse large B-cell lymphoma.","authors":"Mikkel Werling, Alexander D Fuglkjær, Peter Brown, Carsten U Niemann, Rudi Agius","doi":"10.1002/hem3.70336","DOIUrl":"https://doi.org/10.1002/hem3.70336","url":null,"abstract":"<p><p>Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype worldwide. Existing prognostic models, including the National Comprehensive Cancer Network International Prognostic Index (NCCN IPI), rely on small predefined variable sets, discretized inputs, and do not incorporate longitudinal clinical histories or nonlinear relationships. To address these limitations, we present <math> <mrow> <mrow><mrow><mi>M</mi> <msub><mi>L</mi> <mi>All</mi></msub> </mrow> </mrow> </mrow> </math> , a machine learning model developed using clinical and laboratory data from 14,832 patients from the Danish Lymphoid Cancer Research (DALY-CARE) resource (2005-2021). The primary objective was fixed-time risk prediction of treatment failure within 2 years of first-line therapy. Compared with the NCCN IPI at matched specificity, <math> <mrow> <mrow><mrow><mi>M</mi> <msub><mi>L</mi> <mi>All</mi></msub> </mrow> </mrow> </mrow> </math> improved recall relatively by 22% (0.32-0.39), precision by 7% (0.56-0.60), and precision-recall AUC by 28% (0.46-0.59) in a blinded control population. Survival analyses were performed as a complementary evaluation and demonstrated reduced age-related bias in risk stratification. <math> <mrow> <mrow><mrow><mi>M</mi> <msub><mi>L</mi> <mi>All</mi></msub> </mrow> </mrow> </mrow> </math> identified more than four times as many low-risk patients compared to the NCCN IPI, largely by correctly classifying older patients with favorable outcomes. Prognostic performance was nearly identical when evaluated on DLBCL alone and on a cohort including multiple aggressive lymphoma subtypes, suggesting that shared prognostic signals can be leveraged through joint modeling. These findings show that addressing key limitations of existing prognostic models enables more accurate and individualized risk stratification in DLBCL. <math> <mrow> <mrow><mrow><mi>M</mi> <msub><mi>L</mi> <mi>All</mi></msub> </mrow> </mrow> </mrow> </math> provides a general framework for registry-based prognostic modeling that can be adapted to other lymphoma subtypes and healthcare systems.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":"e70336"},"PeriodicalIF":14.6,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13077786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147689848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical efficacy of tasquinimod in myelodysplastic neoplasms: Restoring erythropoiesis and mitigating bone loss.","authors":"Manja Wobus, Heike Weidner, Rebekka Wehner, Anna-Lena Baumann, Kristin Möbus, Ekaterina Balaian, Marie Törngren, Erik Vahtola, Helena Eriksson, Susann Winter, Uwe Platzbecker, Triantafyllos Chavakis, Lorenz Christian Hofbauer, Martina Rauner, Martin Bornhäuser, Katja Sockel","doi":"10.1002/hem3.70352","DOIUrl":"https://doi.org/10.1002/hem3.70352","url":null,"abstract":"<p><p>Myelodysplastic neoplasms (MDSs) are clonal disorders characterized by ineffective hematopoiesis, dysplasia, and a risk of transformation into acute myeloid leukemia. MDS is also associated with a higher incidence of osteoporosis, suggesting a complex interplay between hematopoiesis, the bone marrow (BM) microenvironment, and bone homeostasis. Targeting inflammation has emerged as a promising therapeutic strategy, particularly in lower risk MDS. Tasquinimod (TASQ) is a small-molecule inhibitor of the inflammatory alarmin S100A9, blocking its interaction with TLR4 and RAGE receptors. We investigated the efficacy of TASQ in modulating inflammation and improving disease phenotype using in vitro and in vivo MDS models. Immunofluorescence staining of human BM identified neutrophils and macrophages as primary S100A9 sources. Exposure of mesenchymal stromal cells (MSCs) to S100A9 induced Toll-like receptor 4 (TLR4) downstream signaling, resulting in increased expression of IRAK1, NF-κB-p65, interleukin-1β (IL-1β), IL-18, caspase 1, and PD-L1. These effects were effectively abolished by TASQ. Additionally, TASQ restored the disturbed MSC-mediated hematopoietic support, as demonstrated by increased numbers of cobblestone area-forming cells and colony-forming units. In NHD13 MDS mice, TASQ (30 mg/kg, 12 weeks) improved hemoglobin and red blood cell counts, but exerted no effect in wild-type (WT) mice. Additionally, TASQ improved bone microarchitecture by increasing trabecular number and bone volume, likely a result of reduced osteoclast activity. Our findings suggest that TASQ mitigates inflammasome activation in the MDS BM, improving erythropoiesis and bone health. These results provide a necessary preclinical basis for clinical trials in lower risk MDS patients, in whom anemia and osteoporosis often coexist.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":"e70352"},"PeriodicalIF":14.6,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13077779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147689903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preinfusion risk factors for the development of severe neurotoxicity following CART therapy in pediatric patients","authors":"Caroline Diorio,&nbsp;Regina M. Myers,&nbsp;Yimei Li,&nbsp;Hongyan Liu,&nbsp;Samuel Belfer,&nbsp;Amanda DiNofia,&nbsp;Allison Barz Leahy,&nbsp;Haley Newman,&nbsp;Jillian Dolan,&nbsp;Zachary Martinez,&nbsp;Amira Elhachimi,&nbsp;Robert B. Lindell,&nbsp;Cassidy Mullen,&nbsp;Alexander Li,&nbsp;John Kim,&nbsp;David T. Teachey,&nbsp;Shannon L. Maude,&nbsp;Stephan A. Grupp,&nbsp;Jennifer L. McGuire","doi":"10.1002/hem3.70337","DOIUrl":"10.1002/hem3.70337","url":null,"abstract":"<p>Neurotoxicity is a common and potentially life-threatening complication after chimeric antigen receptor T-cell therapy (CART) for pediatric B-cell acute lymphoblastic leukemia (B-ALL). The only consistently demonstrated clinical risk factor for severe neurotoxicity in prior studies is high, preinfusion bone marrow disease burden (DB). To better prognosticate this syndrome, we sought to identify preinfusion clinical, laboratory, and imaging risk factors for the development of severe neurotoxicity, stratified by DB. We determined the incidence of severe neurotoxicity (defined as Grade ≥3 neurologic event[s]) in children and young adults treated with investigational anti-CD19 or anti-CD22 CART products across eight clinical trials or with commercial tisagenlecleucel. We comprehensively examined the association of putative clinical, laboratory, and imaging factors with the development of severe neurotoxicity. The occurrence of a seizure was included as a secondary outcome. Severe neurotoxicity was observed in 45/442 (10%) patients and was more frequent in the high DB (26/107, 24%) than the low DB (17/312, 5%) cohort. In the high DB cohort, history of a prior transient neurologic insult was associated with severe neurotoxicity (adjusted odds ratio, 5.73; 95% CI, 1.63, 21.7; P = 0.007). In the low DB cohort, no studied risk factors were robustly associated with severe neurotoxicity. Risk factors associated were different in the high and low DB cohorts. Patients with high DB and a previous history of transient neurologic events had a higher risk of severe neurotoxicity. Although the frequency of severe neurotoxicity was much lower in low DB patients, low DB patients accounted for 40% of severe neurotoxicity cases. Future studies should consider patients with high or low DB separately.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13058923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Efficacy and safety of steroid-sparing strategy in the treatment of AIHA associated with KSHV/HHV-8 positive multicentric Castleman disease","authors":"Yannick Dieudonné,&nbsp;Clément Gourguechon,&nbsp;Romain Stammler,&nbsp;Florence Delestre,&nbsp;Boris Sorin,&nbsp;Bertrand Dunogué,&nbsp;Guillaume Dumas,&nbsp;Guillemette Fouquet,&nbsp;Anne-Marie Ronchetti,&nbsp;Romain Paule,&nbsp;Pascal Meliani,&nbsp;Nathalie Pansu,&nbsp;Rodolphe Buzele,&nbsp;Robin Noel,&nbsp;Jehane Fadlallah,&nbsp;Marion Malphettes,&nbsp;Emilie Corvilain,&nbsp;Véronique Meignin,&nbsp;Constance Guillaud,&nbsp;Antoine Dossier,&nbsp;Jérémie Dion,&nbsp;Laurence Gérard,&nbsp;Eric Oksenhendler,&nbsp;Lionel Galicier,&nbsp;David Boutboul","doi":"10.1002/hem3.70304","DOIUrl":"10.1002/hem3.70304","url":null,"abstract":"&lt;p&gt;Multicentric Castleman disease (MCD) related to HHV-8 (human herpesvirus-8 or Kaposi sarcoma-associated herpesvirus, KSHV) is a lymphoproliferative disorder mainly affecting immunocompromised individuals. Flares present with lymphadenopathy, splenomegaly, inflammation, and high HHV-8 viremia.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Diagnosis requires a lymph node biopsy showing plasma-cell or mixed type MCD features with infected large B cells in the mantle zone. Life-threatening complications include hemophagocytic lympho-histiocytosis (HLH) and HHV-8-related lymphoma, while autoimmune manifestations such as dysglycemia, thrombotic thrombocytopenic purpura (TTP), and cytopenias are also observed.&lt;span&gt;&lt;sup&gt;2-5&lt;/sup&gt;&lt;/span&gt; Standard of care relies on rituximab, often combined with etoposide or liposomal doxorubicin, for the management of acute flares.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Autoimmune hemolytic anemia (AIHA) is an acquired autoimmune disorder caused by autoantibody-mediated red blood cells (RBCs) destruction. It is classified as warm or cold AIHA, according to the antibodies' thermal range. Corticosteroids (CS) remain the first-line therapy for primary warm AIHA (wAIHA), with rituximab used as a second-line treatment.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; HHV-8 MCD is a rare but recognized cause of wAIHA, as documented in a few case reports, but the characteristics, evolution, and management of this complication have never been fully addressed. CS are often used with rituximab, as in primary wAIHA, but this strategy might increase Kaposi sarcoma (KS) risk and worsen immune deficiency.&lt;span&gt;&lt;sup&gt;9, 10&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Patients were identified through the French National Reference Center for Castleman Disease (see details in Supplemental Methods). AIHA was defined by hemoglobin (Hb) &lt; 12 g/dL, with ≥2 hemolysis features and a positive direct antiglobulin test (DAT). Patients with any other cause of hemolytic anemia were excluded. Complete response (CR) was defined by Hb &gt;12 g/dL without hemolysis, and partial response (PR) by Hb increase &gt;2 g/dL or normalization of Hb with persistent hemolysis.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Overall response (OR) was defined as the sum of PR and CR.&lt;/p&gt;&lt;p&gt;Between 1995 and 2024, 344 patients with a biopsy-proven HHV-8 MCD were identified. Fifty-nine patients (17%) met AIHA criteria (AIHA+), with a median age at diagnosis of 45 years (Table 1). All patients had MCD flare at AHAI diagnosis, and all had detectable HHV-8 viremia. Thirty-eight patients (64%) were living with HIV (PLWH), including 10 patients who initiated antiretroviral therapy (ART) at the time of AIHA diagnosis. Eight AIHA+ patients (21% of PLWH) had undetectable HIV viremia. Median Hb values were similar between PLWH and HIV-negative patients (5.3 g/dL [interquartile range; IQR 4.3–6.6] vs. 5.1 g/dL [IQR 4.9–5.9], respectively), favoring a minimal direct role of HIV in the genesis of anemia. AIHA occurred during the first flare of MCD in most cases (&lt;i&gt;n&lt;/i","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13058919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645042","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erdheim-Chester disease associated with myeloid neoplasm: Clinical features, molecular landscape, and treatment outcomes","authors":"Ambroise Le Pogam,&nbsp;Matthias Papo,&nbsp;Pierre Hirsch,&nbsp;Fleur Cohen-Aubart,&nbsp;Jean-François Emile,&nbsp;François Delhommeau,&nbsp;Pierre Duffau,&nbsp;Jérôme Razanamahery,&nbsp;Florence Nguyen-Khac,&nbsp;Christopher Nunes Gomes,&nbsp;Felicien Triboulet,&nbsp;Jeanne de La Rochefoucauld,&nbsp;Chloé McAvoy,&nbsp;Estibaliz Lazaro,&nbsp;Mehdi Hage-Sleiman,&nbsp;Damien Roos-Weil,&nbsp;François Chasset,&nbsp;Vincent Jachiet,&nbsp;Arsène Mekinian,&nbsp;Olivier Fain,&nbsp;Zahir Amoura,&nbsp;Jérôme Hadjadj,&nbsp;Julien Haroche","doi":"10.1002/hem3.70349","DOIUrl":"10.1002/hem3.70349","url":null,"abstract":"<p>Erdheim-Chester disease (ECD) is frequently associated with clonal hematopoiesis and myeloid neoplasms (MN), but clinical phenotype and response to kinase inhibitors (KI) in this setting remain unclear. We analyzed 67 patients with ECD associated with MN (ECD-MN) from a French national cohort and assessed ECD treatment response, MN progression, and leukemic transformation. Outcomes were compared with those of 348 patients with ECD without MN. ECD-MN were characterized by low blast counts and favorable MN prognostic scores. Compared with ECD patients without MN, those with MN were older (median 65 vs. 59 years, P &lt; 0.0001) and had more frequent cardiac (54% vs. 37%, P &lt; 0.01), pulmonary (48% vs. 31%, P &lt; 0.01), gastrointestinal (34% vs. 11%, P &lt; 0.0001), and lymph node involvement (31% vs. 8%, P &lt; 0.0001). KI therapy led to higher ECD response rates at 6 and 12 months compared with pegylated-interferon α (Peg-IFN) (96% vs. 58%, P = 0.02). MN progression and leukemic transformation at 6 months occurred, respectively, in 25% and 3% of KI-treated patients versus 25% and 18% of those treated with Peg-IFN. After a median follow-up of 25 (12–38) months on KI, the mutational landscape remained unchanged. Median overall survival was shorter in patients with MN (76 vs. 163 months, P &lt; 0.001). In conclusion, ECD associated with MN represents a distinct clinical entity, marked by broader organ involvement and poorer prognosis. KI therapy provides a superior response without increasing the risk of MN progression or leukemic transformation, supporting its use as a frontline treatment in this population.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13060758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147645076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TWIST2 high expression defines a novel subtype of B-cell precursor acute lymphoblastic leukemia","authors":"Tao Zeng,&nbsp;Ling Zhang,&nbsp;Wenxin Yin,&nbsp;Cuiping You,&nbsp;Henrik Lilljebjörn,&nbsp;Qian Wang,&nbsp;Weina Zhang,&nbsp;Xiaotian Ji,&nbsp;Yuliang Wang,&nbsp;Yongjing Liu,&nbsp;Yali Xie,&nbsp;Xiaoxi Feng,&nbsp;Xiang Zhang,&nbsp;Hua Jiang,&nbsp;Thoas Fioretos,&nbsp;Gang Xiao,&nbsp;Jie Jin,&nbsp;Suning Chen,&nbsp;Jinyan Huang","doi":"10.1002/hem3.70348","DOIUrl":"10.1002/hem3.70348","url":null,"abstract":"&lt;p&gt;B-progenitor acute lymphoblastic leukemia (BCP-ALL) is a hematologic malignancy arising from B-lymphoid progenitor cells.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Through whole-genome, exome, and transcriptome sequencing, numerous subtypes have been identified, including those harboring &lt;i&gt;DUX4&lt;/i&gt; and &lt;i&gt;NUTM1&lt;/i&gt; rearrangements and the &lt;i&gt;CDX2&lt;/i&gt;/&lt;i&gt;UBTF&lt;/i&gt; subtype.&lt;span&gt;&lt;sup&gt;3-10&lt;/sup&gt;&lt;/span&gt; We previously reported &lt;i&gt;MEF2D&lt;/i&gt; and &lt;i&gt;ZNF384&lt;/i&gt; fusions and &lt;i&gt;DUX4&lt;/i&gt;-rearranged cases in 203 patients and defined 14 expression-based subtypes across 1223 cases.&lt;span&gt;&lt;sup&gt;11, 12&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Using bioinformatics approaches, we analyzed transcriptomic data from 3371 BCP-ALL samples across 23 datasets. Hierarchical clustering revealed relationships among samples (Figure 1A; Supporting Information S2: Table 1), using the gene set listed in Supporting Information S2: Table 2. Of the 3371 cases, 3223 were assigned definitive molecular subtypes (proportions and case numbers in Supporting Information S2: Table 3; fusion and mutation profiles in Supporting Information S1: Figure 1A). Uniform Manifold Approximation and Projection (UMAP) visualization closely mirrored the hierarchical clustering results (Figure 1B). This large cohort enabled high-resolution delineation of the BCP-ALL genomic landscape.&lt;/p&gt;&lt;p&gt;We identified 23 BCP-ALL subtypes via UMAP and hierarchical clustering. Notably, a candidate novel cluster (&lt;i&gt;n&lt;/i&gt; = 17) was found adjacent to the &lt;i&gt;CDX2&lt;/i&gt;/&lt;i&gt;UBTF&lt;/i&gt; and &lt;i&gt;TCF3&lt;/i&gt;::&lt;i&gt;HLF&lt;/i&gt; subtypes. (Figure 1A,B; Supporting Information S1: Figure 2; Supporting Information S2: Table 4; for discovery details, see Supporting Information S1: Methods: Molecular Features Searching Based on UMAP Embedding). The most differentially overexpressed gene in this cluster compared with all established subtypes was &lt;i&gt;TWIST2&lt;/i&gt; (Figure 2A,B; Supporting Information S1: Figure 3A,B; Supporting Information S2: Table 5). We therefore designated this entity the “&lt;i&gt;TWIST2&lt;/i&gt;-high” subtype. ALLcatchR&lt;span&gt;&lt;sup&gt;13&lt;/sup&gt;&lt;/span&gt; validated our classification, showing 93% consistency (2998 out of 3223 samples) between predicted and annotated labels, with high credibility across most subtypes (Supporting Information S1: Figure 4A,B). However, predictions for samples with high &lt;i&gt;TWIST2&lt;/i&gt; expression had low confidence (&lt;0.7, reliability &gt; 0.75) and did not align with known subtypes, suggesting unique characteristics for the &lt;i&gt;TWIST2&lt;/i&gt;-high subtype (Supporting Information S1: Figure 4B,C). Analysis of an independent BCP-ALL dataset (309 patients) from the Guangzhou Medical University Affiliated Women and Children's Medical Center identified two samples (A22082800018 and A23020800098) with abnormally high &lt;i&gt;TWIST2&lt;/i&gt; expression (FPKM 12.26 and 12.97). When these samples were incorporated into the original dataset for clustering analysis, they clustered with the &lt;i&gt;TWIST2&lt;/i&gt;-high subtype, supporting the stability of this subtype (Supporting Information S2:","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13052152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological inhibition of sclerostin protects bone from B-cell acute lymphoblastic leukemia-mediated destruction","authors":"Vincent Kuek,&nbsp;Joyce Oommen,&nbsp;Emanuela Ferrari,&nbsp;Jinbo Yuan,&nbsp;Aris N. Economides,&nbsp;Richard B. Lock,&nbsp;Sebastien Malinge,&nbsp;Rishi S. Kotecha,&nbsp;Laurence C. Cheung","doi":"10.1002/hem3.70355","DOIUrl":"10.1002/hem3.70355","url":null,"abstract":"&lt;p&gt;B-cell acute lymphoblastic leukemia (B-ALL) is the most common pediatric cancer. Current therapeutic regimens have improved 5-year event-free survival (EFS) rates to 90%, however clinical outcomes for high-risk subgroups, such as BCR-ABL1&lt;sup&gt;+&lt;/sup&gt; B-ALL and relapsed ALL, remain poor.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; In addition, 16% of newly diagnosed children with ALL present with vertebral compression fractures.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Moreover, 16% of children with ALL undergoing glucocorticoid therapy also experience a high incidence of vertebral fractures, indicating that bone health may be compromised by both leukemia progression and osteotoxicity of chemotherapy.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Recently, preclinical studies have evaluated the use of osteoclast-targeting agents for the treatment of leukemia-induced bone loss.&lt;span&gt;&lt;sup&gt;4-6&lt;/sup&gt;&lt;/span&gt; However, the use of anabolic therapies to improve bone health in children with ALL has not been investigated. Here, we evaluated the therapeutic strategy of pharmacologically restoring osteoblastic cells (OBCs) in murine B-ALL models using a neutralizing antibody targeting sclerostin (Scl-Ab), an osteocyte-secreted protein which inhibits bone formation (Supplemental Methods).&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;First, we evaluated the efficacy of Scl-Ab treatment in the ALL-84 patient-derived xenograft (PDX) immunocompromised NSG mouse model, which was derived from a 14-year-old boy with relapsed B-ALL.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; We first confirmed that ALL-84-bearing mice with high bone marrow (BM) disease burden (97.5 ± 0.33%) exhibited a significant reduction in the number of femoral bone-lining cells expressing osteocalcin (OCN&lt;sup&gt;+&lt;/sup&gt;) compared to the femurs of healthy control mice (Supporting Information S1: Figure 1A). We then treated ALL-84-bearing mice (BM disease burden = 11.64 ± 2.53%) with Scl-Ab or control isotype IgG antibody (Iso-Ab) for 2 weeks (Figure 1A). We found that Scl-Ab significantly increased the number of femoral bone-lining OCN&lt;sup&gt;+&lt;/sup&gt; cells compared to Iso-Ab at the end of treatment (Figure 1B,C). Immunofluorescence staining identified a marginal increase in alkaline phosphatase (ALP&lt;sup&gt;+&lt;/sup&gt;) bone cells following Scl-Ab treatment (Supporting Information S1: Figure 2). Micro-CT scanning revealed that Scl-Ab treatment significantly improved both the trabecular and cortical bone parameters in ALL-84-bearing mice (Figure 1D,E).&lt;/p&gt;&lt;p&gt;Next, we determined whether Scl-Ab treatment could also improve bone health during leukemia progression in a functional immune system, utilizing the PER-M60 murine BCR-ABL1&lt;sup&gt;+&lt;/sup&gt; B-ALL syngeneic model.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; In this model, we again demonstrated that the femurs of leukemic mice contained lower numbers of OCN&lt;sup&gt;+&lt;/sup&gt; bone-lining cells at high BM disease burden (86.8 ± 0.32%) compared to healthy control mice (Supporting Information S1: Figure 1B). We next administered Scl-Ab or Iso-Ab to leukemia-bearing mice continu","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":""},"PeriodicalIF":14.6,"publicationDate":"2026-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70355","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147686345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}