Pub Date : 2026-01-07DOI: 10.1038/s41375-025-02841-x
Noffar Bar, Thomas Martin, Craig C. Hofmeister, Maria-Victoria Mateos, Markus Hansson, Laura Paris, Swathi Namburi, Paz Ribas, Armando Santoro, Paula Rodriguez-Otero, Maria Creignou, Jinjie Chen, Cong Cao, Brian Kiesel, Allison Gaudy, Ethan G. Thompson, Ye Shen, Samah Zarif, Kevin Hsu, Suresh G. Shelat, Michael R. Burgess, Colin Godwin, Luciano J. Costa
B-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers.
{"title":"Alnuctamab, a bivalent B-cell maturation antigen-targeting T cell engager for patients with relapsed or refractory multiple myeloma: results from a phase 1, first-in-human study","authors":"Noffar Bar, Thomas Martin, Craig C. Hofmeister, Maria-Victoria Mateos, Markus Hansson, Laura Paris, Swathi Namburi, Paz Ribas, Armando Santoro, Paula Rodriguez-Otero, Maria Creignou, Jinjie Chen, Cong Cao, Brian Kiesel, Allison Gaudy, Ethan G. Thompson, Ye Shen, Samah Zarif, Kevin Hsu, Suresh G. Shelat, Michael R. Burgess, Colin Godwin, Luciano J. Costa","doi":"10.1038/s41375-025-02841-x","DOIUrl":"https://doi.org/10.1038/s41375-025-02841-x","url":null,"abstract":"B-cell maturation antigen (BCMA)-targeting therapies provide a new approach to treating multiple myeloma (MM). Alnuctamab (ALNUC) is a 2 + 1 immunoglobulin G1-based bispecific antibody binding BCMA and CD3ε receptors on myeloma and T cells, respectively. CC-93269-MM-001 is a first-in-human, phase 1 dose escalation/expansion study investigating ALNUC in relapsed/refractory MM. Patients had ≥3 prior regimens, disease progression ≤60 days of last regimen, and were BCMA-directed therapy-naïve. ALNUC was administered intravenously (IV) and subcutaneously (SC); however, SC was selected for further evaluation due to the more favorable safety profile. Ninety-five patients received ALNUC SC; at data cutoff, 44.2% remained on treatment and median follow-up was 8.0 months. The recommended phase 2 dose was 30 mg. The most common treatment emergent adverse events (any grade/grade 3/4) were CRS (57.9%/0%), and neutropenia (53.7%/43.2%). Infections were also frequent (64.2%/14.7%). ORR was 58.9% for all ALNUC SC-treated patients and 71.4% for the 30-mg cohort; 47/95 (49.5%) were measurable residual disease (MRD) negative. Overall, the safety and efficacy of ALNUC SC were comparable to other BCMA-targeted therapies. These results support improved safety of SC versus IV, and corroborate a step-up dosing strategy to mitigate CRS. Importantly, a schedule that de-intensifies over time provides favorable toxicity that may be applicable to other bispecific engagers.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"57 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145908162","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 : 2025-12-23DOI: 10.1038/s41375-025-02832-y
Yueyao Yang, Xun Liu, Jing Wei, Jia Qin, Qinling Tan, Jie Ji, Fukun Guo, Yi Zheng, Feng Bi, Ming Liu, Gang Wang
Approximately 50% of B-ALL patients exhibit Blinatumomab (CD3/CD19 bispecific T-cell engager, BiTE) resistance, often with high tumor PD-L1 expression, limiting therapeutic efficacy. Combining Blinatumomab with PD-L1 blockade is promising but hindered by continuous infusion, short half-life, and high costs. We developed an economical, non-viral, single-dose intramuscular plasmid gene delivery for sustained (≥4 weeks) in vivo co-expression of CD3/CD19 BiTE and PD-L1 antibodies. This platform integrates T-cell-mediated cytotoxicity, immune checkpoint blockade, and antibody-dependent cytotoxicity. This strategy induced substantial leukemia cell regression, achieving an 80% complete remission (CR) rate in CD19⁺/PD-L1⁺ Nalm-6 xenografts and a 40% CR rate in the CD19 antigen-loss immune escape model. Anti-leukemic efficacy correlated with enhanced CD3⁺, CD8⁺ T-cell, CD3⁺CD56⁺ NKT-like cell expansion, and increased granzyme B/IFN-γ levels. Furthermore, in vivo-produced antibodies promoted B-ALL patient-derived CD3⁺ T-cell proliferation and CD19⁺ tumor cell clearance. This study presents a cost-effective, durable, and potent in vivo immunotherapy integrating T-cell engagement and PD-L1 blockade, offering a promising translational approach for B-ALL.
{"title":"In vivo expression of CD3/CD19 bispecific T-cell engager and α-PD-L1-Fc enables effective and durable immunotherapy for CD19+/PD-L1+ leukemia","authors":"Yueyao Yang, Xun Liu, Jing Wei, Jia Qin, Qinling Tan, Jie Ji, Fukun Guo, Yi Zheng, Feng Bi, Ming Liu, Gang Wang","doi":"10.1038/s41375-025-02832-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02832-y","url":null,"abstract":"Approximately 50% of B-ALL patients exhibit Blinatumomab (CD3/CD19 bispecific T-cell engager, BiTE) resistance, often with high tumor PD-L1 expression, limiting therapeutic efficacy. Combining Blinatumomab with PD-L1 blockade is promising but hindered by continuous infusion, short half-life, and high costs. We developed an economical, non-viral, single-dose intramuscular plasmid gene delivery for sustained (≥4 weeks) in vivo co-expression of CD3/CD19 BiTE and PD-L1 antibodies. This platform integrates T-cell-mediated cytotoxicity, immune checkpoint blockade, and antibody-dependent cytotoxicity. This strategy induced substantial leukemia cell regression, achieving an 80% complete remission (CR) rate in CD19⁺/PD-L1⁺ Nalm-6 xenografts and a 40% CR rate in the CD19 antigen-loss immune escape model. Anti-leukemic efficacy correlated with enhanced CD3⁺, CD8⁺ T-cell, CD3⁺CD56⁺ NKT-like cell expansion, and increased granzyme B/IFN-γ levels. Furthermore, in vivo-produced antibodies promoted B-ALL patient-derived CD3⁺ T-cell proliferation and CD19⁺ tumor cell clearance. This study presents a cost-effective, durable, and potent in vivo immunotherapy integrating T-cell engagement and PD-L1 blockade, offering a promising translational approach for B-ALL.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"1 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808182","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 : 2025-12-23DOI: 10.1038/s41375-025-02836-8
Alexandre Guy, Olivier Mansier, Matisse Decilap, Alexandre Catherineau, Geoffrey Garcia, Sylvie Labrouche-Colomer, Marie-Lise Bats, Françoise Boyer, Jean-Christophe Ianotto, Eric Lippert, Lydia Roy, Suzanne Tavitian, Borhane Slama, Stéphane Girault, Gabriel Etienne, Anne Parry, Arnaud Saint-Lezer, Guillaume Denis, Clémence Médiavilla, Jean-François Viallard, Laurence Legros, Dana Ranta, Mathieu Wemeau, Franck-Emmanuel Nicolini, François Lifermann, Nathalie Cambier, Luc Darnige, François Girodon, Juliette Soret-Dulphy, Émilie Cayssials, Fabienne Vacheret, Léa Sureau, Damien Luque Paz, Valérie Ugo, Jean-Jacques Kiladjian, Rodolphe Thiébaut, Chloe James, on behalf of the French Intergroup of Myeloproliferative Neoplasms (FIM)
Thrombotic risk assessment is crucial in newly diagnosed essential thrombocythemia (ET) and polycythemia vera (PV) patients to guide cytoreductive therapy. We assessed whether thromboinflammation biomarkers would be good candidates to improve thrombosis risk stratification. We prospectively enrolled 394 newly diagnosed, cytoreductive therapy–naïve, ET and PV patients. We measured seven plasma biomarkers of neutrophil, monocyte, platelet, and endothelial activation, including NET markers, and evaluated their association with thrombosis risk scores at diagnosis. Multivariable analysis in the whole MPN cohort showed elevated calprotectin and tissue factor levels in high-risk versus low-risk patients using the conventional two-tiered score. This was also observed in ET patients only, but not in PV patients. Patients with a JAK2V617F allele burden >20% showed higher levels of three markers, including calprotectin, supporting its role in immunothrombosis. In PV patients, calprotectin correlated with the Venous Thrombosis Score (VETS), and five markers were elevated in those with prior venous thrombosis. Lastly, aspirin use was associated with lower H3Cit levels in patients with normal platelet counts, confirming its beneficial effect on NET formation. This is the largest study to date linking thromboinflammation markers to thrombotic risk in MPN patients and identifying potential biomarkers for future thrombosis risk scores.
{"title":"Thromboinflammation is associated with high thrombotic risk in patients with newly diagnosed myeloproliferative neoplasms","authors":"Alexandre Guy, Olivier Mansier, Matisse Decilap, Alexandre Catherineau, Geoffrey Garcia, Sylvie Labrouche-Colomer, Marie-Lise Bats, Françoise Boyer, Jean-Christophe Ianotto, Eric Lippert, Lydia Roy, Suzanne Tavitian, Borhane Slama, Stéphane Girault, Gabriel Etienne, Anne Parry, Arnaud Saint-Lezer, Guillaume Denis, Clémence Médiavilla, Jean-François Viallard, Laurence Legros, Dana Ranta, Mathieu Wemeau, Franck-Emmanuel Nicolini, François Lifermann, Nathalie Cambier, Luc Darnige, François Girodon, Juliette Soret-Dulphy, Émilie Cayssials, Fabienne Vacheret, Léa Sureau, Damien Luque Paz, Valérie Ugo, Jean-Jacques Kiladjian, Rodolphe Thiébaut, Chloe James, on behalf of the French Intergroup of Myeloproliferative Neoplasms (FIM)","doi":"10.1038/s41375-025-02836-8","DOIUrl":"https://doi.org/10.1038/s41375-025-02836-8","url":null,"abstract":"Thrombotic risk assessment is crucial in newly diagnosed essential thrombocythemia (ET) and polycythemia vera (PV) patients to guide cytoreductive therapy. We assessed whether thromboinflammation biomarkers would be good candidates to improve thrombosis risk stratification. We prospectively enrolled 394 newly diagnosed, cytoreductive therapy–naïve, ET and PV patients. We measured seven plasma biomarkers of neutrophil, monocyte, platelet, and endothelial activation, including NET markers, and evaluated their association with thrombosis risk scores at diagnosis. Multivariable analysis in the whole MPN cohort showed elevated calprotectin and tissue factor levels in high-risk versus low-risk patients using the conventional two-tiered score. This was also observed in ET patients only, but not in PV patients. Patients with a JAK2V617F allele burden >20% showed higher levels of three markers, including calprotectin, supporting its role in immunothrombosis. In PV patients, calprotectin correlated with the Venous Thrombosis Score (VETS), and five markers were elevated in those with prior venous thrombosis. Lastly, aspirin use was associated with lower H3Cit levels in patients with normal platelet counts, confirming its beneficial effect on NET formation. This is the largest study to date linking thromboinflammation markers to thrombotic risk in MPN patients and identifying potential biomarkers for future thrombosis risk scores.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"16 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145808184","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 : 2025-12-22DOI: 10.1038/s41375-025-02829-7
Thanh Thanh T. Dinh, Matthew R. Lordo, Amy Y. Zhang, Chinmayee Goda, Nikolas Shilo, Ekaterina Altynova, Michael Ruesch, Parker Kronen, Megan Broughton, Erin Jeremy, Victoria L. Sellers, Xiaoli Zhang, Karilyn T. Larkin, Patrick L. Collins, Adrienne M. Dorrance, Aharon G. Freud, Christopher C. Oakes, Bethany L. Mundy- Bosse
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor overall survival. Understanding how dysregulated immunity contributes to the development and progression of AML is an active area of investigation. Prior work has demonstrated functional defects in natural killer (NK) cells; however, the role of non-NK innate lymphoid cells (ILCs) in AML is incompletely understood. Conventional ILC3s are non-cytotoxic and regulate mucosal immunity through cytokine secretion. In this study, we discovered an expansion of ILC3s in both a murine model of AML and in AML patients. The transcription factor, aryl hydrocarbon receptor (AHR) is required for ILC3 development and function, and AML blasts have been shown to secrete AHR ligands. Modeling studies demonstrated ILC3 expansion was mediated by AHR activation in ILC precursors. ILC3s developed in leukemic settings had increased cytokine production, and co-culture of ILC3s significantly increased AML colony formation, which was mediated by ILC3-derived TNFα and GM-CSF. Furthermore, co-transfer of ILC3s with AML led to more rapid disease progression in vivo and human ILC3 frequency was associated with adverse risk stratification in AML patients. These data support a model in which AML promotes ILC3 expansion and function via an AHR-dependent mechanism to aid AML growth and survival.
{"title":"Leukemia-driven expansion of type 3 innate lymphoid cell facilitates a pro-tumoral microenvironment in acute myeloid leukemia","authors":"Thanh Thanh T. Dinh, Matthew R. Lordo, Amy Y. Zhang, Chinmayee Goda, Nikolas Shilo, Ekaterina Altynova, Michael Ruesch, Parker Kronen, Megan Broughton, Erin Jeremy, Victoria L. Sellers, Xiaoli Zhang, Karilyn T. Larkin, Patrick L. Collins, Adrienne M. Dorrance, Aharon G. Freud, Christopher C. Oakes, Bethany L. Mundy- Bosse","doi":"10.1038/s41375-025-02829-7","DOIUrl":"https://doi.org/10.1038/s41375-025-02829-7","url":null,"abstract":"Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with poor overall survival. Understanding how dysregulated immunity contributes to the development and progression of AML is an active area of investigation. Prior work has demonstrated functional defects in natural killer (NK) cells; however, the role of non-NK innate lymphoid cells (ILCs) in AML is incompletely understood. Conventional ILC3s are non-cytotoxic and regulate mucosal immunity through cytokine secretion. In this study, we discovered an expansion of ILC3s in both a murine model of AML and in AML patients. The transcription factor, aryl hydrocarbon receptor (AHR) is required for ILC3 development and function, and AML blasts have been shown to secrete AHR ligands. Modeling studies demonstrated ILC3 expansion was mediated by AHR activation in ILC precursors. ILC3s developed in leukemic settings had increased cytokine production, and co-culture of ILC3s significantly increased AML colony formation, which was mediated by ILC3-derived TNFα and GM-CSF. Furthermore, co-transfer of ILC3s with AML led to more rapid disease progression in vivo and human ILC3 frequency was associated with adverse risk stratification in AML patients. These data support a model in which AML promotes ILC3 expansion and function via an AHR-dependent mechanism to aid AML growth and survival.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"183 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801567","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 : 2025-12-22DOI: 10.1038/s41375-025-02834-w
Martin Grözinger, Muriel Schlanke, Jana Gröne, Stella Erdmann, Marina Hajiyianni, Alexandra M. Poos, Heidi Thierjung, Elias K. Mai, Sandra Sauer, Dorothee Kaudewitz, Kaya Veelken, Christian S. Michel, Jan Hendrik Frenking, Lilli Sophie Sester, Tim Frederik Weber, Sam Sedaghat, Markus Wennmann, Carsten Müller-Tidow, Heinz-Peter Schlemmer, Stefan Delorme, Marc S. Raab, Hartmut Goldschmidt, Niels Weinhold, Lukas John
Whole-body imaging plays a critical role in assessing multiple myeloma (MM). The structured scoring systems MY-RADS and KIM score have primarily been developed for newly diagnosed patients (NDMM). However, their application and prognostic significance in relapsed/refractory multiple myeloma (RRMM) remains uncertain. To clarify this, we evaluated whole body magnetic resonance imaging (MRI) data from 46 RRMM patients and compared findings to 68 NDMM patients from the GMMG-HD7 trial using both scoring systems. Despite similar overall disease burden, RRMM patients showed significant differences, characterized by increased paramedullary and extramedullary disease and reduced diffuse marrow infiltration compared to NDMM. Both MY-RADS and KIM scores independently correlated with progression-free and overall survival in RRMM. These results highlight distinct biological patterns in RRMM, emphasizing a shift towards bone marrow-independent growth. Our findings suggest that in RRMM, iliac crest biopsies may underestimate disease burden, underlining the importance of imaging complementing bone marrow diagnostics.
{"title":"Structured whole-body MRI highlights clinically relevant disease pattern changes in relapsed/refractory multiple myeloma","authors":"Martin Grözinger, Muriel Schlanke, Jana Gröne, Stella Erdmann, Marina Hajiyianni, Alexandra M. Poos, Heidi Thierjung, Elias K. Mai, Sandra Sauer, Dorothee Kaudewitz, Kaya Veelken, Christian S. Michel, Jan Hendrik Frenking, Lilli Sophie Sester, Tim Frederik Weber, Sam Sedaghat, Markus Wennmann, Carsten Müller-Tidow, Heinz-Peter Schlemmer, Stefan Delorme, Marc S. Raab, Hartmut Goldschmidt, Niels Weinhold, Lukas John","doi":"10.1038/s41375-025-02834-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02834-w","url":null,"abstract":"Whole-body imaging plays a critical role in assessing multiple myeloma (MM). The structured scoring systems MY-RADS and KIM score have primarily been developed for newly diagnosed patients (NDMM). However, their application and prognostic significance in relapsed/refractory multiple myeloma (RRMM) remains uncertain. To clarify this, we evaluated whole body magnetic resonance imaging (MRI) data from 46 RRMM patients and compared findings to 68 NDMM patients from the GMMG-HD7 trial using both scoring systems. Despite similar overall disease burden, RRMM patients showed significant differences, characterized by increased paramedullary and extramedullary disease and reduced diffuse marrow infiltration compared to NDMM. Both MY-RADS and KIM scores independently correlated with progression-free and overall survival in RRMM. These results highlight distinct biological patterns in RRMM, emphasizing a shift towards bone marrow-independent growth. Our findings suggest that in RRMM, iliac crest biopsies may underestimate disease burden, underlining the importance of imaging complementing bone marrow diagnostics.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"28 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145801604","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 : 2025-12-19DOI: 10.1038/s41375-025-02842-w
Christine E Birdwell,Warren Fiskus,Christopher P Mill,Tapan M Kadia,Naval Daver,Courtney D DiNardo,Koji Sasaki,John A Davis,Kaberi Das,Hanxi Hou,Antrix Jain,Anna Malovannaya,Lauren B Flores,Rasoul Pourebrahim,Selina Yuan,Xiaoping Su,Michele Ceribelli,Kapil N Bhalla
MECOM rearrangement in AML involves either inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), where the dislocated GATA2 enhancer drives overexpression of the transcriptional regulator EVI1, causes concomitant GATA2 repression, and promotes AML progression, aggressive phenotype and therapy refractoriness. Treatment with BET protein inhibitor (BETi) induces in vitro and in vivo efficacy in MECOM-r AML cells. Utilizing an unbiased, high-throughput drug screen, focused on mechanistically-annotated drugs, we identified BRD4, PIK3CA, mTOR, BCL-xL and XIAP as dependencies in the MECOM-r AML cells. Monotherapy with mivebresib (BETi), dactolisib (PI3K/mTORi) and LCL161 (IAPi) dose-dependently induced greater lethality in PD MECOM-r versus non-MECOM-r AML cells. RNA-Seq and/or mass spectrometry analyses revealed that treatment with mivebresib or dactolisib downregulated MYC-targets and cell-cycle gene-sets whereas CyTOF and Western analyses also demonstrated reduction in the protein levels of EVI1, c-Myb, c-Myc in MECOM-r AML cells. Combination of mivebresib and dactolisib or LCL161 synergistically induced apoptosis. In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations.
{"title":"BET inhibitor-based combinations targeting novel dependencies in MECOM-rearranged (r) AML.","authors":"Christine E Birdwell,Warren Fiskus,Christopher P Mill,Tapan M Kadia,Naval Daver,Courtney D DiNardo,Koji Sasaki,John A Davis,Kaberi Das,Hanxi Hou,Antrix Jain,Anna Malovannaya,Lauren B Flores,Rasoul Pourebrahim,Selina Yuan,Xiaoping Su,Michele Ceribelli,Kapil N Bhalla","doi":"10.1038/s41375-025-02842-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02842-w","url":null,"abstract":"MECOM rearrangement in AML involves either inv(3)(q21;q26.2) or t(3;3)(q21;q26.2), where the dislocated GATA2 enhancer drives overexpression of the transcriptional regulator EVI1, causes concomitant GATA2 repression, and promotes AML progression, aggressive phenotype and therapy refractoriness. Treatment with BET protein inhibitor (BETi) induces in vitro and in vivo efficacy in MECOM-r AML cells. Utilizing an unbiased, high-throughput drug screen, focused on mechanistically-annotated drugs, we identified BRD4, PIK3CA, mTOR, BCL-xL and XIAP as dependencies in the MECOM-r AML cells. Monotherapy with mivebresib (BETi), dactolisib (PI3K/mTORi) and LCL161 (IAPi) dose-dependently induced greater lethality in PD MECOM-r versus non-MECOM-r AML cells. RNA-Seq and/or mass spectrometry analyses revealed that treatment with mivebresib or dactolisib downregulated MYC-targets and cell-cycle gene-sets whereas CyTOF and Western analyses also demonstrated reduction in the protein levels of EVI1, c-Myb, c-Myc in MECOM-r AML cells. Combination of mivebresib and dactolisib or LCL161 synergistically induced apoptosis. In a MECOM-r AML PDX model, mivebresib with dactolisib or LCL161, was superior to monotherapy or vehicle in reducing AML burden and increasing mouse survival. These findings highlight that cotreatment with BETi and PI3K/mTOR or IAP inhibitor exerts superior in vitro and in vivo efficacy in MECOM-r AML cells and support further evaluation of these BETi-based combinations.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"173 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786152","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 : 2025-12-19DOI: 10.1038/s41375-025-02819-9
Joshua N Gustine,John A Scaringi,Fabian Bauer,Diana D Cirstea,Andrew R Branagan,Benjamin R Puliafito,Marcela V Maus,Matthew J Frigault,Andrew J Yee,Umar Mahmood,Noopur S Raje
{"title":"Prognostic value of serological and PET/CT response kinetics in patients with multiple myeloma treated with BCMA CAR-T.","authors":"Joshua N Gustine,John A Scaringi,Fabian Bauer,Diana D Cirstea,Andrew R Branagan,Benjamin R Puliafito,Marcela V Maus,Matthew J Frigault,Andrew J Yee,Umar Mahmood,Noopur S Raje","doi":"10.1038/s41375-025-02819-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02819-9","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"114 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786154","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 : 2025-12-19DOI: 10.1038/s41375-025-02835-9
Anna Fedenko,Honorata Czapinska,Alwin Krämer,Friedrich Stölzel,Tilmann Bochtler,Matthias Bochtler
SCHEMATIC VIEW OF THE DEVELOPMENT OF CK-AML DRIVEN BY THE TP53 ABSENCE.: The occurrence of the first, often dominant negative TP53 mutation is quickly followed by the loss of the second TP53 allele and numerous further chromosomal aberrations.
{"title":"Etiology of TP53 mutated complex karyotype acute myeloid leukemia.","authors":"Anna Fedenko,Honorata Czapinska,Alwin Krämer,Friedrich Stölzel,Tilmann Bochtler,Matthias Bochtler","doi":"10.1038/s41375-025-02835-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02835-9","url":null,"abstract":"SCHEMATIC VIEW OF THE DEVELOPMENT OF CK-AML DRIVEN BY THE TP53 ABSENCE.: The occurrence of the first, often dominant negative TP53 mutation is quickly followed by the loss of the second TP53 allele and numerous further chromosomal aberrations.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"22 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786156","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 : 2025-12-19DOI: 10.1038/s41375-025-02816-y
Tzu-Chieh Ho, Mark W LaMere, Hiroki Kawano, Daniel K Byun, Elizabeth A LaMere, Yu-Chiao Chiu, Chunmo Chen, Li-Ju Wang, Jian Wang, Baskar Ramdas, Nikolay V Dokholyan, Laura M Calvi, Jane L Liesveld, Craig T Jordan, Rakesh K Singh, Reuben Kapur, Michael W Becker
Therapies for acute myeloid leukemia (AML) face formidable challenges due to relapse, often driven by leukemia stem cells (LSCs). Strategies targeting LSCs hold promise for enhancing outcomes, yet paired comparisons of functionally defined LSCs at diagnosis and relapse remain underexplored. We present transcriptome analyses of functionally defined LSC populations at diagnosis and relapse, revealing significant alterations in IL-1 signaling. Interleukin-1 receptor type I (IL1R1) and interleukin-1 receptor accessory protein (IL1RAP) were notably upregulated in leukemia stem and progenitor cells at both diagnosis and relapse. Knockdown of IL1R1 and IL1RAP reduced the clonogenicity and/or engraftment of primary human AML cells. In leukemic MLL-AF9 mice, Il1r1 knockout reduced LSC frequency and extended survival. To target IL-1 signaling at both diagnosis and relapse, we developed UR241-2, a novel interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) inhibitor. UR241-2 robustly suppressed IL-1/IRAK1/4 signaling, including NF-κB activation and phosphorylation of p65 and p38, following IL-1 stimulation. UR241-2 selectively inhibited LSC clonogenicity in primary human AML cells at both diagnosis and relapse, while sparing normal hematopoietic stem and progenitor cells. It also reduced AML engraftment in leukemic mice. Our findings highlight the therapeutic potential of UR241-2 in targeting IL-1/IRAK1/4 signaling to eradicate LSCs and improve AML outcomes.
{"title":"Targeting IL-1/IRAK1/4 signaling in acute myeloid leukemia stem cells following treatment and relapse.","authors":"Tzu-Chieh Ho, Mark W LaMere, Hiroki Kawano, Daniel K Byun, Elizabeth A LaMere, Yu-Chiao Chiu, Chunmo Chen, Li-Ju Wang, Jian Wang, Baskar Ramdas, Nikolay V Dokholyan, Laura M Calvi, Jane L Liesveld, Craig T Jordan, Rakesh K Singh, Reuben Kapur, Michael W Becker","doi":"10.1038/s41375-025-02816-y","DOIUrl":"10.1038/s41375-025-02816-y","url":null,"abstract":"<p><p>Therapies for acute myeloid leukemia (AML) face formidable challenges due to relapse, often driven by leukemia stem cells (LSCs). Strategies targeting LSCs hold promise for enhancing outcomes, yet paired comparisons of functionally defined LSCs at diagnosis and relapse remain underexplored. We present transcriptome analyses of functionally defined LSC populations at diagnosis and relapse, revealing significant alterations in IL-1 signaling. Interleukin-1 receptor type I (IL1R1) and interleukin-1 receptor accessory protein (IL1RAP) were notably upregulated in leukemia stem and progenitor cells at both diagnosis and relapse. Knockdown of IL1R1 and IL1RAP reduced the clonogenicity and/or engraftment of primary human AML cells. In leukemic MLL-AF9 mice, Il1r1 knockout reduced LSC frequency and extended survival. To target IL-1 signaling at both diagnosis and relapse, we developed UR241-2, a novel interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) inhibitor. UR241-2 robustly suppressed IL-1/IRAK1/4 signaling, including NF-κB activation and phosphorylation of p65 and p38, following IL-1 stimulation. UR241-2 selectively inhibited LSC clonogenicity in primary human AML cells at both diagnosis and relapse, while sparing normal hematopoietic stem and progenitor cells. It also reduced AML engraftment in leukemic mice. Our findings highlight the therapeutic potential of UR241-2 in targeting IL-1/IRAK1/4 signaling to eradicate LSCs and improve AML outcomes.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":""},"PeriodicalIF":13.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145793921","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 : 2025-12-19DOI: 10.1038/s41375-025-02823-z
Catarina M Stein,Raphael Hablesreiter,Friederike Christen,Pelle Löwe,Coral Fustero-Torre,Klara Kopp,Benjamin N Locher,Lena Nitsch,Robert Altwasser,Johanna Franziska Kerschbaum,Lars Bullinger,Leif S Ludwig,Paulina M Strzelecka,Frederik Damm
Autologous stem cell transplantation (ASCT) involves harvesting hematopoietic stem and progenitor cells (HSPCs) prior to chemotherapy and subsequent repopulation of the bone marrow. This process imposes a bottleneck, providing a framework to dissect the unresolved short- and long-term clonal dynamics during hematopoietic reconstitution. By integrating bulk error-corrected targeted sequencing of clonal hematopoiesis (CH)-associated genes with mitochondrial single-cell Assay for Transposase-Accessible Chromatin sequencing (mtscATAC-seq), we characterized mutational trajectories in frequently altered hematological genes and traced clonal evolution through somatic mitochondrial DNA variants, revealing post-transplant cellular heterogeneity and clonal architecture. Among 60 patients (multiple myeloma, n = 51; non-Hodgkin lymphoma, n = 6; Hodgkin lymphoma, n = 3), CH-associated mutations were identified in 53% pre-ASCT, predominantly involving DNMT3A. A transient increase in mutation counts and gene diversity occurred 10-25 days post-ASCT, with a gradual clonal expansion two years post-transplantation. Tandem ASCT amplified clonal complexity, with a twofold increase in mutation count and gene-level diversity, while preserving clonal trajectories across both transplant courses. Mitochondrial single-cell profiling in longitudinal samples of 3 patients showed patient-specific immune reconstitution and clonal dynamics, with balanced multilineage output from graft HSPCs. Collectively, our findings provide a firsthand comprehensive view of ASCT-induced clonal dynamics and immune reconstitution, paving the way for targeted gene-specific post-transplant monitoring.
{"title":"Dynamics of clonal hematopoiesis and cellular responses to stress-induced toxicity in autologous stem cell transplantation.","authors":"Catarina M Stein,Raphael Hablesreiter,Friederike Christen,Pelle Löwe,Coral Fustero-Torre,Klara Kopp,Benjamin N Locher,Lena Nitsch,Robert Altwasser,Johanna Franziska Kerschbaum,Lars Bullinger,Leif S Ludwig,Paulina M Strzelecka,Frederik Damm","doi":"10.1038/s41375-025-02823-z","DOIUrl":"https://doi.org/10.1038/s41375-025-02823-z","url":null,"abstract":"Autologous stem cell transplantation (ASCT) involves harvesting hematopoietic stem and progenitor cells (HSPCs) prior to chemotherapy and subsequent repopulation of the bone marrow. This process imposes a bottleneck, providing a framework to dissect the unresolved short- and long-term clonal dynamics during hematopoietic reconstitution. By integrating bulk error-corrected targeted sequencing of clonal hematopoiesis (CH)-associated genes with mitochondrial single-cell Assay for Transposase-Accessible Chromatin sequencing (mtscATAC-seq), we characterized mutational trajectories in frequently altered hematological genes and traced clonal evolution through somatic mitochondrial DNA variants, revealing post-transplant cellular heterogeneity and clonal architecture. Among 60 patients (multiple myeloma, n = 51; non-Hodgkin lymphoma, n = 6; Hodgkin lymphoma, n = 3), CH-associated mutations were identified in 53% pre-ASCT, predominantly involving DNMT3A. A transient increase in mutation counts and gene diversity occurred 10-25 days post-ASCT, with a gradual clonal expansion two years post-transplantation. Tandem ASCT amplified clonal complexity, with a twofold increase in mutation count and gene-level diversity, while preserving clonal trajectories across both transplant courses. Mitochondrial single-cell profiling in longitudinal samples of 3 patients showed patient-specific immune reconstitution and clonal dynamics, with balanced multilineage output from graft HSPCs. Collectively, our findings provide a firsthand comprehensive view of ASCT-induced clonal dynamics and immune reconstitution, paving the way for targeted gene-specific post-transplant monitoring.","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"93 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145786155","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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