LeukemiaPub Date : 2025-05-28DOI: 10.1038/s41375-025-02646-y
Francesca Palandri, Massimo Breccia, Elena M. Elli, Roberto Latagliata, Giulia Benevolo, Erika Morsia, Mario Tiribelli, Francesco Cavazzini, Alessandra D’Addio, Alessia Tieghi, Mirko Farina, Fabrizio Cavalca, Alessandra Dedola, Florian H. Heidel, Giuseppe A. Palumbo, Elena Rossi, Filippo Branzanti, Valerio De Stefano
{"title":"Impact of ELN clinical signs and symptoms on the thrombotic risk in polycythemia vera patients treated with front-line hydroxyurea","authors":"Francesca Palandri, Massimo Breccia, Elena M. Elli, Roberto Latagliata, Giulia Benevolo, Erika Morsia, Mario Tiribelli, Francesco Cavazzini, Alessandra D’Addio, Alessia Tieghi, Mirko Farina, Fabrizio Cavalca, Alessandra Dedola, Florian H. Heidel, Giuseppe A. Palumbo, Elena Rossi, Filippo Branzanti, Valerio De Stefano","doi":"10.1038/s41375-025-02646-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02646-y","url":null,"abstract":"<p>The European LeukemiaNet recently proposed specific Clinical Signs and Symptoms (CSSs) that may trigger cytoreduction in patients with polycythemia vera (PV) at low thrombotic risk (LR). To evaluate the impact of CSSs on the thrombotic risk of patients at LR, high risk by age only (HR-AGE) or by previous thrombosis (HR-THRO), we conducted a multicenter cooperative study (NCT06134102) involving 739 PV patients treated with first-line hydroxyurea. At hydroxyurea start, 443 patients had at least one CSS. In patients with and without CSSs, the incidence rate ratio of thrombosis was 2.2 and 0.7 per 100 patient-years, respectively (<i>p</i> < 0.001), and the thrombosis-free survival (TFS) adjusted for delayed entry at 5 years was 88.7% and 96.1% (<i>p</i> < 0.001). The best 5-years TFS was observed in LR and HR-AGE with no CSSs (LR, 100%; HR-AGE: 98.1%). LR, HR-AGE patients with CSSs and HR-THRO patients without CSSs had comparable TFS (89.2%, 92.1% and 88.8%, respectively). TFS of HR-THRO patients was 80.2%. In multivariate analysis including each CSS, inadequate hematocrit control (HR: 2.32, <i>p</i> < 0.001), relevant CVRFs (HR: 2.87, <i>p</i> = 0.006), progressive splenomegaly (HR: 4.02, <i>p</i> = 0.03) and previous thrombosis (HR: 3.76, <i>p</i> < 0.001) remained significantly associated with thrombotic risk. CSSs identify an increased thrombotic risk phenotype across all risk categories.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"98 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153323","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-05-28DOI: 10.1038/s41375-025-02652-0
Jun Yan, Chunhua Shi, Guojun Yang, Ze Tian, Hiroki Torikai, Pariya Sukhumalchandra, Shaohua Peng, Edward Chang, Meng Cui, Celine Kerros, Anne Philips, Na Qiao, Mao Zhang, Timothy E. Lofton, Jason K. Allen, Michelle A. Gonzalez, Sathvik Patchametla, Anna Sergeeva, Lisa St. John, Helen He, Dongxing Zha, Jeffrey Molldrem, Gheath Alatrash
{"title":"T cell receptor mimic CAR T cells targeting cathepsin G signal peptide","authors":"Jun Yan, Chunhua Shi, Guojun Yang, Ze Tian, Hiroki Torikai, Pariya Sukhumalchandra, Shaohua Peng, Edward Chang, Meng Cui, Celine Kerros, Anne Philips, Na Qiao, Mao Zhang, Timothy E. Lofton, Jason K. Allen, Michelle A. Gonzalez, Sathvik Patchametla, Anna Sergeeva, Lisa St. John, Helen He, Dongxing Zha, Jeffrey Molldrem, Gheath Alatrash","doi":"10.1038/s41375-025-02652-0","DOIUrl":"https://doi.org/10.1038/s41375-025-02652-0","url":null,"abstract":"<p>There has been a been a paucity of immunotherapy targets in myeloid malignancies. We identified the HLA-A2 (A2)-restricted, cathepsin G (CG)-derived signal peptide, CG1, as a promising immunotherapeutic target. CG1 is presented by HLA-A2 in acute (AML) and chronic (CML) myeloid leukemia. We previously developed a T cell receptor-mimic antibody (TCR-m) that targets CG1/A2, engineered it into a bispecific T cell engager antibody, and demonstrated its safety and efficacy in AML and CML. In this study, we provide data for the engineering, preclinical efficacy, and safety of CG1/A2-targeting chimeric antigen receptor (CAR) T cells (CG1/A2-CAR T), which utilize the CG1/A2 TCR-m constructs. We show that the CG1/A2 TCR-m has high affinity for CG1/A2 monomers and CG1/A2-expressing leukemia, including HLA-A2<sup>+</sup> AML and CML. We demonstrate potent CG1/A2 CAR T killing of HLA-A2<sup>+</sup> AML and CML both in vitro and in vivo. Importantly, we found that CG1/A2-CAR T cells did not affect normal bone marrow hematopoiesis. These results validate signal peptides as immunotherapeutic targets and provide a foundation for the continued clinical development of CG1/A2-CAR T cells in AML and CML.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"171 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-05-28DOI: 10.1038/s41375-025-02656-w
Michelangelo Tesi, Francesco Pegoraro, Francesco Peyronel, Jean-François Emile, Francesco Catamerò, Matthew J. Koster, Gaurav Goyal, Matthew Collin, Paul Milne, Samia Boussouar, Fleur Cohen-Aubart, Matthias Papo, Zahir Amoura, Juvianee I. Estrada-Veras, Kevin O’Brien, Jerome Razanamahery, Radjiv Goulabchand, Ahmed Idbaih, Mathilde de Menthon, Noemie Gensous, Achille Aouba, Emmanuel Ledoult, Tanguy Le Scornet, Antoine Néel, Ronald S. Go, Roei D. Mazor, Corrado Campochiaro, Lorenzo Dagna, Eli L. Diamond, Augusto Vaglio, Julien Haroche
{"title":"Cluster analysis reveals the clinical spectrum of Erdheim-Chester disease","authors":"Michelangelo Tesi, Francesco Pegoraro, Francesco Peyronel, Jean-François Emile, Francesco Catamerò, Matthew J. Koster, Gaurav Goyal, Matthew Collin, Paul Milne, Samia Boussouar, Fleur Cohen-Aubart, Matthias Papo, Zahir Amoura, Juvianee I. Estrada-Veras, Kevin O’Brien, Jerome Razanamahery, Radjiv Goulabchand, Ahmed Idbaih, Mathilde de Menthon, Noemie Gensous, Achille Aouba, Emmanuel Ledoult, Tanguy Le Scornet, Antoine Néel, Ronald S. Go, Roei D. Mazor, Corrado Campochiaro, Lorenzo Dagna, Eli L. Diamond, Augusto Vaglio, Julien Haroche","doi":"10.1038/s41375-025-02656-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02656-w","url":null,"abstract":"<p>Erdheim-Chester disease (ECD) is a clonal-inflammatory neoplasm driven by mutations in MAPK pathway proto-oncogenes, such as <i>BRAF</i>. Clinical manifestations are protean, affecting virtually every system. This cohort study analyzed 661 patients with ECD to classify them based on clinical features and mutational profiles using unsupervised clustering. Nineteen clinical and mutational variables were subjected to hierarchical clustering combined with k-means. A three-cluster model emerged as the most stable. Most patients were classified according to key features, namely <i>BRAF</i><sup><i>V600E</i></sup> mutation, and large-vessel, heart, and perirenal involvement. The “Widespread Disease” (WID) cluster (320 patients, 49%) was associated with the presence of the key features and the “Limited Disease” (LIM) cluster (282 patients, 42%) was associated with their absence. The “<i>MAP2K1</i>-RDD” cluster (MAP) was assigned 59 patients (9%), based on <i>MAP2K1</i> mutation and/or overlapping Rosai-Dorfman-Destombes disease (RDD). Survival analysis revealed worse outcomes for WID compared to LIM (hazard ratio 1.54, 95% CI 1.09–2.17), while no significant survival difference was found for MAP. The identification of these clusters, based on mutational profiles, organ involvement and overlapping conditions, offers a data-driven validation of established clinical observations. These findings substantiate the role of the somatic mutation type in shaping the ECD phenotype.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"5 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144165411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-05-28DOI: 10.1038/s41375-025-02655-x
Yu Zhang, Zinan Feng, Jing Du, Hui Liu, Sijian Yu, Xinquan Liang, Weihua Zhao, Qing Zhang, Xiong Zhang, Danian Nie, Zhiqiang Sun, Xin Du, Xiaojun Xu, Guopan Yu, Pengcheng Shi, Qianwei Liu, Ruoyang Shao, Hong Qu, Wenjie Xiong, Shunqing Wang, Yirong Jiang, Hongyu Zhang, Ziwen Guo, Min Dai, Xuejie Jiang, Dan Xu, Fen Huang, Zhiping Fan, Na Xu, Can Liu, Meiqing Wu, Ren Lin, Hua Jin, Jing Sun, Qifa Liu, Li Xuan
{"title":"High-dose cytarabine with idarubicin consolidation for acute myeloid leukemia in first complete remission: a randomized controlled trial","authors":"Yu Zhang, Zinan Feng, Jing Du, Hui Liu, Sijian Yu, Xinquan Liang, Weihua Zhao, Qing Zhang, Xiong Zhang, Danian Nie, Zhiqiang Sun, Xin Du, Xiaojun Xu, Guopan Yu, Pengcheng Shi, Qianwei Liu, Ruoyang Shao, Hong Qu, Wenjie Xiong, Shunqing Wang, Yirong Jiang, Hongyu Zhang, Ziwen Guo, Min Dai, Xuejie Jiang, Dan Xu, Fen Huang, Zhiping Fan, Na Xu, Can Liu, Meiqing Wu, Ren Lin, Hua Jin, Jing Sun, Qifa Liu, Li Xuan","doi":"10.1038/s41375-025-02655-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02655-x","url":null,"abstract":"<p>Whether adding anthracycline to intermediate- or high-dose cytarabine as consolidation is beneficial remains unclear in acute myeloid leukemia (AML). Eligible AML patients in first complete remission were randomly assigned (1:1) to receive either high-dose cytarabine with idarubicin (IA3 + 3) (idarubicin 10 mg/m<sup>2</sup>, d1-3 and cytarabine 2 g/m<sup>2</sup>, every 12 h, d1-3) or high-dose cytarabine (HDAC) (cytarabine 3 g/m<sup>2</sup>, every 12 h, d1-3) regimens as first consolidation. The primary endpoint was the rate of negative measurable residual disease (MRD<sup>−</sup>) after first consolidation. Between November 2018 and December 2021, 407 patients were assigned to IA3 + 3 (<i>n</i> = 204) or HDAC (<i>n</i> = 203) groups. MRD<sup>−</sup> after first consolidation for IA3 + 3 and HDAC groups was 65.2% (95%CI: 58.6–71.8%) and 53.2% (46.3–60.1%) (<i>P</i> = 0.009). The 3-year cumulative incidence of relapse was 22.6% (95%CI :16.8–29.0%) and 34.0% (27.1–41.1%) (<i>P</i> = 0.014), DFS was 68.4% (61.5–75.3%) and 52.9% (45.4–60.5%) (<i>P</i> = 0.003), OS was 75.5% (69.0–82.1%) and 69.6% (62.4–76.7%) (<i>P</i> = 0.18) and treatment-related mortality was 8.8% (5.2–13.6%) and 13.0% (8.5–18.5%) (<i>P</i> = 0.23) in two groups, respectively. Eighty-seven (43%) and 114 (56%) patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), respectively (<i>P</i> = 0.006). IA3 + 3 regimen results in deeper remissions and reduces relapse compared to HDAC. This deeper remission improves DFS and translates into treatment advantage, with fewer patients undergoing allo-HSCT. (ClinicalTrials.gov, NCT03620955).</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"17 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144165412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-05-27DOI: 10.1038/s41375-025-02647-x
Shi Feng, Ran Kong, Cong Wang, Qingbo Hao, Xiaoyu Xie, Haiyang Wang, Jingjing Han, Yu Zhang, Jan Elsner, Derek Mendy, Michael Haughey, Paul Krenitsky, Veronique Plantevin-Krenitsky, Patrick Papa, Frank Mercurio, Weilin Xie, Xiangxiang Zhou
{"title":"A highly selective and orally bioavailable casein kinase 1 alpha degrader through p53 signaling pathway targets B-cell lymphoma cells","authors":"Shi Feng, Ran Kong, Cong Wang, Qingbo Hao, Xiaoyu Xie, Haiyang Wang, Jingjing Han, Yu Zhang, Jan Elsner, Derek Mendy, Michael Haughey, Paul Krenitsky, Veronique Plantevin-Krenitsky, Patrick Papa, Frank Mercurio, Weilin Xie, Xiangxiang Zhou","doi":"10.1038/s41375-025-02647-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02647-x","url":null,"abstract":"<p>The modest reduction in casein kinase 1 alpha (CK1α) by lenalidomide contributes to its clinical effectiveness in treating del(5q) myelodysplastic syndrome. However, the mechanism by which CK1α impacts lymphoma survival remains inadequately defined. We developed INNO-220, a CRBN-dependent CK1α degrader, by leveraging cytokine expression profiling in T cells. Unlike lenalidomide, INNO-220 is a highly selective and potent degrader of CK1α without affecting IKZF1/3. Screening across lymphoma cell lines revealed that cells harboring wild-type p53 and exhibiting constitutive NF-κB signaling were particularly sensitive to CK1α degradation yet resistant to Bruton tyrosine kinase inhibitors. Moreover, INNO-220 suppresses NF-κB signaling and activates p53 pathway, leading to complete inhibition of lymphoma tumor growth in vivo. Mechanistically, INNO-220 disrupts the assembly and function of the CARD11/BCL10/MALT1 complex, thereby inhibiting NF-κB signaling in stimulated T cells and lymphoma cells that harbor an activating mutation in CARD11. Moreover, we observed that activation of wild-type p53 upon INNO-220 treatment was sufficient to induce potent cancer cell death even in the absence of constitutive NF-κB activity. In summary, our findings introduce a selective CK1α degrader as a novel therapeutic approach for lymphoma, providing both mechanistic insights and a potential patient selection strategy in treating lymphoma and possibly other cancers.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"57 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144145584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-05-26DOI: 10.1038/s41375-025-02653-z
Arwa Bohra, Rafla Hassan, Saurabh Zanwar, Dragan Jevremovic, Horatiu Olteanu, Wilson I. Gonsalves, Gregory Otteson, Pedro Horna, S. Vincent Rajkumar, Shaji Kumar
{"title":"Peripheral Blood Flow Cytometry-based Definition of Plasma Cell Leukemia","authors":"Arwa Bohra, Rafla Hassan, Saurabh Zanwar, Dragan Jevremovic, Horatiu Olteanu, Wilson I. Gonsalves, Gregory Otteson, Pedro Horna, S. Vincent Rajkumar, Shaji Kumar","doi":"10.1038/s41375-025-02653-z","DOIUrl":"https://doi.org/10.1038/s41375-025-02653-z","url":null,"abstract":"<p><b>TO THE EDITOR:</b></p><p>Plasma cell leukemia (PCL), an aggressive form of MM, is defined by the International Myeloma Working Group (IMWG) as the presence of ≥5% circulating plasma cells (CPCs) in the peripheral blood [1]. Moreover, PCL cases are frequently enriched in the translocation t(11;14), which presents with a lympho-plasmacytoid morphology, complicating detection through standard morphological examination [2].</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"33 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144137061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-05-22DOI: 10.1038/s41375-025-02645-z
Vilma Dembitz, Sophie C. James, Paolo Gallipoli
{"title":"Targeting lipid metabolism in acute myeloid leukemia: biological insights and therapeutic opportunities","authors":"Vilma Dembitz, Sophie C. James, Paolo Gallipoli","doi":"10.1038/s41375-025-02645-z","DOIUrl":"https://doi.org/10.1038/s41375-025-02645-z","url":null,"abstract":"<p>Metabolic rewiring is a hallmark of malignant transformation in leukemic cells and the potential offered by its therapeutic targeting has garnered significant attention. The development of clinically relevant metabolic targeted therapies in acute myeloid leukemia (AML) has mostly focused on targeting mitochondrial energy production, but progress has been hampered by generalized toxicities. An alternative strategy is to shift the focus from targeting energy production to targeting more specialized metabolic functions, such as energy storage, the regulation of oxidative stress and availability of cofactors needed for the function of specific metabolic reactions. Lipid metabolism plays a role in many of these metabolic functions and its importance in AML maintenance and response to therapy is being increasingly recognized but needs to be adequately interpreted in the context of its interaction with the microenvironment, particularly the adipose niche. In this review, we provide an overview of our current understanding of AML cellular metabolic dependencies on fatty acid and lipid metabolism and discuss their relevance in the context of functional interactions with adipocytes. We highlight unresolved questions about how to best target lipid metabolism and suggest approaches needed to fully understand the interplay between malignant cells and their niche in the context of metabolic dependencies.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"57 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-05-22DOI: 10.1038/s41375-025-02549-y
Victoria Berg, Anna Lollies, Markus Schneider, Patricia Johansson, Marc A. Weniger, Emma Albertini, Fabio Facchetti, Stefano Ascani, Abubakar Moawia, Susanne Bens, Anja Fischer, Reiner Siebert, Wolfram Klapper, Luisa Lorenzi, Enrico Tiacci, Sylvia Hartmann, Bettina Budeus, Martin-Leo Hansmann, Ralf Küppers
{"title":"Common origin and somatic mutation patterns of composite lymphomas and leukemias","authors":"Victoria Berg, Anna Lollies, Markus Schneider, Patricia Johansson, Marc A. Weniger, Emma Albertini, Fabio Facchetti, Stefano Ascani, Abubakar Moawia, Susanne Bens, Anja Fischer, Reiner Siebert, Wolfram Klapper, Luisa Lorenzi, Enrico Tiacci, Sylvia Hartmann, Bettina Budeus, Martin-Leo Hansmann, Ralf Küppers","doi":"10.1038/s41375-025-02549-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02549-y","url":null,"abstract":"<p>When two lymphomas occur concurrently or sequentially in a patient, it is a major question whether they derive from the same lymphocyte or hematopoietic precursor cell or developed independently. We studied four composite classic Hodgkin lymphomas (HL) and other mature B-cell lymphomas, and two composite mature B- and T-cell neoplasias by whole exome sequencing (WES). Analysis of their IGV genes revealed that three composite B-cell lymphomas originated from common germinal center-experienced B cells. WES identified shared somatic mutations in the lymphomas of these clonally related composite lymphomas, indicating their derivation from a common, pre-malignant precursor. Most mutations were restricted to one or the other of these lymphomas, likely explaining how distinct lymphomas developed from a common ancestral B cell. In the two B-cell/T-cell lymphoma cases, and a composite clonally unrelated HL/chronic lymphocytic leukemia, the lymphoma partners did not share any somatic mutations. In three cases, we identified potentially oncogenic variants also in cells serving as constitutional controls. These variants may have contributed to development of a composite lymphoma/leukemia. We provide additional evidence of frequent clonal relation in composite lymphomas, highlight the multistep transformation process of related lymphomas with a likely pre-malignant intermediate common precursor, and support the importance of constitutional variants in lymphomagenesis.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"136 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"KK2845, a PBD dimer-containing antibody-drug conjugate targeting TIM-3-expressing AML","authors":"Jian Zou, Haruka Kinosada, Shin-ichiro Takayanagi, Toshihiko Ishii, Toru Amano, Kaito Nihira, Shohei Kanie, Maiko Adachi, Harunobu Tahara, Teppei Sakoda, Yoshikane Kikushige, Koichi Akashi, Hidetaka Satou","doi":"10.1038/s41375-025-02642-2","DOIUrl":"https://doi.org/10.1038/s41375-025-02642-2","url":null,"abstract":"<p>Acute myeloid leukemia (AML) is a common hematopoietic malignancy with high recurrence rates, and there is an urgent need for new therapeutic agents. T-cell immunoglobulin mucin-3 (TIM-3) is expressed on the surface of both LSCs and blasts in most AML patients, but not in normal hematopoietic stem cells (HSCs). We have developed KK2845, an antibody drug conjugate (ADC) that consists of an anti-TIM-3 fully human IgG1 antibody, a valine-alanine linker and a highly potent DNA cross-linking pyrrolobenzodiazepine (PBD) dimer SG3199. KK2845 exhibited potent cytotoxicity against AML cells both in vitro and in vivo. The cytotoxicity against AML cells was almost comparable between KK2845 and CD33-ADC, an anti-CD33 antibody conjugated with PBD dimer that has shown high remission rates in clinical studies. In addition to the cytotoxicity depending on PBD dimer, KK2845 also showed potent antibody-dependent cell cytotoxicity (ADCC) activity against AML cells. KK2845 showed less cytotoxicity against human normal bone marrow cells than CD33-ADC. The pharmacokinetics of KK2845 in cynomolgus monkey after intravenous infusion demonstrated a favorable profile. Taken together, these data suggest that KK2845 could be a novel ADC therapeutic in AML.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"32 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
LeukemiaPub Date : 2025-05-20DOI: 10.1038/s41375-025-02628-0
Gamze Tari Crochet, Selcen Ari-Yuka, Anja Fischer, Mohamed Chour, Alexis Claudel, Nouhoum Sako, Cyrielle Robe, Julie Naudet, Alexis Gonon, Diana Laure Mboumba, Nicolas Ortonne, Vincent Alcazer, Marie-Hélène Delfau-Larue, Reiner Siebert, Philippe Gaulard, François Lemonnier
{"title":"Induction of p53-mediated apoptosis by azacitidine in patient-derived xenograft follicular helper T-cell lymphoma model","authors":"Gamze Tari Crochet, Selcen Ari-Yuka, Anja Fischer, Mohamed Chour, Alexis Claudel, Nouhoum Sako, Cyrielle Robe, Julie Naudet, Alexis Gonon, Diana Laure Mboumba, Nicolas Ortonne, Vincent Alcazer, Marie-Hélène Delfau-Larue, Reiner Siebert, Philippe Gaulard, François Lemonnier","doi":"10.1038/s41375-025-02628-0","DOIUrl":"https://doi.org/10.1038/s41375-025-02628-0","url":null,"abstract":"<p>Follicular helper T-cell lymphoma (TFHL) is the most common non-cutaneous T-cell lymphoma in the Western world and is associated with a poor prognosis. Neoplastic cells rely heavily on the tumor microenvironment, demonstrated by the absence of TFHL-derived cell lines, which hinders therapeutic progress. To overcome this limitation, we developed and characterized patient-derived xenograft TFHL (TFHL-PDXs). Fifteen TFHLs were implanted into immunodeficient mice, generating nine PDXs. The tumor microenvironment was detected in the first passage but progressively disappeared in subsequent passages. <i>TET2</i> mutations persisted in all cases and TFHL-specific mutations were observed in most. The models were treated with azacitidine and patient sensitivity was fully recapitulated. To elucidate the mechanism of action of azacitidine, we analyzed the differences in DNA methylation and gene expression in six TFHL-PDX models. Global DNA hypomethylation occurred in azacitidine-treated cells in drug-sensitive models but not in the resistant ones. DNA hypomethylation was associated with global upregulation of gene expression, including that of various cancer-related pathways, suggestive of p53-pathway-mediated cytotoxicity. Overall, the PDXs recapitulated TFHL features and exhibited sensitivity to azacitidine. They also made it possible to decipher the mechanism responsible for the effect of azacitidine, revealing the activation of p53-mediated apoptosis associated with DNA hypomethylation.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"132 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144097101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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