Pub Date : 2026-01-19DOI: 10.1038/s41375-025-02847-5
Delphine Rea, Slawomira Kyrcz-Krzemien, Paolo Sportoletti, Jiří Mayer, Arpad Illes, Anna Angona Figueras, Alexander Kiani, Aude Charbonnier, Theodoros Marinakis, Leif Stenke, Juan Luis Steegmann, Giuseppe Saglio, Andrzej Hellmann, Dietger Niederwieser, Peter Schuld, Gianantonio Rosti
The phase 3 ENESTPath study investigated treatment-free remission (TFR) rates in patients with chronic Philadelphia chromosome-positive (Ph+) and/or BCR::ABL1+ chronic myeloid leukemia who had not achieved deep molecular response (DMR) after >2 years of imatinib treatment and were switched to nilotinib 300 mg twice daily (BID). After 24 months of treatment, patients with a stable DMR were randomized to either enter the TFR phase (Arm 1) or continue nilotinib consolidation for an additional 12 months and then enter the TFR phase if in stable DMR (Arm 2). The primary endpoint was the proportion of patients who remained in TFR (≥MR4.0 [BCR::ABL1IS ≤ 0.01%]) without molecular relapse at the end of 12 months. Of the 620 patients enrolled, 239 (38.5%) achieved stable MR4.0 and were randomized to Arm 1 (n = 120) or Arm 2 (n = 119). In the TFR phase, MR4.0 rates at 12 months (Arm 1: 31.9%, Arm 2: 37.5%; p = 0.383) and 24 months (Arm 1: 29.4%, Arm 2: 30.8%) revealed no differences in TFR success between 2 and 3 years of nilotinib. Irrespective of the consolidation duration, switching to nilotinib 300 mg BID provided the opportunity to achieve TFR if patients were unable to reach stable DMR with first-line imatinib.
{"title":"Treatment-free remission after two nilotinib consolidation durations in chronic myeloid leukemia treated with imatinib: Phase 3 ENESTPath results.","authors":"Delphine Rea, Slawomira Kyrcz-Krzemien, Paolo Sportoletti, Jiří Mayer, Arpad Illes, Anna Angona Figueras, Alexander Kiani, Aude Charbonnier, Theodoros Marinakis, Leif Stenke, Juan Luis Steegmann, Giuseppe Saglio, Andrzej Hellmann, Dietger Niederwieser, Peter Schuld, Gianantonio Rosti","doi":"10.1038/s41375-025-02847-5","DOIUrl":"https://doi.org/10.1038/s41375-025-02847-5","url":null,"abstract":"<p><p>The phase 3 ENESTPath study investigated treatment-free remission (TFR) rates in patients with chronic Philadelphia chromosome-positive (Ph+) and/or BCR::ABL1<sup>+</sup> chronic myeloid leukemia who had not achieved deep molecular response (DMR) after >2 years of imatinib treatment and were switched to nilotinib 300 mg twice daily (BID). After 24 months of treatment, patients with a stable DMR were randomized to either enter the TFR phase (Arm 1) or continue nilotinib consolidation for an additional 12 months and then enter the TFR phase if in stable DMR (Arm 2). The primary endpoint was the proportion of patients who remained in TFR (≥MR<sup>4.0</sup> [BCR::ABL1<sup>IS</sup> ≤ 0.01%]) without molecular relapse at the end of 12 months. Of the 620 patients enrolled, 239 (38.5%) achieved stable MR<sup>4.0</sup> and were randomized to Arm 1 (n = 120) or Arm 2 (n = 119). In the TFR phase, MR<sup>4.0</sup> rates at 12 months (Arm 1: 31.9%, Arm 2: 37.5%; p = 0.383) and 24 months (Arm 1: 29.4%, Arm 2: 30.8%) revealed no differences in TFR success between 2 and 3 years of nilotinib. Irrespective of the consolidation duration, switching to nilotinib 300 mg BID provided the opportunity to achieve TFR if patients were unable to reach stable DMR with first-line imatinib.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146003636","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}
Aberrant activation of NF-κB transcription factors is a hallmark of human lymphomas. Most lymphoma-intrinsic as well as microenvironment-induced NF-κB activation occurs upstream of the key kinase IKK2, therefore affecting additional pathways. Here, we show that canonical NF-κB signaling in mouse B cells, induced through the expression of one or two copies of a constitutively active IKK2 variant, dose-dependently drives lymphomagenesis. The observed phenotype and stereotypic B cell receptor clonality resemble human small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL). Stronger IKK2 signaling drives early B1a cell expansion and uniform SLL/CLL-like lymphomagenesis, while intermediate signals cause more heterogeneous malignancies. Mechanistically, constitutive IKK2 signals provide a profound cell-intrinsic competitive advantage to B1a cells and dose-dependently synergize with TCL1 overexpression in driving aggressive CLL. Further, strong constitutive NF-κB activation overcomes critical microenvironmental dependencies of TCL1-driven lymphomas. Our findings establish canonical NF-κB as an oncogenic driver in lymphoma and reveal reduced microenvironment dependency as a key NF-κB-mediated mechanism, thus highlighting its therapeutic relevance.
{"title":"Strong constitutive NF-κB signaling in B cells drives SLL/CLL-like lymphomagenesis and overcomes microenvironmental dependencies.","authors":"Valeria Soberón,Lena Osswald,Andrew Moore,Dominika Sosnowska,Gene Swinerd,Jingyu Chen,Seren Baygün,Carina Diehl,Gönül Seyhan,Laura Kraus,Vanessa Gölling,Ricarda Trapp,Thomas J O'Neill,Sabrina Bortoluzzi,Daniel Kovacs,Tim Ammon,Pankaj Singroul,Yuliia Hubarzhevska,Rupert Öllinger,Sebastian Mueller,Olga Baranov,Piero Giansanti,Felix Gillhuber,Sonja Grath,Oliver Weigert,Andreas Rosenwald,Yoshiteru Sasaki,Klaus Rajewsky,Katja Steiger,Florian Bassermann,Roland Rad,Daniel Krappmann,Ingo Ringshausen,Marc Schmidt-Supprian","doi":"10.1038/s41375-025-02844-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02844-8","url":null,"abstract":"Aberrant activation of NF-κB transcription factors is a hallmark of human lymphomas. Most lymphoma-intrinsic as well as microenvironment-induced NF-κB activation occurs upstream of the key kinase IKK2, therefore affecting additional pathways. Here, we show that canonical NF-κB signaling in mouse B cells, induced through the expression of one or two copies of a constitutively active IKK2 variant, dose-dependently drives lymphomagenesis. The observed phenotype and stereotypic B cell receptor clonality resemble human small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL). Stronger IKK2 signaling drives early B1a cell expansion and uniform SLL/CLL-like lymphomagenesis, while intermediate signals cause more heterogeneous malignancies. Mechanistically, constitutive IKK2 signals provide a profound cell-intrinsic competitive advantage to B1a cells and dose-dependently synergize with TCL1 overexpression in driving aggressive CLL. Further, strong constitutive NF-κB activation overcomes critical microenvironmental dependencies of TCL1-driven lymphomas. Our findings establish canonical NF-κB as an oncogenic driver in lymphoma and reveal reduced microenvironment dependency as a key NF-κB-mediated mechanism, thus highlighting its therapeutic relevance.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"58 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986500","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}
KMT2A-rearranged infant leukaemia is one of the most severe malignancies in infants and children, and is characterised by a very aggressive phenotype and lineage plasticity. KMT2A::MLLT3 is among the most common translocations initiating leukaemia in infants, where it can manifest with a myeloid or lymphoid leukaemia phenotype. The cell-of-origin and the mechanisms driving lineage choice in KMT2A::MLLT3+ infant leukaemia are poorly understood. In this study, we show that a subset of foetal lymphoid-primed multipotent progenitors (LMPPs) expressing the Colony-Stimulating Factor 1 receptor (CSF1R) gives rise to acute myeloid leukaemia (AML) upon KMT2A::MLLT3 induction in a mouse model, with the myeloid phenotype, at least in part, being dependent on CSF1R signalling. In line with their leukaemia-propagating properties, KMT2A::MLLT3 + CSF1R+ LMPPs possess a stem cell-like and myeloid-biased expression signature and require autophagy to expand and form blast-like colonies in methylcellulose. Interrogation of public datasets confirms the existence of a human foetal-restricted CSF1R+ LMPP population at early stages of embryonic development. Finally, CSF1R inhibition on a KMT2A::MLLT3+ paediatric leukaemia cell line resulted in significant cell death, suggesting that CSF1R could be therapeutically targeted in these patients. Our findings suggest that KMT2A::MLLT3+ infant AML may originate from foetal liver CSF1R+ LMPPs, and that these patients may benefit from anti-CSF1R-CAR-T cell therapy.
kmt2a重排婴儿白血病是婴儿和儿童中最严重的恶性肿瘤之一，其特征是非常具有侵略性的表型和谱系可塑性。KMT2A::MLLT3是引发婴儿白血病最常见的易位之一，它可以表现为骨髓性或淋巴性白血病表型。KMT2A::MLLT3+婴儿白血病的细胞起源和驱动谱系选择的机制尚不清楚。在这项研究中，我们发现在小鼠模型中，表达集落刺激因子1受体（CSF1R）的胎儿淋巴细胞引发的多能祖细胞（lmpp）亚群在KMT2A::MLLT3诱导下引起急性髓系白血病（AML），髓系表型至少部分依赖于CSF1R信号传导。根据其白血病传播特性，KMT2A::MLLT3 + CSF1R+ lmpp具有干细胞样和骨髓偏倚的表达特征，需要自噬才能在甲基纤维素中扩增并形成blast样菌落。对公共数据集的调查证实，在胚胎发育的早期阶段存在人类胎儿限制性CSF1R+ LMPP群体。最后，CSF1R对KMT2A::MLLT3+儿科白血病细胞系的抑制导致了显著的细胞死亡，这表明CSF1R可能是这些患者的治疗靶点。我们的研究结果表明，KMT2A::MLLT3+婴儿AML可能起源于胎儿肝脏CSF1R+ lmpp，这些患者可能受益于抗CSF1R- car - t细胞治疗。
{"title":"CSF1R marks a subset of foetal haematopoietic multipotent progenitor cells with acute myeloid leukaemia propagation properties.","authors":"Giuseppina Camiolo,Daniel González Silvera,Tom Leah,Jürg Schwaller,Katrin Ottersbach","doi":"10.1038/s41375-025-02856-4","DOIUrl":"https://doi.org/10.1038/s41375-025-02856-4","url":null,"abstract":"KMT2A-rearranged infant leukaemia is one of the most severe malignancies in infants and children, and is characterised by a very aggressive phenotype and lineage plasticity. KMT2A::MLLT3 is among the most common translocations initiating leukaemia in infants, where it can manifest with a myeloid or lymphoid leukaemia phenotype. The cell-of-origin and the mechanisms driving lineage choice in KMT2A::MLLT3+ infant leukaemia are poorly understood. In this study, we show that a subset of foetal lymphoid-primed multipotent progenitors (LMPPs) expressing the Colony-Stimulating Factor 1 receptor (CSF1R) gives rise to acute myeloid leukaemia (AML) upon KMT2A::MLLT3 induction in a mouse model, with the myeloid phenotype, at least in part, being dependent on CSF1R signalling. In line with their leukaemia-propagating properties, KMT2A::MLLT3 + CSF1R+ LMPPs possess a stem cell-like and myeloid-biased expression signature and require autophagy to expand and form blast-like colonies in methylcellulose. Interrogation of public datasets confirms the existence of a human foetal-restricted CSF1R+ LMPP population at early stages of embryonic development. Finally, CSF1R inhibition on a KMT2A::MLLT3+ paediatric leukaemia cell line resulted in significant cell death, suggesting that CSF1R could be therapeutically targeted in these patients. Our findings suggest that KMT2A::MLLT3+ infant AML may originate from foetal liver CSF1R+ LMPPs, and that these patients may benefit from anti-CSF1R-CAR-T cell therapy.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"81 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-14DOI: 10.1038/s41375-025-02851-9
Alberto Hernández-Sánchez, Ángela Villaverde Ramiro, Eric Sträng, Amin T. Turki, María Abáigar, Jurjen Versluis, Ian Thomas, Marta Sobas, Javier Martínez Elicegui, Gastone Castellani, Axel Benner, Raúl Azibeiro, Jesse M. Tettero, Rabea Mecklenbrauck, Joaquín Martínez-López, Marta Pratcorona, Ken I. Mills, Guillermo Sanz, Maria Teresa Voso, Lehmann Sören, Christoph Röllig, Christian Thiede, Klaus H. Metzeler, Konstanze Döhner, Michael Heuser, Torsten Haferlach, Peter JM Valk, Nigel Russell, Jesús María Hernández-Rivas, Brian Huntly, Gert Ossenkoppele, Hartmut Döhner, Lars Bullinger
NPM1-mutated (NPM1-mut) acute myeloid leukemia (AML) is generally associated with a more favorable outcome, although the presence of additional gene mutations can influence patient prognosis. We analyzed intensively-treated adult NPM1-mut AML patients included in the HARMONY Alliance database. A newly developed risk classification, which included combinations of co-mutations in FLT3-ITD, DNMT3A, IDH1/IDH2, and TET2 genes, was applied to a training cohort of NPM1-mut AML patients included in clinical trials (n = 1001), an internal validation cohort more representative of real-world settings (n = 762), and an external validation cohort enrolled in UK-NCRI trials (n = 585). The HARMONY classification considered 51.8% of the NPM1-mut AML training cohort patients as favorable, 24.8% as intermediate, and 23.4% as adverse risk, with median overall survival (OS) of 14.4, 2.2, and 0.9 years, respectively; p < 0.001), thereby reclassifying 42.7% of NPM1-mut patients into a different European LeukemiaNet (ELN) 2022 risk category. These results were confirmed both in an internal and external validation cohort. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) showed the highest benefit in the NPM1-mut adverse-risk subgroup. The HARMONY classification provides the basis for a refined genetic risk stratification for adult NPM1-mut AML with potential clinical impact on allo-HSCT decision-making.
{"title":"Unravelling co-mutational patterns with prognostic implications in NPM1 mutated adult acute myeloid leukemia – a HARMONY study","authors":"Alberto Hernández-Sánchez, Ángela Villaverde Ramiro, Eric Sträng, Amin T. Turki, María Abáigar, Jurjen Versluis, Ian Thomas, Marta Sobas, Javier Martínez Elicegui, Gastone Castellani, Axel Benner, Raúl Azibeiro, Jesse M. Tettero, Rabea Mecklenbrauck, Joaquín Martínez-López, Marta Pratcorona, Ken I. Mills, Guillermo Sanz, Maria Teresa Voso, Lehmann Sören, Christoph Röllig, Christian Thiede, Klaus H. Metzeler, Konstanze Döhner, Michael Heuser, Torsten Haferlach, Peter JM Valk, Nigel Russell, Jesús María Hernández-Rivas, Brian Huntly, Gert Ossenkoppele, Hartmut Döhner, Lars Bullinger","doi":"10.1038/s41375-025-02851-9","DOIUrl":"10.1038/s41375-025-02851-9","url":null,"abstract":"NPM1-mutated (NPM1-mut) acute myeloid leukemia (AML) is generally associated with a more favorable outcome, although the presence of additional gene mutations can influence patient prognosis. We analyzed intensively-treated adult NPM1-mut AML patients included in the HARMONY Alliance database. A newly developed risk classification, which included combinations of co-mutations in FLT3-ITD, DNMT3A, IDH1/IDH2, and TET2 genes, was applied to a training cohort of NPM1-mut AML patients included in clinical trials (n = 1001), an internal validation cohort more representative of real-world settings (n = 762), and an external validation cohort enrolled in UK-NCRI trials (n = 585). The HARMONY classification considered 51.8% of the NPM1-mut AML training cohort patients as favorable, 24.8% as intermediate, and 23.4% as adverse risk, with median overall survival (OS) of 14.4, 2.2, and 0.9 years, respectively; p < 0.001), thereby reclassifying 42.7% of NPM1-mut patients into a different European LeukemiaNet (ELN) 2022 risk category. These results were confirmed both in an internal and external validation cohort. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) showed the highest benefit in the NPM1-mut adverse-risk subgroup. The HARMONY classification provides the basis for a refined genetic risk stratification for adult NPM1-mut AML with potential clinical impact on allo-HSCT decision-making.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"418-428"},"PeriodicalIF":13.4,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02851-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145968382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1038/s41375-025-02831-z
Valeria Santini, Amer M. Zeidan, Koen Van Eygen, Pierre Fenaux, Ulrich Germing, Yazan F. Madanat, Azra Raza, Michael R. Savona, Mikkael A. Sekeres, Sylvain Thépot, Marco G. Raddi, Thomas Boyer, Libo Sun, Ying Wan, Tymara Berry, Qi Xia, Fei Huang, Souria Dougherty, Shyamala Navada, Faye Feller, Rami S. Komrokji, Uwe Platzbecker
Existing treatments for lower-risk myelodysplastic syndromes/neoplasms (LR-MDS) focus on symptom relief. Until recently, altering the disease course was rarely considered a therapeutic objective. The first-in-class, direct, competitive telomerase inhibitor, imetelstat, demonstrated significantly higher rates of red blood cell (RBC) transfusion independence (TI) versus placebo in patients with non-del(5q), RBC transfusion-dependent LR-MDS who were relapsed/refractory to or ineligible for erythropoiesis-stimulating agents in the Phase 3 IMerge study (NCT02598661). In this exploratory analysis of IMerge, patients treated with imetelstat had greater sustained reductions in variant allele frequency of multiple mutations versus placebo recipients, which was positively associated with RBC-TI duration. Subsequent analyses showed that 70% of patients with a cytogenetic response with imetelstat achieved ≥1-year RBC-TI. Additionally, higher rates of ≥1-year RBC-TI were observed in patients with maximum variant allele frequency reduction of ≥50% in SF3B1 (58% vs. 7%), TET2 (90% vs. 9%), DNMT3A (100% vs. 13%), or ASXL1 (50% vs. 0%) and patients with ≥50% bone marrow ring sideroblast reduction (46% vs. 0%) versus patients who did not. Lastly, 60% of patients with ≥1-year RBC-TI had ≥50% reduction in telomerase activity/human telomerase reverse transcriptase RNA. These results suggest that imetelstat targets clonal progenitor cells and may modify LR-MDS biology.
现有的低风险骨髓增生异常综合征/肿瘤（LR-MDS）治疗侧重于症状缓解。直到最近，改变病程很少被认为是一种治疗目标。在IMerge iii期研究（NCT02598661）中，一流的直接、竞争性端粒酶抑制剂imetelstat在非del（5q）、红细胞输注依赖的lmds患者中显示出明显高于安慰剂的红细胞输注独立性（TI）率，这些患者复发/难治性或不适合使用促红细胞生成药物。在IMerge的探索性分析中，与安慰剂相比，接受伊美司他治疗的患者在多种突变的变异等位基因频率上有更大的持续降低，这与RBC-TI持续时间呈正相关。随后的分析显示，70%使用依美特司他获得细胞遗传学应答的患者达到了≥1年的RBC-TI。此外，在SF3B1 （58% vs. 7%）、TET2 （90% vs. 9%）、DNMT3A （100% vs. 13%）或ASXL1 （50% vs. 0%）中最大变异等位基因频率降低≥50%的患者，以及骨髓环铁细胞减少≥50%的患者（46% vs. 0%）中，≥1年的红细胞- ti发生率较高。最后，60%的≥1年RBC-TI患者端粒酶活性/人端粒酶逆转录酶RNA降低≥50%。这些结果表明，imetelstat靶向克隆祖细胞，并可能改变LR-MDS的生物学特性。
{"title":"Modulation of the clonal burden in patients with lower-risk myelodysplastic neoplasms treated with imetelstat","authors":"Valeria Santini, Amer M. Zeidan, Koen Van Eygen, Pierre Fenaux, Ulrich Germing, Yazan F. Madanat, Azra Raza, Michael R. Savona, Mikkael A. Sekeres, Sylvain Thépot, Marco G. Raddi, Thomas Boyer, Libo Sun, Ying Wan, Tymara Berry, Qi Xia, Fei Huang, Souria Dougherty, Shyamala Navada, Faye Feller, Rami S. Komrokji, Uwe Platzbecker","doi":"10.1038/s41375-025-02831-z","DOIUrl":"10.1038/s41375-025-02831-z","url":null,"abstract":"Existing treatments for lower-risk myelodysplastic syndromes/neoplasms (LR-MDS) focus on symptom relief. Until recently, altering the disease course was rarely considered a therapeutic objective. The first-in-class, direct, competitive telomerase inhibitor, imetelstat, demonstrated significantly higher rates of red blood cell (RBC) transfusion independence (TI) versus placebo in patients with non-del(5q), RBC transfusion-dependent LR-MDS who were relapsed/refractory to or ineligible for erythropoiesis-stimulating agents in the Phase 3 IMerge study (NCT02598661). In this exploratory analysis of IMerge, patients treated with imetelstat had greater sustained reductions in variant allele frequency of multiple mutations versus placebo recipients, which was positively associated with RBC-TI duration. Subsequent analyses showed that 70% of patients with a cytogenetic response with imetelstat achieved ≥1-year RBC-TI. Additionally, higher rates of ≥1-year RBC-TI were observed in patients with maximum variant allele frequency reduction of ≥50% in SF3B1 (58% vs. 7%), TET2 (90% vs. 9%), DNMT3A (100% vs. 13%), or ASXL1 (50% vs. 0%) and patients with ≥50% bone marrow ring sideroblast reduction (46% vs. 0%) versus patients who did not. Lastly, 60% of patients with ≥1-year RBC-TI had ≥50% reduction in telomerase activity/human telomerase reverse transcriptase RNA. These results suggest that imetelstat targets clonal progenitor cells and may modify LR-MDS biology.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"397-409"},"PeriodicalIF":13.4,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02831-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Individuals with history of chemo- or radiotherapy frequently exhibit somatic mosaicism in the blood, often involving mutations in genes responsible for DNA damage responses (DDR), such as CHEK2. However, the mechanisms by which CHEK2 mutations promote the expansion of mutant cells following chemo- or radiotherapy remain poorly understood. Here, we demonstrate that loss of CHEK2 confers resistance to chemotherapy in hematopoietic stem and progenitor cells (HSPCs). Through a CRISPR-based screen, we identified CHEK2 as a gene whose loss enhances resistance to cytotoxic chemotherapies. A complementary drug screen revealed that CHEK2-mutant cells are also resistant to DNA hypomethylating agents. Chek2-deficient HSPCs persist in vivo following chemotherapy exposure and exhibit elevated levels of DNA damage compared to wild-type cells. Our findings establish that CHEK2 loss promotes chemoresistance in HSPCs, offering new insights into the role of CHEK2 in therapy-related clonal hematopoiesis observed in cancer patients.
{"title":"CHEK2 loss endows chemotherapy resistance to hematopoietic stem cells.","authors":"Jing Zhou,Tianyuan Hu,Dian Li,Sanming Li,Minhua Li,Xiangguo Shi,Daisuke Nakada","doi":"10.1038/s41375-025-02850-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02850-w","url":null,"abstract":"Individuals with history of chemo- or radiotherapy frequently exhibit somatic mosaicism in the blood, often involving mutations in genes responsible for DNA damage responses (DDR), such as CHEK2. However, the mechanisms by which CHEK2 mutations promote the expansion of mutant cells following chemo- or radiotherapy remain poorly understood. Here, we demonstrate that loss of CHEK2 confers resistance to chemotherapy in hematopoietic stem and progenitor cells (HSPCs). Through a CRISPR-based screen, we identified CHEK2 as a gene whose loss enhances resistance to cytotoxic chemotherapies. A complementary drug screen revealed that CHEK2-mutant cells are also resistant to DNA hypomethylating agents. Chek2-deficient HSPCs persist in vivo following chemotherapy exposure and exhibit elevated levels of DNA damage compared to wild-type cells. Our findings establish that CHEK2 loss promotes chemoresistance in HSPCs, offering new insights into the role of CHEK2 in therapy-related clonal hematopoiesis observed in cancer patients.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"15 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1038/s41375-025-02857-3
Rohtesh S Mehta,Yosra M Aljawai,Partow Kebriaei,Gabriela Rondon,Warren Fingrut,Portia Smallbone,Betul Oran,Amanda Olson,Richard E Champlin,Elizabeth J Shpall
The prevailing fixed-hierarchy approach to donor selection for allogeneic hematopoietic cell transplantation (HCT) fails to capture critical interactions between donor age and type. We addressed this by analyzing 1713 adult recipients of matched related (MRD), matched unrelated (MUD), or haploidentical donors, receiving post-transplantation cyclophosphamide, using both regularized-Cox and XGBoost machine learning models. Our analysis revealed that the overall, independent association of donor age with survival was modest; however, its importance became pivotal within specific, context-dependent trade-offs. For example, while age-matched MRD and MUD were equivalent, a younger MUD was superior to an older MRD for elderly recipients. The survival advantage of MUD over haploidentical donors was consistent and magnified with increasing recipient age. We identified a non-linear relationship between baseline risk and the benefit of a matched versus a haploidentical donor; with the gain being maximal for intermediate-risk patients but attenuated in the highest-risk stratum. Our framework quantifies the gap that persists even between HLA-favorable haploidentical donors and matched donors. These findings provide a quantitative framework -the principles of which we have made explorable via an interactive web application -for a personalized, risk-adapted approach to donor selection. The clinical utility of this model must be confirmed in future validation studies.
{"title":"Modeling donor age and type trade-offs for personalized selection in allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide prophylaxis.","authors":"Rohtesh S Mehta,Yosra M Aljawai,Partow Kebriaei,Gabriela Rondon,Warren Fingrut,Portia Smallbone,Betul Oran,Amanda Olson,Richard E Champlin,Elizabeth J Shpall","doi":"10.1038/s41375-025-02857-3","DOIUrl":"https://doi.org/10.1038/s41375-025-02857-3","url":null,"abstract":"The prevailing fixed-hierarchy approach to donor selection for allogeneic hematopoietic cell transplantation (HCT) fails to capture critical interactions between donor age and type. We addressed this by analyzing 1713 adult recipients of matched related (MRD), matched unrelated (MUD), or haploidentical donors, receiving post-transplantation cyclophosphamide, using both regularized-Cox and XGBoost machine learning models. Our analysis revealed that the overall, independent association of donor age with survival was modest; however, its importance became pivotal within specific, context-dependent trade-offs. For example, while age-matched MRD and MUD were equivalent, a younger MUD was superior to an older MRD for elderly recipients. The survival advantage of MUD over haploidentical donors was consistent and magnified with increasing recipient age. We identified a non-linear relationship between baseline risk and the benefit of a matched versus a haploidentical donor; with the gain being maximal for intermediate-risk patients but attenuated in the highest-risk stratum. Our framework quantifies the gap that persists even between HLA-favorable haploidentical donors and matched donors. These findings provide a quantitative framework -the principles of which we have made explorable via an interactive web application -for a personalized, risk-adapted approach to donor selection. The clinical utility of this model must be confirmed in future validation studies.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"1 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1038/s41375-025-02859-1
Andreas Burchert, Franck E. Nicolini, Philipp le Coutre, Susanne Saussele, Andreas Hochhaus, Evin Tuere, Stephan K. Metzelder, Kim Pauck, Holger Garn, Hartmann Raifer, Magdalena Huber, Norbert Gattermann, Martina Crysandt, Philippe Schafhausen, Matthias Bormann, Markus P. Radsak, Agnès Guerci-Bresler, Thomas Illmer, Maria E. Goebeler, Peter Herhaus, Lino L. Teichmann, Georg-Nikolaus Franke, Fabian Lang, Stefan W. Krause, Robert Möhle, Martine Klausmann, Frank Stegelmann, Christoph Lutz, Gabriel Etienne, Andrea Stoltefuß, Joachim R. Göthert, Thomas Ernst, Maisun Abu-Samra, Heinz-Gert Höffkes, Andreas Neubauer, Ying Wang, Paul Weiland, Clara Otto, Lea Kiessler, Theresa Weber, Lea Kroning, Andrea Nist, Thorsten Stiewe, Rüdiger Hehlmann, Behnaz Aminossadati, Michael Wittenberg, Kerstin Winterstein, Thomas Oellerich, Marcus Lechner, Markus Pfirrmann, Carmen Schade-Brittinger, Paul Klemm, Christian Michel
Treatment-free remission (TFR) after discontinuation of ABL tyrosine kinase inhibitors (TKIs) is an important therapeutic goal in chronic myeloid leukemia (CML). Interferon-α (IFN) has been suggested to promote durable TFR. The phase 3 ENDURE trial (NCT03117816; EUDRA-CT 2016-001030-94) prospectively tested this hypothesis in patients with stable deep molecular remission after TKI therapy. A total of 203 patients were randomised 1:1 to receive ropeginterferon alfa-2b (ropeg-IFN; 100 µg subcutaneously every two weeks for 15 months, n = 95) or observation alone (n = 108) after TKI discontinuation. The primary endpoint was molecular relapse-free survival (MRFS), defined as time to loss of major molecular response (MMR) or death. At a median follow-up of 36 months, 25-month MRFS was 56% (95% confidence interval (CI), 45–66) with ropeg-IFN and 59% (95% CI, 49–68) with observation (hazard ratio (HR), 1.02; 95% CI, 0.68–1.55; P = 0.91). Among 83 patients with molecular data after TKI restart, 79 (95%) regained at least MMR, 78 within 12 months (median 3 months, interquartile range: 2-4 months). Ropeg-IFN was well tolerated (median administered dose of 92 µg, range 3–104), and no new safety signals were observed. Ropeg-IFN maintenance did not improve the probability of sustained TFR after TKI discontinuation.
{"title":"Randomized phase 3 trial of Ropeginterferon alfa-2b versus surveillance after tyrosine kinase inhibitor discontinuation in chronic myeloid leukemia (ENDURE/CML-IX)","authors":"Andreas Burchert, Franck E. Nicolini, Philipp le Coutre, Susanne Saussele, Andreas Hochhaus, Evin Tuere, Stephan K. Metzelder, Kim Pauck, Holger Garn, Hartmann Raifer, Magdalena Huber, Norbert Gattermann, Martina Crysandt, Philippe Schafhausen, Matthias Bormann, Markus P. Radsak, Agnès Guerci-Bresler, Thomas Illmer, Maria E. Goebeler, Peter Herhaus, Lino L. Teichmann, Georg-Nikolaus Franke, Fabian Lang, Stefan W. Krause, Robert Möhle, Martine Klausmann, Frank Stegelmann, Christoph Lutz, Gabriel Etienne, Andrea Stoltefuß, Joachim R. Göthert, Thomas Ernst, Maisun Abu-Samra, Heinz-Gert Höffkes, Andreas Neubauer, Ying Wang, Paul Weiland, Clara Otto, Lea Kiessler, Theresa Weber, Lea Kroning, Andrea Nist, Thorsten Stiewe, Rüdiger Hehlmann, Behnaz Aminossadati, Michael Wittenberg, Kerstin Winterstein, Thomas Oellerich, Marcus Lechner, Markus Pfirrmann, Carmen Schade-Brittinger, Paul Klemm, Christian Michel","doi":"10.1038/s41375-025-02859-1","DOIUrl":"10.1038/s41375-025-02859-1","url":null,"abstract":"Treatment-free remission (TFR) after discontinuation of ABL tyrosine kinase inhibitors (TKIs) is an important therapeutic goal in chronic myeloid leukemia (CML). Interferon-α (IFN) has been suggested to promote durable TFR. The phase 3 ENDURE trial (NCT03117816; EUDRA-CT 2016-001030-94) prospectively tested this hypothesis in patients with stable deep molecular remission after TKI therapy. A total of 203 patients were randomised 1:1 to receive ropeginterferon alfa-2b (ropeg-IFN; 100 µg subcutaneously every two weeks for 15 months, n = 95) or observation alone (n = 108) after TKI discontinuation. The primary endpoint was molecular relapse-free survival (MRFS), defined as time to loss of major molecular response (MMR) or death. At a median follow-up of 36 months, 25-month MRFS was 56% (95% confidence interval (CI), 45–66) with ropeg-IFN and 59% (95% CI, 49–68) with observation (hazard ratio (HR), 1.02; 95% CI, 0.68–1.55; P = 0.91). Among 83 patients with molecular data after TKI restart, 79 (95%) regained at least MMR, 78 within 12 months (median 3 months, interquartile range: 2-4 months). Ropeg-IFN was well tolerated (median administered dose of 92 µg, range 3–104), and no new safety signals were observed. Ropeg-IFN maintenance did not improve the probability of sustained TFR after TKI discontinuation.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"410-417"},"PeriodicalIF":13.4,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02859-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-08DOI: 10.1038/s41375-025-02845-7
Fanny Gonzales, Constanze Schneider, Gabriela Alexe, Shan Lin, Delan Khalid, Montserrat Alvarez, Allen Basanthakumar, Jana M. Ellegast, Lucy Merickel, Silvi Salhotra, Audrey Taillon, Mariateresa Giaimo, Mark Wunderlich, Marc Ansari, Jennifer A. Perry, Barbara Degar, Yana Pikman, Kimberly Stegmaier
CBFA2T3::GLIS2-positive pediatric acute myeloid leukemia (AML) remains one of the worst prognostic AML subgroups. To uncover innovative targeted therapy approaches in this disease subtype we performed genome-scale CRISPR-Cas9 screening that highlighted a strong, selective dependency on JAK2 compared to other types of cancer. Using a doxycycline-inducible JAK2 knockout (KO) system, we validated JAK2 dependency in CBFA2T3::GLIS2 cell lines, observing impaired proliferation in vitro and in vivo and apoptosis induction in vitro. Both type I (ruxolitinib) and type II (CHZ868) JAK2 inhibitors showed selective in vitro activity in CBFA2T3::GLIS2-positive AML models. To identify resistance and sensitizer mechanisms to JAK2 inhibitors, we used CRISPR-Cas9 ruxolitinib anchor screening in CBFA2T3::GLIS2 AML. sgRNAs targeting negative regulators of the MAPK pathway were enriched in the ruxolitinib-treated cells. Similarly, CBFA2T3::GLIS2 AML sublines grown to resistance under chronic ruxolitinib treatment expressed pathogenic NRAS mutations. Both approaches converged on MAPK pathway activation as a resistance mechanism to ruxolitinib treatment. Combining ruxolitinib with MEK inhibitors showed a synergistic effect in cell lines and patient-derived xenograft (PDX) cells expressing the fusion and in vivo activity in a CBFA2T3::GLIS2 AML PDX, suggesting a potential approach to target this signaling circuitry in this poor outcome AML subtype.
CBFA2T3:: glis2阳性的儿童急性髓性白血病（AML）仍然是预后最差的AML亚群之一。为了发现这种疾病亚型的创新靶向治疗方法，我们进行了基因组规模的CRISPR-Cas9筛选，与其他类型的癌症相比，突出了对JAK2的强烈选择性依赖。利用强力霉素诱导的JAK2敲除（KO）系统，我们验证了CBFA2T3::GLIS2细胞系对JAK2的依赖性，观察了体外和体内增殖受损以及体外诱导凋亡的情况。I型（ruxolitinib）和II型（CHZ868） JAK2抑制剂在CBFA2T3:: glis2阳性AML模型中均显示选择性体外活性。为了确定对JAK2抑制剂的耐药和增敏机制，我们在CBFA2T3::GLIS2 AML中使用CRISPR-Cas9 ruxolitinib锚点筛选。靶向MAPK通路负调节因子的sgrna在ruxolitinib处理的细胞中富集。同样，CBFA2T3::GLIS2 AML亚群在慢性ruxolitinib治疗下产生耐药性，表达致病性NRAS突变。两种方法都将MAPK通路激活作为对ruxolitinib治疗的耐药机制。ruxolitinib联合MEK抑制剂在表达CBFA2T3::GLIS2 AML PDX的融合和体内活性的细胞系和患者来源的异种移植物（PDX）细胞中显示出协同作用，这表明在这种预后不良的AML亚型中靶向这种信号通路的潜在方法。
{"title":"Identifying targeted therapies for CBFA2T3::GLIS2 acute myeloid leukemia","authors":"Fanny Gonzales, Constanze Schneider, Gabriela Alexe, Shan Lin, Delan Khalid, Montserrat Alvarez, Allen Basanthakumar, Jana M. Ellegast, Lucy Merickel, Silvi Salhotra, Audrey Taillon, Mariateresa Giaimo, Mark Wunderlich, Marc Ansari, Jennifer A. Perry, Barbara Degar, Yana Pikman, Kimberly Stegmaier","doi":"10.1038/s41375-025-02845-7","DOIUrl":"10.1038/s41375-025-02845-7","url":null,"abstract":"CBFA2T3::GLIS2-positive pediatric acute myeloid leukemia (AML) remains one of the worst prognostic AML subgroups. To uncover innovative targeted therapy approaches in this disease subtype we performed genome-scale CRISPR-Cas9 screening that highlighted a strong, selective dependency on JAK2 compared to other types of cancer. Using a doxycycline-inducible JAK2 knockout (KO) system, we validated JAK2 dependency in CBFA2T3::GLIS2 cell lines, observing impaired proliferation in vitro and in vivo and apoptosis induction in vitro. Both type I (ruxolitinib) and type II (CHZ868) JAK2 inhibitors showed selective in vitro activity in CBFA2T3::GLIS2-positive AML models. To identify resistance and sensitizer mechanisms to JAK2 inhibitors, we used CRISPR-Cas9 ruxolitinib anchor screening in CBFA2T3::GLIS2 AML. sgRNAs targeting negative regulators of the MAPK pathway were enriched in the ruxolitinib-treated cells. Similarly, CBFA2T3::GLIS2 AML sublines grown to resistance under chronic ruxolitinib treatment expressed pathogenic NRAS mutations. Both approaches converged on MAPK pathway activation as a resistance mechanism to ruxolitinib treatment. Combining ruxolitinib with MEK inhibitors showed a synergistic effect in cell lines and patient-derived xenograft (PDX) cells expressing the fusion and in vivo activity in a CBFA2T3::GLIS2 AML PDX, suggesting a potential approach to target this signaling circuitry in this poor outcome AML subtype.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"40 2","pages":"383-396"},"PeriodicalIF":13.4,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02845-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145919902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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