Pub Date : 2025-12-18DOI: 10.1182/blood.2025028914
Dorien Pastoors, Marije Havermans, Roger Mulet-Lazaro, Leonie Smeenk, Sophie Ottema, Claudia Erpelinck-Verschueren, Stanley van Herk, Maikel Anthonissen, Tim Grob, Shruthi Subramanian, Julie A I Thoms, John E Pimanda, Bas J Wouters, Berna Beverloo, Torsten Haferlach, Claudia Haferlach, Johannes Zuber, Eric Bindels, Ruud Delwel
Abstract: The transcription factor MECOM, located at 3q26, is essential for hematopoietic stem cells in healthy individuals. Enhancer translocations, due to 3q26 rearrangements, drive out-of-context MECOM expression in one of the most aggressive subtypes of acute myeloid leukemia (AML). Aberrantly expressed MECOM is essential for the survival and immature phenotype of these leukemia cells. Direct depletion of MECOM using an endogenous auxin-inducible degron immediately upregulates expression of CEBPA, which encodes a transcription factor required for neutrophil development and is frequently mutated in other AML subtypes. MECOM depletion is accompanied by a severe loss of CD34 and gain of mature myeloid cell surface marker CD15. MECOM exerts its inhibitory effect on differentiation by binding to the +42-kilobase CEBPA enhancer. This is partially dependent on the interaction between MECOM and its corepressor CTBP2. We demonstrate that CEBPA overexpression can bypass the MECOM-mediated block of differentiation. In addition, patients with AML with MECOM overexpression through enhancer hijacking show significantly reduced CEBPA levels. Our study directly connects 2 major players in normal and malignant hematopoiesis, MECOM and CEBPA, and unveils how MECOM maintains self-renewal by repressing CEBPA-induced differentiation.
{"title":"MECOM is a master repressor of myeloid differentiation through dose control of CEBPA in acute myeloid leukemia.","authors":"Dorien Pastoors, Marije Havermans, Roger Mulet-Lazaro, Leonie Smeenk, Sophie Ottema, Claudia Erpelinck-Verschueren, Stanley van Herk, Maikel Anthonissen, Tim Grob, Shruthi Subramanian, Julie A I Thoms, John E Pimanda, Bas J Wouters, Berna Beverloo, Torsten Haferlach, Claudia Haferlach, Johannes Zuber, Eric Bindels, Ruud Delwel","doi":"10.1182/blood.2025028914","DOIUrl":"10.1182/blood.2025028914","url":null,"abstract":"<p><strong>Abstract: </strong>The transcription factor MECOM, located at 3q26, is essential for hematopoietic stem cells in healthy individuals. Enhancer translocations, due to 3q26 rearrangements, drive out-of-context MECOM expression in one of the most aggressive subtypes of acute myeloid leukemia (AML). Aberrantly expressed MECOM is essential for the survival and immature phenotype of these leukemia cells. Direct depletion of MECOM using an endogenous auxin-inducible degron immediately upregulates expression of CEBPA, which encodes a transcription factor required for neutrophil development and is frequently mutated in other AML subtypes. MECOM depletion is accompanied by a severe loss of CD34 and gain of mature myeloid cell surface marker CD15. MECOM exerts its inhibitory effect on differentiation by binding to the +42-kilobase CEBPA enhancer. This is partially dependent on the interaction between MECOM and its corepressor CTBP2. We demonstrate that CEBPA overexpression can bypass the MECOM-mediated block of differentiation. In addition, patients with AML with MECOM overexpression through enhancer hijacking show significantly reduced CEBPA levels. Our study directly connects 2 major players in normal and malignant hematopoiesis, MECOM and CEBPA, and unveils how MECOM maintains self-renewal by repressing CEBPA-induced differentiation.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"3098-3105"},"PeriodicalIF":23.1,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249702","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 : 2025-12-18DOI: 10.1182/blood.2025030884
A Rita Fragoso,João T Barata
{"title":"LEF1 intragenic deletions: is Wnt'er coming for T-ALL?","authors":"A Rita Fragoso,João T Barata","doi":"10.1182/blood.2025030884","DOIUrl":"https://doi.org/10.1182/blood.2025030884","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"16 1","pages":"3005-3006"},"PeriodicalIF":20.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771433","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 : 2025-12-18DOI: 10.1182/blood.2025031179
Jens Hillengass
{"title":"More than an emotional support PET.","authors":"Jens Hillengass","doi":"10.1182/blood.2025031179","DOIUrl":"https://doi.org/10.1182/blood.2025031179","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"1 1","pages":"3006-3008"},"PeriodicalIF":20.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771575","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 : 2025-12-18DOI: 10.1182/blood.2025030083
Cathelijne Fokkema,Luca Bertamini,Madelon M E de Jong,Sabrin Tahri,Davine Hofste Op Bruinink,Zoltan Kellermayer,Natalie Papazian,Chelsea den Hollander,Michael Vermeulen,Elodie C G Stoetman,Gregory van Beek,Remco Hoogenboezem,Vincent H J van der Velden,Cyrille Hulin,Aurore Perrot,Philippe Moreau,Melissa Rowe,Diego Vieyra,Robin Carson,Mark van Duin,Mathijs Arnoud Sanders,Annemiek Broijl,Peter Sonneveld,Tom Cupedo
High levels of circulating tumor cells (CTC) are a powerful predictor of poor outcomes in newly diagnosed multiple myeloma, yet the mechanistic underpinnings of this correlation remain unknown. To investigate whether CTC-related pathobiology is driven by a specific circulating tumor cell subset, paired bone marrow and blood samples from newly-diagnosed multiple myeloma patients were analyzed by single-cell transcriptomics and whole-genome sequencing. This revealed that down to the individual clone level, CTCs and paired bone marrow cells are transcriptionally similar, without evidence for a distinct circulating population. In contrast, bone marrow myeloma cells from patients with high CTC levels showed increased proliferation and unbalanced primary genetic events, including enrichment for MAF and CCND translocations. To investigate impact of heterogenic genomic events on CTC levels, whole-exome and bulk-RNA sequencing from the MMRF CoMMpass dataset were analyzed and validated in our in-house datasets. Bone marrow tumor cells from patients with high CTC levels were uniformly characterized by transcriptomic signatures of proliferation. Additionally, CTC levels were uniquely dependent on primary genomic events, as well as high-risk secondary genomic events, including amplification1q, deletion1p, deletion13q, biallelic TP53 mutations, and increased APOBEC-induced mutations even in patients without MAF translocations. Finally, we developed a model that predicts the impact of genetic alterations and tumor burden on CTC levels. In sum, we show that CTC are the net result of tumor burden, primary translocations, and secondary genomic events, making CTC a powerful biomarker for genomics-driven high-risk disease in newly diagnosed myeloma patients.
{"title":"Circulating tumor cells in myeloma are a compound biomarker for bone marrow high-risk genomic alterations and tumor load.","authors":"Cathelijne Fokkema,Luca Bertamini,Madelon M E de Jong,Sabrin Tahri,Davine Hofste Op Bruinink,Zoltan Kellermayer,Natalie Papazian,Chelsea den Hollander,Michael Vermeulen,Elodie C G Stoetman,Gregory van Beek,Remco Hoogenboezem,Vincent H J van der Velden,Cyrille Hulin,Aurore Perrot,Philippe Moreau,Melissa Rowe,Diego Vieyra,Robin Carson,Mark van Duin,Mathijs Arnoud Sanders,Annemiek Broijl,Peter Sonneveld,Tom Cupedo","doi":"10.1182/blood.2025030083","DOIUrl":"https://doi.org/10.1182/blood.2025030083","url":null,"abstract":"High levels of circulating tumor cells (CTC) are a powerful predictor of poor outcomes in newly diagnosed multiple myeloma, yet the mechanistic underpinnings of this correlation remain unknown. To investigate whether CTC-related pathobiology is driven by a specific circulating tumor cell subset, paired bone marrow and blood samples from newly-diagnosed multiple myeloma patients were analyzed by single-cell transcriptomics and whole-genome sequencing. This revealed that down to the individual clone level, CTCs and paired bone marrow cells are transcriptionally similar, without evidence for a distinct circulating population. In contrast, bone marrow myeloma cells from patients with high CTC levels showed increased proliferation and unbalanced primary genetic events, including enrichment for MAF and CCND translocations. To investigate impact of heterogenic genomic events on CTC levels, whole-exome and bulk-RNA sequencing from the MMRF CoMMpass dataset were analyzed and validated in our in-house datasets. Bone marrow tumor cells from patients with high CTC levels were uniformly characterized by transcriptomic signatures of proliferation. Additionally, CTC levels were uniquely dependent on primary genomic events, as well as high-risk secondary genomic events, including amplification1q, deletion1p, deletion13q, biallelic TP53 mutations, and increased APOBEC-induced mutations even in patients without MAF translocations. Finally, we developed a model that predicts the impact of genetic alterations and tumor burden on CTC levels. In sum, we show that CTC are the net result of tumor burden, primary translocations, and secondary genomic events, making CTC a powerful biomarker for genomics-driven high-risk disease in newly diagnosed myeloma patients.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"6 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777394","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 : 2025-12-17DOI: 10.1182/blood.2025029971
Andy Itsara,Victoria M Rogness,Laura Samples,Constance M Yuan,Hao-Wei Wang,Inhye E Ahn,Mohammed Z H Farooqui,Xin Tian,Clare Sun,Emily Tomasulo,Susan Soto,Jeanine Superata,Larisa Bezkorovaynaya,Thomas E Hughes,Pia K Nierman,Adrian Wiestner
BTK inhibitors improve outcomes for patients with chronic lymphocytic leukemia (CLL). Long-term data with continuous therapy are limited. With a median follow-up of 10.0 years, we report final results on 84 patients with TP53 aberrations (del(17p) or TP53 mutation) or ≥65 years of age treated with 420mg of single-agent ibrutinib daily until progression or unacceptable toxicity. 52 (61.9%) patients were previously untreated, 56 (66.7%) had unmutated IGHV, and 53 (63.1%) had TP53 aberrations, including 34 who were treatment-naive. As of July 31, 2024, 9 (10.7%) patients continued ibrutinib, 39 (46.4%) discontinued ibrutinib for progressive disease, 31 (36.9%) for adverse events, and 5 (5.9%) withdrew consent. The median progression-free survival (PFS) was 7.2 years; median overall survival (OS) was not reached. In patients with and without TP53 aberrations, median PFS was 5.6 years and not reached, and 10-year OS was 51.3% and 75.3%, respectively. The estimated 10-year PFS and OS for patients with TP53-aberrant CLL treated in first line was 38.6% and 65.7%, respectively. Minimal residual disease (MRD) was quantified by peripheral blood flow cytometry annually. Undetectable MRD (at 10-4) was achieved in 13 (15.5%) patients after a median of 5 years. Twelve patients maintained uMRD, the longest observation ongoing at 8.0 years. Seventeen (42.5%) patients with best response of high MRD (>10-2) remained progression-free for over 5 years. These results highlight durable benefits and deepening responses with ibrutinib, including in high-risk CLL. Whether patients maintaining uMRD for years can safely discontinue therapy should be assessed prospectively. Clinicaltrials.gov: NCT01500733.
{"title":"A Decade of Ibrutinib for CLL with and without TP53 Aberration: Final Report on an Investigator-Sponsored Phase 2 Study.","authors":"Andy Itsara,Victoria M Rogness,Laura Samples,Constance M Yuan,Hao-Wei Wang,Inhye E Ahn,Mohammed Z H Farooqui,Xin Tian,Clare Sun,Emily Tomasulo,Susan Soto,Jeanine Superata,Larisa Bezkorovaynaya,Thomas E Hughes,Pia K Nierman,Adrian Wiestner","doi":"10.1182/blood.2025029971","DOIUrl":"https://doi.org/10.1182/blood.2025029971","url":null,"abstract":"BTK inhibitors improve outcomes for patients with chronic lymphocytic leukemia (CLL). Long-term data with continuous therapy are limited. With a median follow-up of 10.0 years, we report final results on 84 patients with TP53 aberrations (del(17p) or TP53 mutation) or ≥65 years of age treated with 420mg of single-agent ibrutinib daily until progression or unacceptable toxicity. 52 (61.9%) patients were previously untreated, 56 (66.7%) had unmutated IGHV, and 53 (63.1%) had TP53 aberrations, including 34 who were treatment-naive. As of July 31, 2024, 9 (10.7%) patients continued ibrutinib, 39 (46.4%) discontinued ibrutinib for progressive disease, 31 (36.9%) for adverse events, and 5 (5.9%) withdrew consent. The median progression-free survival (PFS) was 7.2 years; median overall survival (OS) was not reached. In patients with and without TP53 aberrations, median PFS was 5.6 years and not reached, and 10-year OS was 51.3% and 75.3%, respectively. The estimated 10-year PFS and OS for patients with TP53-aberrant CLL treated in first line was 38.6% and 65.7%, respectively. Minimal residual disease (MRD) was quantified by peripheral blood flow cytometry annually. Undetectable MRD (at 10-4) was achieved in 13 (15.5%) patients after a median of 5 years. Twelve patients maintained uMRD, the longest observation ongoing at 8.0 years. Seventeen (42.5%) patients with best response of high MRD (>10-2) remained progression-free for over 5 years. These results highlight durable benefits and deepening responses with ibrutinib, including in high-risk CLL. Whether patients maintaining uMRD for years can safely discontinue therapy should be assessed prospectively. Clinicaltrials.gov: NCT01500733.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"56 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765442","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 : 2025-12-17DOI: 10.1182/blood.2025030151
Sanjal H Desai,Alison J Moskowitz,Reid W Merryman,Harsh R Shah,Levi D Pederson,Susan Geyer,Nivetha Ganesan,Tiffany Chang,Tamer Othman,Ayo Samuel Falade,Gunjan L Shah,Urshila Durani,Nuttavut Sumransub,Lay She Ng,Kelsey Baron,Shin Yeu Ong,Kevin Yoon,Stephen M Ansell,Philippe Armand,Siddharth Iyengar,Ivana N Micallef,Robert N Stuver,Alex F Herrera,Matthew G Mei
Combination therapy incorporating PD-1 blockade results in unprecedented response rates in both frontline and relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). Prior retrospective studies have suggested benefit for PD-1 blockade pre-ASCT but included few patients receiving PD-1 blockade with cytotoxic chemotherapy. To explore the impact of anti-PD-1 based salvage on outcomes for patients with R/R cHL, we retrospectively reviewed 1280 patients with R/R cHL who underwent ASCT from 2010-2022 at 6 transplant centers, none of whom received PD-1 blockade as part of frontline therapy. 25% received a PD-1 inhibitor at any point prior to ASCT (10% in conjunction with chemotherapy), 28% received salvage BV without PD-1 blockade, and the rest received salvage chemotherapy alone. Patients who received PD-1 inhibitors at any point before ASCT had a significantly higher 2-year PFS compared to patients who received BV without PD-1 inhibitors or patients receiving chemotherapy alone (88.2%, 70.2%, 67.4%, p < 0.0001). When restricted to patients in complete response (CR) pre-ASCT, the benefit of PD-1 blockade remained significant. PD-1 blockade pre-ASCT is independently associated with superior post-ASCT outcomes and patients proceeding to ASCT should be treated with PD-1-based salvage.
{"title":"PD-1-based combinations before autologous transplant are associated with improved outcomes in classical Hodgkin lymphoma.","authors":"Sanjal H Desai,Alison J Moskowitz,Reid W Merryman,Harsh R Shah,Levi D Pederson,Susan Geyer,Nivetha Ganesan,Tiffany Chang,Tamer Othman,Ayo Samuel Falade,Gunjan L Shah,Urshila Durani,Nuttavut Sumransub,Lay She Ng,Kelsey Baron,Shin Yeu Ong,Kevin Yoon,Stephen M Ansell,Philippe Armand,Siddharth Iyengar,Ivana N Micallef,Robert N Stuver,Alex F Herrera,Matthew G Mei","doi":"10.1182/blood.2025030151","DOIUrl":"https://doi.org/10.1182/blood.2025030151","url":null,"abstract":"Combination therapy incorporating PD-1 blockade results in unprecedented response rates in both frontline and relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). Prior retrospective studies have suggested benefit for PD-1 blockade pre-ASCT but included few patients receiving PD-1 blockade with cytotoxic chemotherapy. To explore the impact of anti-PD-1 based salvage on outcomes for patients with R/R cHL, we retrospectively reviewed 1280 patients with R/R cHL who underwent ASCT from 2010-2022 at 6 transplant centers, none of whom received PD-1 blockade as part of frontline therapy. 25% received a PD-1 inhibitor at any point prior to ASCT (10% in conjunction with chemotherapy), 28% received salvage BV without PD-1 blockade, and the rest received salvage chemotherapy alone. Patients who received PD-1 inhibitors at any point before ASCT had a significantly higher 2-year PFS compared to patients who received BV without PD-1 inhibitors or patients receiving chemotherapy alone (88.2%, 70.2%, 67.4%, p < 0.0001). When restricted to patients in complete response (CR) pre-ASCT, the benefit of PD-1 blockade remained significant. PD-1 blockade pre-ASCT is independently associated with superior post-ASCT outcomes and patients proceeding to ASCT should be treated with PD-1-based salvage.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"4 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765439","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 : 2025-12-17DOI: 10.1182/blood.2025029572
Tomas Jelinek,David Žihala,Aintzane Zabaleta,Ioannis V Kostopoulos,Ondrej Soucek,Ondrej Venglar,Cristina Moreno,Despina Fotiou,Eva Radova,Luis-Esteban Tamariz-Amador,Foteini Theodorakakou,Ludmila Muronova,Andrea Manubens,Ourania Tsitsilonis,Tereza Popková,Carmen Gonzalez,Anjana Anilkumar Sithara,Francesco Corrado,Nayda Bidikian,Camila Guerrero,Veronika Kapustova,Daniel Bilek,Patrick Ryan Hagner,Marta Larrayoz,Jose A Martínez-Climent,Lucie Broskevičová,Jana Mihalyova,Maximillian Merz,Tereza Sevcikova,Irene M Ghobrial,Jesús F San-Miguel,Meletios A Dimopoulos,Paula Rodriguez-Otero,Jakub Radocha,Efstathios Kastritis,Bruno Paiva,Roman Hajek
Infections remain a key challenge during treatment of multiple myeloma (MM) patients with anti-BCMA and -GPRC5D bispecific antibodies (bsAbs). However, the underlying mechanism behind different rates and severity of infections induced by the two bsAbs remains poorly understood. Single-cell RNA-sequencing performed in bone marrow aspirates of 11 MM patients and 8 healthy donors revealed BCMA expression on mature B cells and, surprisingly, in small pre-B cells within B-cell precursors. By contrast, GPRC5D expression was restricted to normal and malignant plasma cells (PCs). Next-generation flow cytometry immune profiling showed that anti-BCMA bsAbs severely depleted bone marrow (BM) mature B cells (4.9%→0%; p<0.001) and normal PCs (0.17% → <0.0002%; p<0.001) during treatment of 62 relapsed MM patients. This was observed in early and late time points of therapy. Additional flow cytometry (N=31) and single-cell RNA-sequencing studies (N=8) demonstrated that, in contrast to anti-GPRC5D, anti-BCMA bsAbs also depleted immature and small pre-B cells. The MIcγ1 mouse model was used as a negative control of BCMA expression in all stages of the B-cell lineage, which confirmed no depletion of any B-cell subset after anti-BCMA treatment. In conclusion, we show that while GPRC5D bsAbs selectively target PCs, anti-BCMA bsAbs target both PCs and B cells from the small pre-B stage onwards. Our study provides mechanistic insight into the increased infection risk with anti-BCMA therapy and lays a foundation for individualized bsAb strategies in MM. Moreover, dual targeting of B cells and PCs may have therapeutic potential in other B cell malignancies or autoimmune diseases.
{"title":"Selective depletion of B-cell subsets underlies increased risk of infection in MM patients treated with anti-BCMA vs -GPRC5D bsAbs.","authors":"Tomas Jelinek,David Žihala,Aintzane Zabaleta,Ioannis V Kostopoulos,Ondrej Soucek,Ondrej Venglar,Cristina Moreno,Despina Fotiou,Eva Radova,Luis-Esteban Tamariz-Amador,Foteini Theodorakakou,Ludmila Muronova,Andrea Manubens,Ourania Tsitsilonis,Tereza Popková,Carmen Gonzalez,Anjana Anilkumar Sithara,Francesco Corrado,Nayda Bidikian,Camila Guerrero,Veronika Kapustova,Daniel Bilek,Patrick Ryan Hagner,Marta Larrayoz,Jose A Martínez-Climent,Lucie Broskevičová,Jana Mihalyova,Maximillian Merz,Tereza Sevcikova,Irene M Ghobrial,Jesús F San-Miguel,Meletios A Dimopoulos,Paula Rodriguez-Otero,Jakub Radocha,Efstathios Kastritis,Bruno Paiva,Roman Hajek","doi":"10.1182/blood.2025029572","DOIUrl":"https://doi.org/10.1182/blood.2025029572","url":null,"abstract":"Infections remain a key challenge during treatment of multiple myeloma (MM) patients with anti-BCMA and -GPRC5D bispecific antibodies (bsAbs). However, the underlying mechanism behind different rates and severity of infections induced by the two bsAbs remains poorly understood. Single-cell RNA-sequencing performed in bone marrow aspirates of 11 MM patients and 8 healthy donors revealed BCMA expression on mature B cells and, surprisingly, in small pre-B cells within B-cell precursors. By contrast, GPRC5D expression was restricted to normal and malignant plasma cells (PCs). Next-generation flow cytometry immune profiling showed that anti-BCMA bsAbs severely depleted bone marrow (BM) mature B cells (4.9%→0%; p<0.001) and normal PCs (0.17% → <0.0002%; p<0.001) during treatment of 62 relapsed MM patients. This was observed in early and late time points of therapy. Additional flow cytometry (N=31) and single-cell RNA-sequencing studies (N=8) demonstrated that, in contrast to anti-GPRC5D, anti-BCMA bsAbs also depleted immature and small pre-B cells. The MIcγ1 mouse model was used as a negative control of BCMA expression in all stages of the B-cell lineage, which confirmed no depletion of any B-cell subset after anti-BCMA treatment. In conclusion, we show that while GPRC5D bsAbs selectively target PCs, anti-BCMA bsAbs target both PCs and B cells from the small pre-B stage onwards. Our study provides mechanistic insight into the increased infection risk with anti-BCMA therapy and lays a foundation for individualized bsAb strategies in MM. Moreover, dual targeting of B cells and PCs may have therapeutic potential in other B cell malignancies or autoimmune diseases.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"1 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765438","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}
Antibody-drug conjugates (ADCs) have emerged as promising targeted therapies in acute myeloid leukemia (AML). However, most ADCs exhibit off-target binding to normal hematopoietic stem and myeloid progenitor cells, resulting in adverse hemato-toxicity and narrow therapeutic windows, limiting their clinical application to young and fit AML patients eligible for intensive curative therapies. Proteoglycans with high levels of the glycosaminoglycan oncofetal chondroitin sulfate (ofCS), are abundantly expressed in solid cancers while being absent or lowly expressed in normal adult tissues. Here, we report high ofCS levels on bone marrow (BM) cells of AML patients and AML patient-derived xenografts (PDXs), while BM cells of healthy subjects showed low or undetectable ofCS levels. Consistently, an anti-ofCS antibody demonstrated binding and internalization into AML cells, and anti-ofCS ADCs effectively killed AML cells in vitro. Moreover, anti-ofCS ADC treatment significantly prolonged survival of AML PDXs compared to controls and was associated with low toxicity. Hence, anti-ofCS ADC could represent an effective therapy with acceptable toxicity applicable for all AML patients, including those ineligible or unresponsive to current intensive curative therapies. In conclusion, our study for the first time demonstrates that a glycosaminoglycan like ofCS represents a druggable target for development of effective antibody-based AML therapies.
{"title":"The glycosaminoglycan oncofetal chondroitin sulfate represents a novel target for antibody drug-conjugate therapy for AML.","authors":"Joana Mujollari,Montserrat Estruch Alrich,Priya Khadgawat,Swati Choudhary,Tobias Gustavsson,Robert Dagil,Norbert Redlinger,Caroline Løppke,Elena Vidal Calvo,Mie Anemone Nordmaj,Thor Grundtvig Theander,Olaf Heidenreich,Yen Nguyen,Shuyu Qin,Anne Louise Tølbøll Sørensen,Kristen Grønbæk,Bo T Porse,Brigitte Kircher,Jan Mueller,Mette Agerbæk,Ali Salanti,Kim Theilgaard-Mönch","doi":"10.1182/blood.2024028147","DOIUrl":"https://doi.org/10.1182/blood.2024028147","url":null,"abstract":"Antibody-drug conjugates (ADCs) have emerged as promising targeted therapies in acute myeloid leukemia (AML). However, most ADCs exhibit off-target binding to normal hematopoietic stem and myeloid progenitor cells, resulting in adverse hemato-toxicity and narrow therapeutic windows, limiting their clinical application to young and fit AML patients eligible for intensive curative therapies. Proteoglycans with high levels of the glycosaminoglycan oncofetal chondroitin sulfate (ofCS), are abundantly expressed in solid cancers while being absent or lowly expressed in normal adult tissues. Here, we report high ofCS levels on bone marrow (BM) cells of AML patients and AML patient-derived xenografts (PDXs), while BM cells of healthy subjects showed low or undetectable ofCS levels. Consistently, an anti-ofCS antibody demonstrated binding and internalization into AML cells, and anti-ofCS ADCs effectively killed AML cells in vitro. Moreover, anti-ofCS ADC treatment significantly prolonged survival of AML PDXs compared to controls and was associated with low toxicity. Hence, anti-ofCS ADC could represent an effective therapy with acceptable toxicity applicable for all AML patients, including those ineligible or unresponsive to current intensive curative therapies. In conclusion, our study for the first time demonstrates that a glycosaminoglycan like ofCS represents a druggable target for development of effective antibody-based AML therapies.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"39 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765440","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 : 2025-12-17DOI: 10.1182/blood.2025028703
Yiru Yan,Jinqin Liu,Songyang Zhao,Fuhui Li,Lin Yang,Zefeng Xu,Tiejun Qin,Xiaofan Zhu,Wenbin An,Zhongxun Shi,Wenyi Shen,Peihong Zhang,Gang Huang,Raajit K Rampal,Zhijian Xiao,Bing Li
Proinflammatory signaling is a hallmark of myeloproliferative neoplasms (MPNs). Several studies have shown that monocytes are a major source of proinflammatory cytokines and monocyte-derived fibrocytes play a pivotal role in the pathogenesis of myelofibrosis (MF). To further explore the role of monocytes in MF, we generated inducible NrasG12D/+Jak2V617F/+ (NJ) mice. Recipients transplanted with NJ BM cells developed MF with an early onset of anemia and monocytosis. In vitro, NJ recipients' BM nucleated cells exhibited increased quantity of CD45+CollagenI+ fibrocytes, which were mainly derived from the Ly6chigh monocytes. RNA sequencing identified a significant elevated expression of CD38 (a nicotinamide adenine dinucleotide (NAD)+ hydrolase) in Ly6chigh monocytes from NJ mice, which results in pronounced lower level of NAD+. In humans, CD14+ monocytes from MF patients showed significantly higher expression of CD38 than controls and monocytes from polycythemia vera (PV) patients with grade 1 fibrosis had higher CD38 expression than those without fibrosis. Finally, boosting NAD+ via pharmacological CD38 targeting or NAD+ precursor supplementation inhibited the differentiation of fibrocytes in vitro and targeting CD38 can effectively prevent the onset of fibrosis in vivo. Collectively, our findings shed light on the role of CD38 in monocytes and suggest potential clinical applications such as use of CD38 as a biomarker of fibrotic progression and potential clinical utility of CD38 inhibition in patients with MF.
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