Pub Date : 2025-09-16DOI: 10.1038/s41375-025-02769-2
Mikko Purhonen, Mikael Tatun, Katariina Luukkainen, Kevin Hung, Henri Sundquist, Oda Tafjord, Stina Söderlund, Shady Adnan-Awad, Anni Dohlen, Johanna Heikkinen, Perttu Koskenvesa, Sanna Siitonen, Satu Mustjoki, Naranie Shanmuganathan, Coral Bryce, Signe Danielsson, Henrik Hjorth-Hansen, Ulla Olsson-Strömberg, Takashi Kumagai, Shinya Kimura, David M. Ross, Oscar Brück
Treatment-free remission (TFR) has become a therapeutic objective for selected chronic-phase chronic myeloid leukemia (CP CML). However, no standardized biomarker is yet in clinical use. In this multi-center study, we explored the potential of bone marrow (BM) cytomorphology given its global accessibility and integral role in clinical diagnostics. We included diagnostic BM aspirate samples of 113 CP CML patients from seven clinical sites having attempted first TKI discontinuation. We digitized cytomorphological slides into 100x-magnified high-resolution images and analyzed these with deep learning-based image analysis. We profiled the BM cytomorphological fingerprint of CP CML patients and recapitulated the known granulocytic predominance and reduction of lymphoid, monocytic and erythroid cells in comparison to an extensive cohort of 942 control BM samples. We discovered neutrophil abundance and granulocytic maturation to associate with sustained TFR. We confirmed these visually and demonstrated their independent impact over known clinical factors. Our study underlines the potential of computational BM cytomorphology to identify novel clinical biomarkers and suggests that granulocytic expansion and maturation at diagnosis could reflect intrinsic disease pathology influencing TFR maintenance.
{"title":"Granulocyte abundance and maturation state at diagnosis predicts treatment-free remission in CML","authors":"Mikko Purhonen, Mikael Tatun, Katariina Luukkainen, Kevin Hung, Henri Sundquist, Oda Tafjord, Stina Söderlund, Shady Adnan-Awad, Anni Dohlen, Johanna Heikkinen, Perttu Koskenvesa, Sanna Siitonen, Satu Mustjoki, Naranie Shanmuganathan, Coral Bryce, Signe Danielsson, Henrik Hjorth-Hansen, Ulla Olsson-Strömberg, Takashi Kumagai, Shinya Kimura, David M. Ross, Oscar Brück","doi":"10.1038/s41375-025-02769-2","DOIUrl":"10.1038/s41375-025-02769-2","url":null,"abstract":"Treatment-free remission (TFR) has become a therapeutic objective for selected chronic-phase chronic myeloid leukemia (CP CML). However, no standardized biomarker is yet in clinical use. In this multi-center study, we explored the potential of bone marrow (BM) cytomorphology given its global accessibility and integral role in clinical diagnostics. We included diagnostic BM aspirate samples of 113 CP CML patients from seven clinical sites having attempted first TKI discontinuation. We digitized cytomorphological slides into 100x-magnified high-resolution images and analyzed these with deep learning-based image analysis. We profiled the BM cytomorphological fingerprint of CP CML patients and recapitulated the known granulocytic predominance and reduction of lymphoid, monocytic and erythroid cells in comparison to an extensive cohort of 942 control BM samples. We discovered neutrophil abundance and granulocytic maturation to associate with sustained TFR. We confirmed these visually and demonstrated their independent impact over known clinical factors. Our study underlines the potential of computational BM cytomorphology to identify novel clinical biomarkers and suggests that granulocytic expansion and maturation at diagnosis could reflect intrinsic disease pathology influencing TFR maintenance.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 12","pages":"2968-2977"},"PeriodicalIF":13.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02769-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068055","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 : 2025-09-15DOI: 10.1038/s41375-025-02767-4
Daniel Pollyea, Tessa Kerre, Dries Deeren, Yves Beguin, Tara L. Lin, David A. Sallman, Sebastien Anguille, William G. Blum, Anne Flament, Eytan Breman, Caroline Lonez
The NKG2D receptor binds eight ligands (NKG2DL) overexpressed in a wide range of malignancies, but largely absent on non-neoplastic cells. Initial clinical evaluation of NKG2DL chimeric antigen receptor (CAR) T-cells (CYAD-01) in patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) or myelodysplastic neoplasia (MDS) demonstrated low durability of responses and short cell persistence. Two Phase I trials were initiated to evaluate the effect of lymphodepletion prior to a single CAR T-cell infusion in a similar r/r AML/MDS patient population. The DEPLETHINK trial (NCT03466320) evaluated CYAD-01 while the CYCLE-1 trial (NCT04167696) evaluated a next-generation NKG2DL CAR, CYAD-02, where the two main NKG2D ligands MICA and B are downregulated, to increase CAR T-cell persistence. Seventeen and twelve patients were treated in the DEPLETHINK and CYCLE-1 trials, and confirmed the good tolerability of both products with cytokine release syndrome (CRS) grade 3 or 4 reported in 25% and 33.3% of patients, respectively. CYAD-02 presented an higher engraftment and an improved clinical activity (17% objective response rate) compared to CYAD-01 (no objective response). Altogether, our data provide proof of principle that knock-down of MICA/B can enhance CAR T-cell persistence and efficacy while maintaining a good safety profile.
{"title":"Downregulation of MICA/MICB improves cell persistence and clinical activity of NKG2DL CAR T-cells in patients with relapsed or refractory acute myeloid leukemia or myelodysplastic neoplasia","authors":"Daniel Pollyea, Tessa Kerre, Dries Deeren, Yves Beguin, Tara L. Lin, David A. Sallman, Sebastien Anguille, William G. Blum, Anne Flament, Eytan Breman, Caroline Lonez","doi":"10.1038/s41375-025-02767-4","DOIUrl":"10.1038/s41375-025-02767-4","url":null,"abstract":"The NKG2D receptor binds eight ligands (NKG2DL) overexpressed in a wide range of malignancies, but largely absent on non-neoplastic cells. Initial clinical evaluation of NKG2DL chimeric antigen receptor (CAR) T-cells (CYAD-01) in patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) or myelodysplastic neoplasia (MDS) demonstrated low durability of responses and short cell persistence. Two Phase I trials were initiated to evaluate the effect of lymphodepletion prior to a single CAR T-cell infusion in a similar r/r AML/MDS patient population. The DEPLETHINK trial (NCT03466320) evaluated CYAD-01 while the CYCLE-1 trial (NCT04167696) evaluated a next-generation NKG2DL CAR, CYAD-02, where the two main NKG2D ligands MICA and B are downregulated, to increase CAR T-cell persistence. Seventeen and twelve patients were treated in the DEPLETHINK and CYCLE-1 trials, and confirmed the good tolerability of both products with cytokine release syndrome (CRS) grade 3 or 4 reported in 25% and 33.3% of patients, respectively. CYAD-02 presented an higher engraftment and an improved clinical activity (17% objective response rate) compared to CYAD-01 (no objective response). Altogether, our data provide proof of principle that knock-down of MICA/B can enhance CAR T-cell persistence and efficacy while maintaining a good safety profile.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 12","pages":"2907-2915"},"PeriodicalIF":13.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02767-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059612","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 : 2025-09-15DOI: 10.1038/s41375-025-02771-8
Damia Romero-Moya, Eric Torralba-Sales, Cristina Calvo, Oskar Marin-Bejar, Maria Magallon-Mosella, Maximiliano Distefano, Joan Pera, Julio Castaño, Francesca De Giorgio, Jessica Gonzalez, Arnau Iglesias, Clara Berenguer-Balaguer, Marcel Schilling, Mireya Plass, Lorenzo Pasquali, Albert Català, Oscar Molina, Marcin W. Wlodarski, Anna Bigas, Alessandra Giorgetti
GATA2 deficiency is a monogenic transcriptopathy disorder characterized by bone marrow failure (BMF), immunodeficiency, and a high risk of developing myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Although informative mouse models have been developed, the mechanisms by which GATA2 haploinsufficiency drives disease initiation in humans remain incompletely understood. To address this, we developed a novel humanized model using CRISPR/Cas9 technology to knock-in GATA2-R398W variant in primary cord blood CD34⁺ cells. Additionally, we introduced specific mutations in SETBP1 and ASXL1 to model distinct premalignant stages of GATA2 deficiency. Through clonal competition and serial transplantation assays, we demonstrated that human CD34+ cells harboring the GATA2 mutation exhibit significantly reduced fitness in vivo when compete with wild-type cells. Notably, this fitness disadvantage persists even when GATA2 mutations are combined with oncogenic SETBP1 and ASXL1 drivers, underscoring the dominant, deleterious effect of GATA2 deficiency on hematopoietic stem cell function. Functional in vitro analyses revealed that GATA2-R398W mutation impairs cell proliferation, disrupts cell cycle progression, and induces mitotic defects, which may contribute to hematopoietic stem/progenitor cell loss and impaired self-renewal. Transcriptomic profiles of GATA2-mutant cells revealed that these functional defects are associated with reduced HSC self-renewal capacity and upregulation of the pre-aging phenotype. Our work highlights the feasibility of generating a human GATA2 deficiency model suitable for studying the biological consequences of various GATA2 variants and the generation of a platform to test potential phenotype-rescuing therapeutics.
{"title":"CRISPR-engineered human GATA2 deficiency model uncovers mitotic dysfunction and premature aging in HSPCs, impairing hematopoietic fitness","authors":"Damia Romero-Moya, Eric Torralba-Sales, Cristina Calvo, Oskar Marin-Bejar, Maria Magallon-Mosella, Maximiliano Distefano, Joan Pera, Julio Castaño, Francesca De Giorgio, Jessica Gonzalez, Arnau Iglesias, Clara Berenguer-Balaguer, Marcel Schilling, Mireya Plass, Lorenzo Pasquali, Albert Català, Oscar Molina, Marcin W. Wlodarski, Anna Bigas, Alessandra Giorgetti","doi":"10.1038/s41375-025-02771-8","DOIUrl":"10.1038/s41375-025-02771-8","url":null,"abstract":"GATA2 deficiency is a monogenic transcriptopathy disorder characterized by bone marrow failure (BMF), immunodeficiency, and a high risk of developing myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). Although informative mouse models have been developed, the mechanisms by which GATA2 haploinsufficiency drives disease initiation in humans remain incompletely understood. To address this, we developed a novel humanized model using CRISPR/Cas9 technology to knock-in GATA2-R398W variant in primary cord blood CD34⁺ cells. Additionally, we introduced specific mutations in SETBP1 and ASXL1 to model distinct premalignant stages of GATA2 deficiency. Through clonal competition and serial transplantation assays, we demonstrated that human CD34+ cells harboring the GATA2 mutation exhibit significantly reduced fitness in vivo when compete with wild-type cells. Notably, this fitness disadvantage persists even when GATA2 mutations are combined with oncogenic SETBP1 and ASXL1 drivers, underscoring the dominant, deleterious effect of GATA2 deficiency on hematopoietic stem cell function. Functional in vitro analyses revealed that GATA2-R398W mutation impairs cell proliferation, disrupts cell cycle progression, and induces mitotic defects, which may contribute to hematopoietic stem/progenitor cell loss and impaired self-renewal. Transcriptomic profiles of GATA2-mutant cells revealed that these functional defects are associated with reduced HSC self-renewal capacity and upregulation of the pre-aging phenotype. Our work highlights the feasibility of generating a human GATA2 deficiency model suitable for studying the biological consequences of various GATA2 variants and the generation of a platform to test potential phenotype-rescuing therapeutics.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 12","pages":"3015-3025"},"PeriodicalIF":13.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02771-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059611","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 : 2025-09-15DOI: 10.1038/s41375-025-02745-w
E. Onur Karakaslar, Eva M. Argiro, Nadine E. Struckman, Ramin Shirali HZ, Jeppe F. Severens, M. Willy Honders, Susan L. Kloet, Hendrik Veelken, Marcel JT Reinders, Marieke Griffioen, Erik B. van den Akker
NPM1-mutated AML is one of the largest entities in international classification systems of myeloid neoplasms, which are based on integrating morphologic and clinical data with genomic data. Previous research, however, indicates that bulk transcriptomics-based subtyping may improve prognostication and therapy guidance. Here, we characterized the heterogeneity in NPM1-mutated AML by performing single-cell RNA-sequencing and spectral flow cytometry on 16 AML belonging to three distinct subtypes previously identified by bulk transcriptomics. Using single-cell expression profiling we generated a comprehensive atlas of NPM1-mutated AML, collectively reconstituting complete myelopoiesis. The three NPM1-mutated transcriptional subtypes showed consistent differences in the proportions of myeloid cell clusters with distinct patterns in lineage commitment and maturational arrest. In all samples, leukemic cells were detected across different myeloid cell clusters, indicating that NPM1-mutated AML are heavily skewed but not fully arrested in myelopoiesis. Same-sample multi-color spectral flow cytometry recapitulated these skewing patterns, indicating that the three NPM1-mutated subtypes can be consistently identified across platforms. Moreover, our analyses highlighted differences in the abundance of rare hematopoietic stem cells suggesting that skewing occurs early in myelopoiesis. To conclude, by harnessing single-cell RNA-sequencing and spectral flow cytometry, we provide a detailed description of three distinct and reproducible patterns in lineage skewing in NPM1-mutated AML that may have potential relevance for prognosis and treatment of patients with NPM1-mutated AML.
{"title":"Resolving inter- and intra-patient heterogeneity in NPM1-mutated AML at single-cell resolution","authors":"E. Onur Karakaslar, Eva M. Argiro, Nadine E. Struckman, Ramin Shirali HZ, Jeppe F. Severens, M. Willy Honders, Susan L. Kloet, Hendrik Veelken, Marcel JT Reinders, Marieke Griffioen, Erik B. van den Akker","doi":"10.1038/s41375-025-02745-w","DOIUrl":"10.1038/s41375-025-02745-w","url":null,"abstract":"NPM1-mutated AML is one of the largest entities in international classification systems of myeloid neoplasms, which are based on integrating morphologic and clinical data with genomic data. Previous research, however, indicates that bulk transcriptomics-based subtyping may improve prognostication and therapy guidance. Here, we characterized the heterogeneity in NPM1-mutated AML by performing single-cell RNA-sequencing and spectral flow cytometry on 16 AML belonging to three distinct subtypes previously identified by bulk transcriptomics. Using single-cell expression profiling we generated a comprehensive atlas of NPM1-mutated AML, collectively reconstituting complete myelopoiesis. The three NPM1-mutated transcriptional subtypes showed consistent differences in the proportions of myeloid cell clusters with distinct patterns in lineage commitment and maturational arrest. In all samples, leukemic cells were detected across different myeloid cell clusters, indicating that NPM1-mutated AML are heavily skewed but not fully arrested in myelopoiesis. Same-sample multi-color spectral flow cytometry recapitulated these skewing patterns, indicating that the three NPM1-mutated subtypes can be consistently identified across platforms. Moreover, our analyses highlighted differences in the abundance of rare hematopoietic stem cells suggesting that skewing occurs early in myelopoiesis. To conclude, by harnessing single-cell RNA-sequencing and spectral flow cytometry, we provide a detailed description of three distinct and reproducible patterns in lineage skewing in NPM1-mutated AML that may have potential relevance for prognosis and treatment of patients with NPM1-mutated AML.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 12","pages":"2916-2925"},"PeriodicalIF":13.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02745-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059610","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 : 2025-09-12DOI: 10.1038/s41375-025-02758-5
Jack Bakewell, Anthony V. Moorman, Sarra L. Ryan
The DUX4 gene, located within repetitive subtelomeric arrays on chromosomes 4 and 10, plays a critical role in early embryogenesis and has been implicated in several human diseases, including facioscapulohumeral muscular dystrophy (FSHD) and cancer. In B-cell acute lymphoblastic leukemia (B-ALL), DUX4 rearrangements (DUX4-r) define a distinct genomic subtype affecting 5–10% of cases, which is more frequent among older children and teenagers. These rearrangements produce truncated DUX4 proteins with neomorphic transcriptional activity, resulting in aberrant gene expression programs and alternative splicing that disrupt normal B-cell precursor development. Patients with DUX4-r B-ALL often present with poor initial treatment responses, though they typically achieve excellent long-term survival rates with intensive chemotherapy regimens. The cryptic nature of DUX4 rearrangements has historically posed significant challenges to accurate detection, but recent advancements in next-generation sequencing technologies, including RNA and long-read sequencing, and improved immunophenotyping strategies—such as the use of CD371 as a surrogate marker—are enhancing diagnostic accuracy. This review explores the genetic and biological features of DUX4 and its rearrangements, shedding light on their role in leukemogenesis and associated clinical outcomes. Additionally, we highlight emerging technologies that enable the detection of DUX4-r and discuss their implications for clinical use and research. An improved understanding of DUX4 biology and its oncogenic potential may pave the way for novel treatment strategies, ultimately improving outcomes for patients with DUX4-r B-ALL.
{"title":"DUX4-rearranged B-ALL: deciphering a biological and clinical conundrum","authors":"Jack Bakewell, Anthony V. Moorman, Sarra L. Ryan","doi":"10.1038/s41375-025-02758-5","DOIUrl":"10.1038/s41375-025-02758-5","url":null,"abstract":"The DUX4 gene, located within repetitive subtelomeric arrays on chromosomes 4 and 10, plays a critical role in early embryogenesis and has been implicated in several human diseases, including facioscapulohumeral muscular dystrophy (FSHD) and cancer. In B-cell acute lymphoblastic leukemia (B-ALL), DUX4 rearrangements (DUX4-r) define a distinct genomic subtype affecting 5–10% of cases, which is more frequent among older children and teenagers. These rearrangements produce truncated DUX4 proteins with neomorphic transcriptional activity, resulting in aberrant gene expression programs and alternative splicing that disrupt normal B-cell precursor development. Patients with DUX4-r B-ALL often present with poor initial treatment responses, though they typically achieve excellent long-term survival rates with intensive chemotherapy regimens. The cryptic nature of DUX4 rearrangements has historically posed significant challenges to accurate detection, but recent advancements in next-generation sequencing technologies, including RNA and long-read sequencing, and improved immunophenotyping strategies—such as the use of CD371 as a surrogate marker—are enhancing diagnostic accuracy. This review explores the genetic and biological features of DUX4 and its rearrangements, shedding light on their role in leukemogenesis and associated clinical outcomes. Additionally, we highlight emerging technologies that enable the detection of DUX4-r and discuss their implications for clinical use and research. An improved understanding of DUX4 biology and its oncogenic potential may pave the way for novel treatment strategies, ultimately improving outcomes for patients with DUX4-r B-ALL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 12","pages":"2835-2847"},"PeriodicalIF":13.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02758-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035224","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 : 2025-09-12DOI: 10.1038/s41375-025-02762-9
Lærke Sloth Andersen, Ricardo Berenguer Navarro, Sara Ekberg, Sæmundur Rögnvaldsson, Marína Rós Levy, Ingigerður Sólveig Sverrisdóttir, Brynjar Viðarsson, Páll Torfi Önundarson, Bjarni A. Agnarsson, Margrét Sigurðardóttir, Ingunn Þorsteinsdóttir, Ísleifur Ólafsson, Ásdís Rósa Þórðardóttir, Elías Eyþórsson, Ásbjörn Jónsson, Andri Ólafsson, Brian G. M. Durie, Stephen Harding, Ola Landgren, Thorvardur Jón Löve, Sigurður Yngvi Kristinsson, Sigrún Thorsteinsdóttir
Infections are a major cause of morbidity and mortality in multiple myeloma (MM). While increased infection risk has been shown in monoclonal gammopathy of undetermined significance (MGUS), data are limited for smoldering multiple myeloma (SMM). We used data from the iStopMM study, which screened 75,422 Icelandic individuals aged ≥40 years for MM precursors. Individuals diagnosed with SMM were matched by age and sex with MGUS-free comparators (1:5 ratio) and with individuals with MGUS (1:1 ratio). Infection outcomes were derived from nationwide registries of ICD-10 diagnostic codes and antimicrobial prescriptions. Cox proportional hazards models estimated infection risk, adjusted for immunoparesis. 188 SMM individuals were matched to 188 MGUS individuals and 162 SMM individuals were matched to 810 comparators. Individuals with SMM had significantly more infections (HR 1.36, 95% CI 1.07–1.73) and antibacterial prescriptions (HR 1.24, 95% CI 1.01–1.52) than the comparators. Compared to MGUS, individuals with SMM also had more infections (HR 1.37, 95% CI 1.00–1.87). Adjusting for immunoparesis attenuated the associations, suggesting it may partially mediate infection risk. This first screened cohort of SMM shows a significantly increased infection risk, compared to both MGUS and to individuals without MM precursors, suggesting an underrecognized infection burden in SMM.
感染是多发性骨髓瘤（MM）发病和死亡的主要原因。虽然未确定意义的单克隆γ病（MGUS）显示感染风险增加，但阴燃型多发性骨髓瘤（SMM）的数据有限。我们使用来自iStopMM研究的数据，该研究筛选了75,422名年龄≥40岁的冰岛人的MM前体。诊断为SMM的个体按年龄和性别与无MGUS比较者（1:5）和患有MGUS的个体（1:1）匹配。感染结果来源于ICD-10诊断代码和抗菌药物处方的全国登记。Cox比例风险模型估计感染风险，调整免疫麻痹。188个SMM个体与188个MGUS个体相匹配，162个SMM个体与810个比较个体相匹配。SMM患者的感染（HR 1.36, 95% CI 1.07-1.73）和抗菌药物处方（HR 1.24, 95% CI 1.01-1.52）明显高于对照组。与MGUS相比，SMM个体也有更多的感染（HR 1.37, 95% CI 1.00-1.87）。调整免疫轻瘫减弱了这种关联，表明免疫轻瘫可能部分介导感染风险。与MGUS和没有MM前体的个体相比，首次筛选的SMM队列显示感染风险显着增加，这表明SMM的感染负担未被充分认识。
{"title":"Increased risk of infections in smoldering multiple myeloma: results from the screened iStopMM study","authors":"Lærke Sloth Andersen, Ricardo Berenguer Navarro, Sara Ekberg, Sæmundur Rögnvaldsson, Marína Rós Levy, Ingigerður Sólveig Sverrisdóttir, Brynjar Viðarsson, Páll Torfi Önundarson, Bjarni A. Agnarsson, Margrét Sigurðardóttir, Ingunn Þorsteinsdóttir, Ísleifur Ólafsson, Ásdís Rósa Þórðardóttir, Elías Eyþórsson, Ásbjörn Jónsson, Andri Ólafsson, Brian G. M. Durie, Stephen Harding, Ola Landgren, Thorvardur Jón Löve, Sigurður Yngvi Kristinsson, Sigrún Thorsteinsdóttir","doi":"10.1038/s41375-025-02762-9","DOIUrl":"10.1038/s41375-025-02762-9","url":null,"abstract":"Infections are a major cause of morbidity and mortality in multiple myeloma (MM). While increased infection risk has been shown in monoclonal gammopathy of undetermined significance (MGUS), data are limited for smoldering multiple myeloma (SMM). We used data from the iStopMM study, which screened 75,422 Icelandic individuals aged ≥40 years for MM precursors. Individuals diagnosed with SMM were matched by age and sex with MGUS-free comparators (1:5 ratio) and with individuals with MGUS (1:1 ratio). Infection outcomes were derived from nationwide registries of ICD-10 diagnostic codes and antimicrobial prescriptions. Cox proportional hazards models estimated infection risk, adjusted for immunoparesis. 188 SMM individuals were matched to 188 MGUS individuals and 162 SMM individuals were matched to 810 comparators. Individuals with SMM had significantly more infections (HR 1.36, 95% CI 1.07–1.73) and antibacterial prescriptions (HR 1.24, 95% CI 1.01–1.52) than the comparators. Compared to MGUS, individuals with SMM also had more infections (HR 1.37, 95% CI 1.00–1.87). Adjusting for immunoparesis attenuated the associations, suggesting it may partially mediate infection risk. This first screened cohort of SMM shows a significantly increased infection risk, compared to both MGUS and to individuals without MM precursors, suggesting an underrecognized infection burden in SMM.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 12","pages":"2997-3003"},"PeriodicalIF":13.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02762-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035223","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 : 2025-09-11DOI: 10.1038/s41375-025-02751-y
Robert Peter Gale, Andreas Hochhaus
{"title":"Are real world data real world data?","authors":"Robert Peter Gale, Andreas Hochhaus","doi":"10.1038/s41375-025-02751-y","DOIUrl":"10.1038/s41375-025-02751-y","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 10","pages":"2311-2312"},"PeriodicalIF":13.4,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02751-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145035796","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 : 2025-09-11DOI: 10.1038/s41375-025-02752-x
Farideh Miraki-Moud, Linda Ariza-McNaughton, Thinzar KoKo, Jad Othman, Randal Stronge, Johann de Bono, Nigel Russell, Ian Thomas, Amanda Gilkes, Alan Burnett, Leandro Rodrigues Santiago, Fay Cafferty, Leo Taussig, Allan Thornhill, Simon O’Connor, Dominique Bonnet, David C. Taussig
Male sex is associated with worse outcome in acute myeloid leukemia (AML) in many studies. We analyzed the survival of 4281 patients treated with intensive chemotherapy in the AML17 and AML19 trials based on sex. Men had a significantly lower remission rate than women. Men had a higher incidence of adverse cytogenetic features and a lower incidence of the relatively favorable NPM1 mutation. However, male sex was an independent risk factor for survival in multi-variate analysis. We hypothesized that androgen signaling in men could worsen outcomes by protecting AML cells from chemotherapy. We demonstrated high levels of androgen receptor (AR) expression in AML across cytogenetic risk groups. We showed the AR expression was induced by IL-6 signaling in vitro and correlates with poor overall survival. Androgens had no effect on survival of primary AML cells in vitro, nor did they impact gene expression. Androgens did not protect AML cells against chemotherapy either in vitro or in vivo. Similar results were observed with estrogen signaling through estrogen receptor in vitro in AML cells. In conclusion, targeting the androgen pathway may not be a promising clinical strategy and sex hormone signaling in AML cells does not explain the poorer outcomes of men.
{"title":"Acute myeloid leukaemia cells express high levels of androgen receptor but do not depend on androgen signaling for survival","authors":"Farideh Miraki-Moud, Linda Ariza-McNaughton, Thinzar KoKo, Jad Othman, Randal Stronge, Johann de Bono, Nigel Russell, Ian Thomas, Amanda Gilkes, Alan Burnett, Leandro Rodrigues Santiago, Fay Cafferty, Leo Taussig, Allan Thornhill, Simon O’Connor, Dominique Bonnet, David C. Taussig","doi":"10.1038/s41375-025-02752-x","DOIUrl":"10.1038/s41375-025-02752-x","url":null,"abstract":"Male sex is associated with worse outcome in acute myeloid leukemia (AML) in many studies. We analyzed the survival of 4281 patients treated with intensive chemotherapy in the AML17 and AML19 trials based on sex. Men had a significantly lower remission rate than women. Men had a higher incidence of adverse cytogenetic features and a lower incidence of the relatively favorable NPM1 mutation. However, male sex was an independent risk factor for survival in multi-variate analysis. We hypothesized that androgen signaling in men could worsen outcomes by protecting AML cells from chemotherapy. We demonstrated high levels of androgen receptor (AR) expression in AML across cytogenetic risk groups. We showed the AR expression was induced by IL-6 signaling in vitro and correlates with poor overall survival. Androgens had no effect on survival of primary AML cells in vitro, nor did they impact gene expression. Androgens did not protect AML cells against chemotherapy either in vitro or in vivo. Similar results were observed with estrogen signaling through estrogen receptor in vitro in AML cells. In conclusion, targeting the androgen pathway may not be a promising clinical strategy and sex hormone signaling in AML cells does not explain the poorer outcomes of men.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 12","pages":"2895-2906"},"PeriodicalIF":13.4,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41375-025-02752-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032045","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 : 2025-09-11DOI: 10.1038/s41375-025-02763-8
Marisol Miranda-Galvis, Kellen C. Tjioe, Muhannad Sharara, McKenzie Maloney, Amany R. Keruakous, Anand Jillella, Vamsi Kota, Avirup Guha, Jorge E. Cortes
Despite advances in tyrosine kinase inhibitor (TKI) therapy, outcomes in chronic myeloid leukemia remain (CML) highly variable, underscoring the need to explore determinants beyond conventional clinical indicators. This study examined the relationship between allostatic load (AL), a biomarker-based index of cumulative chronic stress, social determinants of health (SDH), and treatment outcomes. In a retrospective cohort of 194 patients, AL was calculated using 23 biomarkers spanning cardiovascular, metabolic, hematologic, renal, and hepatic systems. Higher AL was associated with adverse SDH and behavioral factors, including greater extreme poverty (p = 0.02), limited transportation access (p = 0.02), reliance on public health coverage (p = 0.03), and physical inactivity (p = 0.05). Each unit increase in AL reduced the odds of achieving optimal molecular response by 18% (p = 0.02). All 11 disease progressions to advanced CML and all 9 deaths occurred in the high AL group, who also had higher rates of composite adverse events, including loss of molecular response, TKI failure, disease progression, and mortality (p = 0.03). These findings position AL as a promising integrative biomarker to identify high-risk patients facing combined physiological stress burden and social disadvantage, enabling oncology practices to refine risk stratification and implement personalized, multidisciplinary interventions.
{"title":"Estimating the burden of chronic stress through allostatic load in patients with chronic myeloid leukemia","authors":"Marisol Miranda-Galvis, Kellen C. Tjioe, Muhannad Sharara, McKenzie Maloney, Amany R. Keruakous, Anand Jillella, Vamsi Kota, Avirup Guha, Jorge E. Cortes","doi":"10.1038/s41375-025-02763-8","DOIUrl":"10.1038/s41375-025-02763-8","url":null,"abstract":"Despite advances in tyrosine kinase inhibitor (TKI) therapy, outcomes in chronic myeloid leukemia remain (CML) highly variable, underscoring the need to explore determinants beyond conventional clinical indicators. This study examined the relationship between allostatic load (AL), a biomarker-based index of cumulative chronic stress, social determinants of health (SDH), and treatment outcomes. In a retrospective cohort of 194 patients, AL was calculated using 23 biomarkers spanning cardiovascular, metabolic, hematologic, renal, and hepatic systems. Higher AL was associated with adverse SDH and behavioral factors, including greater extreme poverty (p = 0.02), limited transportation access (p = 0.02), reliance on public health coverage (p = 0.03), and physical inactivity (p = 0.05). Each unit increase in AL reduced the odds of achieving optimal molecular response by 18% (p = 0.02). All 11 disease progressions to advanced CML and all 9 deaths occurred in the high AL group, who also had higher rates of composite adverse events, including loss of molecular response, TKI failure, disease progression, and mortality (p = 0.03). These findings position AL as a promising integrative biomarker to identify high-risk patients facing combined physiological stress burden and social disadvantage, enabling oncology practices to refine risk stratification and implement personalized, multidisciplinary interventions.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"39 11","pages":"2735-2744"},"PeriodicalIF":13.4,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032120","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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