HemaSphere最新文献

{"title":"Fitusiran treatment modulates the ratio between alpha- and beta-antithrombin isoforms.","authors":"Geneviève McCluskey, Hortense Maynadié, Delphine Borgel, Laurent Frenzel, Annie Harroche, Elsa Bianchini, Stephanie Roullet, Olivier D Christophe, Cecile V Denis, Caterina Casari, Peter J Lenting","doi":"10.1002/hem3.70376","DOIUrl":"https://doi.org/10.1002/hem3.70376","url":null,"abstract":"<p><p>Antithrombin (AT) circulates as two distinct isoforms, alpha- and beta-AT, which differ in their glycosylation profiles; alpha-AT is fully glycosylated at positions Asn¹²⁸, Asn¹⁶⁷, Asn¹⁸⁷, and Asn²²⁴, whereas beta-AT lacks Asn¹⁶⁷ glycosylation. The ratio of alpha-AT/beta-AT is approximately 9:1 in plasma, with beta-AT being a stronger inhibitor due to its increased affinity for heparin. Post-transcriptional silencing of AT via fitusiran has been shown to efficiently ameliorate the hemostatic balance in hemophilia. In this study, we analyzed if and how fitusiran affected the distribution of alpha-AT and beta-AT. Using different experimental approaches (isoform-specific activity, antigen, and immunoprecipitation assays), we were able to distinguish beta-AT and alpha-AT. Fitusiran treatment reduced the total AT activity to less than 20% of normal in both <i>F8</i> ^-/--mice and hemophilia A patients. Compared to controls, a 3.8- and 3.3-fold increase in the amount of beta-AT activity relative to residual total AT activity was detected in <i>F8</i> ^-/--mice and fitusiran-treated patients, respectively (P < 0.0001). Furthermore, the ratio of beta-AT/total AT antigen levels increased 1.8-fold in the human patient samples (from 0.09 ± 0.03 to 0.16 ± 0.01; P = 0.003), which coincided with an increased intensity of the beta-AT band detected in immunoprecipitation assays. It is noteworthy that this increase in the beta-AT/total AT ratio significantly increased its anticoagulant potential. Finally, we measured beta-AT/total AT ratios also in unrelated pathologies: congenital AT deficiency and advanced liver cirrhosis. Both conditions were also associated with an up to twofold higher ratio of beta-AT/total AT. Altogether, our results demonstrate that reduced AT production modulates the ratio between beta-AT and alpha-AT.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 ","pages":"e70376"},"PeriodicalIF":14.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13146349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837415","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":"Outcomes and salvage strategies for large B-cell lymphoma progressing after second-line CAR T-cell therapy: A DESCAR-T study from the LYSA group.","authors":"Pierre Sesques, Guillaume Manson, Guillaume Cartron, François-Xavier Gros, Franck Morschhauser, Cristina Castilla-Llorente, Gabriel Brisou, Pierre Bories, Catherine Thieblemont, Laurianne Drieu La Rochelle, Benoit Tessoulin, Axel André, Cedric Rossi, Jérôme Paillassa, Stephanie Guidez, Antoine Capes, Laura Herbreteau, Sylvain Choquet, Jacques-Olivier Bay, Adrien Chauchet, Laure Lebras, Fabien Claves, Julie Abraham, Jean-Valère Malfuson, Marie-Thérèse Rubio, Justine Decroocq, Luc-Matthieu Fornecker, Gandhi Damaj, Ludovic Fouillet, Magalie Joris, Michael Loschi, Olivier Hermine, Hadia Hafirassou, Emelie Van Zele, Vivien Dupont, Steven Le Gouill, Roch Houot, Vincent Camus","doi":"10.1002/hem3.70356","DOIUrl":"https://doi.org/10.1002/hem3.70356","url":null,"abstract":"<p><p>Relapse after chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL) is associated with a dismal prognosis. Although Phase 3 trials have established CAR T-cells as standard second-line (2L) therapy, outcomes and optimal management after relapse in this setting remain unknown because no real-world data are currently available. We conducted a multicenter retrospective study using the French DESCAR-T registry, including patients with LBCL who relapsed after 2L CAR T-cell therapy with axicabtagene ciloleucel or lisocabtagene maraleucel. The objective was to describe postrelapse treatments, outcomes, and prognostic factors. Among the 893 patients treated with 2L CAR T-cells, 297 (33%) relapsed and were analyzed. Median time to relapse was 2.7 months, with 35% of these relapses occurring within 2 months. Among the 231 treated patients, bispecific antibody (BsAb)-based regimens were the most common type of salvage therapy (65%). The overall response rate after relapse was 39.1%, with a complete response rate of 27.6%. Notably, despite the use of BsAb-based therapy in 65% of patients, the median overall survival (OS2) after relapse was only 6.5 months (median progression-free survival [PFS2]: 3.4 months). Patients treated with BsAb monotherapy achieved a median OS of 7.1 months. Multivariate analysis revealed that early relapse (<6 months), an Eastern Cooperative Oncology Group (ECOG) ≥ 2, and an elevated C-reactive protein (≥30 mg/L) were independently associated with poor OS. This study represents the first real-world analysis of outcomes after relapse following 2L CAR T-cell therapy. Despite the more frequent incorporation of BsAbs into the therapeutic landscape, overall prognosis and treatment efficacy remain dismal, highlighting the urgent need for innovative therapeutic strategies and dedicated prospective trials in this emerging double-refractory population.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 5","pages":"e70356"},"PeriodicalIF":14.6,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837430","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":"Dissecting minimal residual disease dynamics to improve outcome prediction in mantle cell lymphoma: Data from the Fondazione Italiana Linfomi (FIL)-MCL0208 clinical trial.","authors":"Francesca Cordero, Simone Ferrero, Simone Pernice, Elisa Genuardi, Daniela Volpatto, Roberta Sirovich, Aurora Maria Civita, Andrea Evangelista, Simone Ragaini, Alice Di Rocco, Alessandro Re, Vittorio Stefoni, Federica Cavallo, Carola Boccomini, Monica Balzarotti, Vittorio Ruggero Zilioli, Maria Gomes da Silva, Luca Arcaini, Melania Celli, Gian Maria Zaccaria, Dora Tortarolo, Marco Beccuti, Eva Hoster, Christiane Pott, Elizabeth Macintyre, Olivier Hermine, Martin Dreyling, Marco Ladetto","doi":"10.1002/hem3.70375","DOIUrl":"https://doi.org/10.1002/hem3.70375","url":null,"abstract":"<p><p>Recent clinical trials have underscored the value of repeated minimal residual disease (MRD) measurements as a highly sensitive method for detecting subclinical disease and enabling dynamic risk stratification in hematologic malignancies. Despite its clinical potential, the complex and heterogeneous nature of MRD kinetics presents significant challenges for interpreting and integrating it into routine clinical decision-making. In this study, we present a comprehensive, model-based workflow for the longitudinal analysis of MRD trajectories designed to improve relapse risk prediction. We applied this newly developed workflow to a cohort of patients with mantle cell lymphoma (MCL). MRD measurements were collected from both bone marrow (BM) and peripheral blood (PB) over time, stored in the Fondazione Italiana Linfomi MCL0208 clinical trial. Using our functional MRD workflow, we defined four MRD dynamics that collapsed into two clinically relevant groups: favorable (rapid, sustained negativization) and unfavorable (persistent or fluctuating MRD). Patients with unfavorable profiles showed significantly shorter time to progression (TTP), with hazard ratio (HR) = 4.18 (95% CI: 2.44-7.14) in BM and HR = 5.71 (95% CI: 2.86-11.42) in PB. External validation in the European MCL Network \"Younger trial\" confirmed the predictive power of this stratification, with Kaplan-Meier analyses demonstrating significant prognostic discrimination. The most informative temporal windows for patient clustering vary by tissue. Early-phase BM assessments offer greater discriminatory power, whereas late-phase assessments are most informative in PB. These findings indicate that longitudinal MRD assessment in PB represents a clinically actionable strategy that could reduce dependence on invasive BM procedures.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 ","pages":"e70375"},"PeriodicalIF":14.6,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13129670/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814576","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":"Chronic lymphocytic leukemia with <i>IGH</i>::<i>BCL3</i>-translocation is characterized by a homogeneous and distinct genetic and epigenetic landscape.","authors":"Cosima Drewes, Cristina López, Juan Emilio Martinez-Manjón, Nnamdi Okeke, Billy Jebaraj, Susanne Bens, Björn Brändl, Martin J S Dyer, Barbara Eichhorst, Anja Fischer, Kirsten Fischer, Sandra Robrecht, Michael Hallek, Selina Glaser, Sina Hillebrecht, Sandrine Jayne, Helene Kretzmer, Anja Mottok, Franz-Josef Müller, Christof Schneider, Ole Ammerpohl, Coral Del Val, Stephan Stilgenbauer, Eugen Tausch, Reiner Siebert","doi":"10.1002/hem3.70354","DOIUrl":"https://doi.org/10.1002/hem3.70354","url":null,"abstract":"<p><p>Approximately 1% of chronic lymphocytic leukemia (CLL) cases harbor a translocation juxtaposing the <i>immunoglobulin heavy chain</i> (<i>IGH</i>) and <i>B-cell lymphoma 3</i> (<i>BCL3</i>) loci. Aiming at comprehensive molecular characterization of <i>IGH</i>::<i>BCL3-</i>positive B-cell neoplasms, we here investigated samples from 84 patients using fluorescence in situ hybridization (FISH), whole-genome and targeted sequencing, and DNA methylation analyses. Junctional sequences obtained in 27 patients showed breakpoints upstream of <i>BCL3</i> in all CLL cases. <i>IGH</i> breaks were presumably driven by aberrant class-switch recombination in 26/27 cases, frequently involving <i>IGHA</i> (12/26). Notably, 95% (78/82) of patients carried an unmutated <i>IGHV</i> with significant CLL stereotype subset #8 enrichment. Trisomy 12 (61%, 51/83) and mutations affecting <i>NOTCH1</i> (32%, 25/79), <i>BRAF</i> (14%, 11/79), and <i>FBXW7</i> (14%, 11/79) were frequent aberrations. DNA methylation analysis assigned 77% (51/66) of patients with <i>IGH</i>::<i>BCL3-</i>translocation with at least 60% tumor cell content to the naive B-cell-like group but unraveled a distinct and during follow-up stable signature resembling in part plasma cell-like epigenetic features. A binary DNA methylation classifier using 20 CpGs could distinguish <i>IGH</i>::<i>BCL3</i>-translocated CLL samples from other CLL subtypes. In an efficacy cohort of 3832 previously untreated patients from GCLLSG trials, <i>IGH::BCL3</i> was associated with shorter progression-free survival (PFS) and overall survival (OS) in 28 patients when treated with chemoimmunotherapy, but not in those receiving venetoclax. Our findings highlight the genetic and epigenetic homogeneity of <i>IGH</i>::<i>BCL3</i>-translocated CLL samples and their differences from other types of CLL, suggesting <i>IGH</i>::<i>BCL3</i> leukemic B-cell neoplasms to be a biological distinct type within the spectrum of mature lymphatic leukemia/CLL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 5","pages":"e70354"},"PeriodicalIF":14.6,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13126245/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814528","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":"In vivo CAR therapies: Turning the patient into their own CAR factory.","authors":"François Vilcot, Carole-Anne Brugère, Jaime Fuentealba, Roch Houot","doi":"10.1002/hem3.70328","DOIUrl":"https://doi.org/10.1002/hem3.70328","url":null,"abstract":"<p><p>Over the past decade, ex vivo autologous chimeric antigen receptor (CAR)-T-cell therapies have reshaped the treatment of B-cell malignancies. Despite their remarkable clinical efficacy, their application remains limited by complex manufacturing processes, demanding logistics, long turnaround times, and substantial costs. In vivo CAR approaches are emerging as a potential solution to address these barriers by enabling direct induction of CAR expression in T cells and other immune cells through in-patient delivery of genetic constructs. This review provides an overview of the current landscape of in vivo CAR therapies. We describe the major delivery platforms under clinical development, with a focus on lentiviral vectors (LVVs) and lipid nanoparticles (LNPs), and discuss their distinct features in terms of manufacturing, mechanism of action, safety, therapeutic applications, and optimization strategies. We also summarize ongoing clinical trials exploring in vivo CAR approaches for hematologic malignancies, solid tumors, and autoimmune diseases. Finally, we highlight the key scientific and clinical challenges that remain, and examine strategies under investigation to overcome these limitations and advance in vivo CAR therapies toward broader clinical translation.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 5","pages":"e70328"},"PeriodicalIF":14.6,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13127696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814551","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":"Factors associated with response to rituximab in patients with immune thrombocytopenia.","authors":"Galina Tsykunova, Eskild Bendix Kristiansen, Tor Henrik Anderson Tvedt, Henrik Frederiksen, Christian Fynbo Christiansen, Marie Linder, Shahram Bahmanyar, Waleed Ghanima","doi":"10.1002/hem3.70373","DOIUrl":"https://doi.org/10.1002/hem3.70373","url":null,"abstract":"<p><p>Rituximab is a well-established treatment for adult immune thrombocytopenia (ITP), with ~60% initial response (IR) and 20%-30% long-term remissions. We conducted a register-based cohort study of 759 ITP patients in Sweden, Denmark, and Norway treated with rituximab (2009-2018) to identify factors associated with response. IR-platelet count ≥ 30 × 10⁹/L or ≥2-fold increase from baseline without bleeding and platelet-elevating therapy in the prior 8 weeks, assessed 3-6 months post-treatment-occurred in 66.3%. IR in non-pretreated patients (receiving rituximab as first-line therapy) was 65% and 67% in pretreated (second-line or later) patients. Response incidence rates were 1.67 (95% CI 1.32-2.08) and 1.77 (95% CI 1.60-1.95) per person-years, respectively. Median response duration was 5.4 years (interquartile range [IQR] 2.6; 7.4), and 1.9 (IQR 0.4; 5.4), respectively. Sustained response (SR)-platelet ≥ 30 × 10⁹/L without bleeding and platelet-elevating therapy after IR-was 53.3% at 2 years and 31.4% at 5 years. Across evaluated covariates, no clear associations with IR were observed, indicating similar short-term effectiveness across patient subgroups. Exploratory models identified inconsistent associations with comorbidity burden and corticosteroid co-administration in some strata. Achieving complete response (platelet ≥ 100 × 10⁹/L and absence of bleeding) at 6 months was the strongest predictor of SR at 2 years (risk ratio [RR] 3.87, 95% CI 2.95-5.12) and 5 years (RR 4.30; 95% CI 2.95-6.27). Of 83 patients re-treated after first relapse, 60% responded; among 19 re-treated after second relapse, 63% responded. Our findings confirm rituximab response rates in ITP and highlight complete IR as the strongest predictor of long-term outcomes.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 5","pages":"e70373"},"PeriodicalIF":14.6,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13123189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769827","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":"Correction to \"Posttransplantation clonal dynamics of hematopoietic stem cells carrying prenatal and early-life <i>DNMT3A</i> mutations\".","authors":"","doi":"10.1002/hem3.70365","DOIUrl":"https://doi.org/10.1002/hem3.70365","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.1002/hem3.70262.].</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":"e70365"},"PeriodicalIF":14.6,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13122108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770002","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":"A single <i>JAK2</i>-V617F hematopoietic stem cell can initiate myeloproliferative neoplasm when transplanted into non-conditioned recipient mice.","authors":"Quentin Kimmerlin, Morgane Hilpert, Nils Hansen, Alexandre Guy, Marc Usart, Jan Stetka, Patryk Sobieralski, Tiago Almeida Fonseca, Hui Hao-Shen, Radek C Skoda","doi":"10.1002/hem3.70359","DOIUrl":"https://doi.org/10.1002/hem3.70359","url":null,"abstract":"<p><p>Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells (HSCs) that are most frequently caused by acquired somatic mutations in <i>JAK2</i>. A number of conditional mouse models of <i>JAK2</i>-V617F-driven MPN have been generated that rely on Cre-LoxP-mediated activation, resulting in polyclonal disease. To more closely mimic the monoclonal origin of human MPN, transplantations of single purified <i>JAK2</i>-mutant HSCs or bone marrow (BM) at limiting dilutions into lethally irradiated recipient mice have been previously performed. However, irradiation is known to alter the BM microenvironment and also to induce transient aplasia accompanied by elevated cytokine levels that promote the expansion of the mutant clone. To overcome these limitations, we examined whether <i>JAK2-</i>V617F-mutant HSCs are able to engraft and initiate MPN in non-conditioned recipients. We found that BM from two different MPN models, one expressing the human <i>JAK2</i>-V617F, and another expressing the mouse <i>Jak2</i>-V617F, efficiently engrafted and initiated MPN in non-irradiated immunocompromised <i>Rag2</i> ^<i>-/-</i> recipients. MPN evolved even in transplantations at limiting dilutions, showing the high competitiveness of single <i>JAK2</i>-mutant HSCs. In contrast, BM from mice expressing the human <i>JAK2</i>-V617F failed to engraft in non-conditioned immunocompetent C57BL/6 mice, while BM from mice expressing the mouse <i>Jak2</i>-V617F engrafted and initiated MPN, suggesting that mouse JAK2-V617F protein, which differs from the endogenous JAK2 in only one amino acid, was tolerated. Our results show that <i>JAK2</i>-V617F mutant HSCs can outcompete resident non-mutated HSCs even in the absence of elevated cytokine levels and without the need of emptying stem cell niches by irradiation.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 5","pages":"e70359"},"PeriodicalIF":14.6,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13123196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769843","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":"Complement and transplant-associated thrombotic microangiopathy: Current and future approaches.","authors":"Massimo Cugno, Francesco Onida, Bernhard Lämmle","doi":"10.1002/hem3.70370","DOIUrl":"https://doi.org/10.1002/hem3.70370","url":null,"abstract":"","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":"e70370"},"PeriodicalIF":14.6,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13105240/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770045","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":"A microRNA expression signature in infant t(4;11) KMT2A::AFF1+ BCP-ALL uncovers novel therapeutic targets.","authors":"Camille Malouf, Alasdair Duguid, Kirsten S Vrenken, Tom Leah, Ragini Medhi, Giuseppina Camiolo, Leslie Nitsche, Hélène Jakobczyk, Rishi S Kotecha, Richard A Anderson, Neil A Barrett, Owen P Smith, Ronald W Stam, Katrin Ottersbach","doi":"10.1002/hem3.70353","DOIUrl":"https://doi.org/10.1002/hem3.70353","url":null,"abstract":"<p><p>Infants and children with KMT2A::AFF1+ leukemia have a dismal prognosis and are therefore in urgent need for more efficient and less aggressive therapy. In this study, we investigated three microRNAs that are downregulated in KMT2A::AFF1+ B-cell precursor acute lymphoblastic leukemia (BCP-ALL): miR-194, miR-99b, and miR-125a-5p. When overexpressed, all three microRNAs impaired the survival of KMT2A::AFF1+ leukemic blasts and the maintenance of KMT2A::AFF1+ BCP-ALL. We identified microRNA target genes responsible for this phenotype that are upregulated in KMT2A::AFF1+ BCP-ALL: CA5B, PPP3CA, and PPP2R5C. Importantly, using a drug-repurposing approach, we found that inhibition of CA5B, PPP3CA, and PP2A by acetazolamide, tacrolimus, and LB-100, respectively, showed high toxicity toward KMT2A::AFF1+ leukemic blasts and reduced leukemia burden in vivo. Furthermore, acetazolamide was able to prolong the survival of patient-derived xenotransplant models in combination with infant ALL induction therapy. This study highlights how the unique microRNA expression signature of patients with KMT2A::AFF1+ BCP-ALL can be used to uncover novel therapeutic avenues and accelerate drug repurposing. It also indicates potential new drug combinations for less toxic chemotherapy.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 4","pages":"e70353"},"PeriodicalIF":14.6,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13103725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147770031","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}