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.
{"title":"The role of CD38 in monocytes during fibrotic progression of myeloproliferative neoplasms.","authors":"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","doi":"10.1182/blood.2025028703","DOIUrl":"https://doi.org/10.1182/blood.2025028703","url":null,"abstract":"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.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"29 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145765441","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 : 2025-12-15DOI: 10.1182/blood.2025029875
Lianjun Zhang,HyunJun Kang,Melissa Valerio,Dinh Hoa Hoang,Khyatiben V Pathak,Krystine Garcia-Mansfield,Xiyuan Lu,Wancheng Guo,Yu-Hsuan Fu,Xin He,Ying-Chieh Chen,Zhenhua Chen,Lucy Y Ghoda,Ralf Buettner,Zhuo Li,Amanda Blackmon,Ling Li,Bin Zhang,Patrick Pirrotte,Guido Marcucci,Ya-Huei Kuo,Le Xuan Truong Nguyen
Leukemic stem cells (LSCs) in acute myeloid leukemia (AML) depend on oxidative phosphorylation (OXPHOS) sustained by fatty acid oxidation (FAO) and mitochondrial fusion (mitofusion). We demonstrate that miR-126 maintains LSC function by promoting BCL-2-dependent FAO, OXPHOS, and mitofusion, whereas its inhibition disrupts mitochondrial metabolism, induces mitochondrial fission (mitofission), and triggers apoptosis. Mechanistically, miR-126 stabilizes BCL-2 via the SPRED1/ERK axis, which upregulates CPT1B (FAO) and NRF2 (antioxidant response) while regulating mitochondrial dynamics through DRP1 phosphorylation (inhibiting mitofission) and MFN1/2 phosphorylation (enhancing mitofusion). miRisten, a CpG-conjugated anti-miR-126 oligonucleotide now in clinical trials (NCT07025564), synergized with venetoclax (VEN) to suppress FAO/OXPHOS, promote mitofission, and impair LSC homeostasis. In vivo, miRisten potentiated the VEN/azacitidine (AZA) regimen, an FDA-approved therapy for older or unfit AML patients, significantly prolonging survival in patient-derived xenograft models. VEN/miRisten combination also reduced LSC burden and restored VEN sensitivity, establishing miR-126 inhibition as a transformative therapeutic strategy in AML.
{"title":"Pharmacological Inhibition of miR-126 Enhances Venetoclax Activity in Acute Myeloid Leukemia.","authors":"Lianjun Zhang,HyunJun Kang,Melissa Valerio,Dinh Hoa Hoang,Khyatiben V Pathak,Krystine Garcia-Mansfield,Xiyuan Lu,Wancheng Guo,Yu-Hsuan Fu,Xin He,Ying-Chieh Chen,Zhenhua Chen,Lucy Y Ghoda,Ralf Buettner,Zhuo Li,Amanda Blackmon,Ling Li,Bin Zhang,Patrick Pirrotte,Guido Marcucci,Ya-Huei Kuo,Le Xuan Truong Nguyen","doi":"10.1182/blood.2025029875","DOIUrl":"https://doi.org/10.1182/blood.2025029875","url":null,"abstract":"Leukemic stem cells (LSCs) in acute myeloid leukemia (AML) depend on oxidative phosphorylation (OXPHOS) sustained by fatty acid oxidation (FAO) and mitochondrial fusion (mitofusion). We demonstrate that miR-126 maintains LSC function by promoting BCL-2-dependent FAO, OXPHOS, and mitofusion, whereas its inhibition disrupts mitochondrial metabolism, induces mitochondrial fission (mitofission), and triggers apoptosis. Mechanistically, miR-126 stabilizes BCL-2 via the SPRED1/ERK axis, which upregulates CPT1B (FAO) and NRF2 (antioxidant response) while regulating mitochondrial dynamics through DRP1 phosphorylation (inhibiting mitofission) and MFN1/2 phosphorylation (enhancing mitofusion). miRisten, a CpG-conjugated anti-miR-126 oligonucleotide now in clinical trials (NCT07025564), synergized with venetoclax (VEN) to suppress FAO/OXPHOS, promote mitofission, and impair LSC homeostasis. In vivo, miRisten potentiated the VEN/azacitidine (AZA) regimen, an FDA-approved therapy for older or unfit AML patients, significantly prolonging survival in patient-derived xenograft models. VEN/miRisten combination also reduced LSC burden and restored VEN sensitivity, establishing miR-126 inhibition as a transformative therapeutic strategy in AML.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"13 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759931","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}
Efficient derivation of transplantable hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is constrained by epigenetic silencing. Through a CRISPR/Cas9 screen with a BCL11A-eGFP reporter, we identified epigenetic reader SP140 suppressing hematopoiesis. Transient genetic or pharmacologic inhibition of SP140 in hPSC-derived teratoma and embryoid body cultures promoted robust multilineage hematopoiesis and accelerated production of HSCs with serial transplantability and durable reconstitution in immunodeficient mice. Mechanistically, SP140 blockade unlocked transcription at endothelial-to-hematopoietic transition (EHT) loci through topoisomerase 1-dependent chromatin remodeling, activating key hematopoietic and stem cell programs. Transcriptomic analysis showed activation of these regulators upon SP140 inhibition, which was prevented by topoisomerase 1 blockade. CUT&Tag profiling identified SP140 binding at EHT and HSC-specification gene loci. SP140's function as an epigenetic gatekeeper was conserved in diverse hPSCs and murine embryo models, where its downregulation enhanced physiological HSC emergence. Importantly, selective SP140 inhibition in a chemically defined, scalable protocol enabled rapid in vitro generation of bona fide human HSCs suitable for transplantation. These findings identify transient SP140 inhibition as an effective strategy to overcome epigenetic barriers and unlock clinically relevant HSC specification from hPSCs, advancing regenerative hematopoiesis and cell therapy.
{"title":"Transient SP140 inhibition unlocks hematopoietic stem cell fate from human pluripotent stem cells.","authors":"Xingjie Liu,Zhiwei Zhang,Xinyu Cui,Rui Guo,Xiaoyan Ding,Liyang Ma,Pentao Liu,Yong Yu","doi":"10.1182/blood.2025032084","DOIUrl":"https://doi.org/10.1182/blood.2025032084","url":null,"abstract":"Efficient derivation of transplantable hematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is constrained by epigenetic silencing. Through a CRISPR/Cas9 screen with a BCL11A-eGFP reporter, we identified epigenetic reader SP140 suppressing hematopoiesis. Transient genetic or pharmacologic inhibition of SP140 in hPSC-derived teratoma and embryoid body cultures promoted robust multilineage hematopoiesis and accelerated production of HSCs with serial transplantability and durable reconstitution in immunodeficient mice. Mechanistically, SP140 blockade unlocked transcription at endothelial-to-hematopoietic transition (EHT) loci through topoisomerase 1-dependent chromatin remodeling, activating key hematopoietic and stem cell programs. Transcriptomic analysis showed activation of these regulators upon SP140 inhibition, which was prevented by topoisomerase 1 blockade. CUT&Tag profiling identified SP140 binding at EHT and HSC-specification gene loci. SP140's function as an epigenetic gatekeeper was conserved in diverse hPSCs and murine embryo models, where its downregulation enhanced physiological HSC emergence. Importantly, selective SP140 inhibition in a chemically defined, scalable protocol enabled rapid in vitro generation of bona fide human HSCs suitable for transplantation. These findings identify transient SP140 inhibition as an effective strategy to overcome epigenetic barriers and unlock clinically relevant HSC specification from hPSCs, advancing regenerative hematopoiesis and cell therapy.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"14 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759962","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 : 2025-12-15DOI: 10.1182/blood.2024028196
Jiaoyi Chen, Benson Z Wu, Federico Gaiti
The evolutionary history of cancers is encoded in molecular patterns that provide critical insights into the mechanisms of tumor progression. However, reconstructing cancer lineages in patient tumors remains challenging, as conventional sequencing captures only static snapshots of an ongoing evolutionary process. DNA methylation at CpG sites is a heritable epigenetic mark that accumulates stochastic errors - termed epimutations - at rates far exceeding those of somatic DNA mutations. These epimutations serve as a 'molecular clock' and can be harnessed for retrospective lineage tracing. When applied at single-cell resolution, methylation-based lineage tracing enables the reconstruction of cancer phylogenies and provides a powerful framework for studying the dynamics of treatment resistance, cell-state heritability, and metastasis directly in human tumors. In this review, we outline the strengths and challenges of single-cell DNA methylation-based lineage tracing, highlight key insights gained from its application with an emphasis on hematological cancers where relevant, and discuss its future potential in advancing our understanding of cancer evolution.
{"title":"Methylation-based lineage tracing in cancer.","authors":"Jiaoyi Chen, Benson Z Wu, Federico Gaiti","doi":"10.1182/blood.2024028196","DOIUrl":"https://doi.org/10.1182/blood.2024028196","url":null,"abstract":"<p><p>The evolutionary history of cancers is encoded in molecular patterns that provide critical insights into the mechanisms of tumor progression. However, reconstructing cancer lineages in patient tumors remains challenging, as conventional sequencing captures only static snapshots of an ongoing evolutionary process. DNA methylation at CpG sites is a heritable epigenetic mark that accumulates stochastic errors - termed epimutations - at rates far exceeding those of somatic DNA mutations. These epimutations serve as a 'molecular clock' and can be harnessed for retrospective lineage tracing. When applied at single-cell resolution, methylation-based lineage tracing enables the reconstruction of cancer phylogenies and provides a powerful framework for studying the dynamics of treatment resistance, cell-state heritability, and metastasis directly in human tumors. In this review, we outline the strengths and challenges of single-cell DNA methylation-based lineage tracing, highlight key insights gained from its application with an emphasis on hematological cancers where relevant, and discuss its future potential in advancing our understanding of cancer evolution.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.1,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145762278","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 : 2025-12-15DOI: 10.1182/blood.2025029210
Jorge E Cortes,Timothy P Hughes,Jianxiang Wang,Dong-Wook Kim,Dennis Dong Hwan Kim,Jiri Mayer,Yoew-Tee Goh,Philipp le Coutre,Gabriel Etienne,Inho Kim,David Andorsky,Felice Bombaci,Ghayas C Issa,Naoto Takahashi,Shruti Kapoor,Rajendra Jinwal,Kamel Malek,Tracey McCulloch,Lillian Yau,Richard A Larson,Andreas Hochhaus
Many patients receiving frontline tyrosine kinase inhibitors (TKIs) for chronic phase chronic myeloid leukemia (CML-CP) experience inadequate disease control and/or adverse events (AEs) that impair quality of life. Treatments offering optimal efficacy, safety, and tolerability will support long-term therapy. In the primary analysis from ASC4FIRST, a phase 3 randomized trial comparing asciminib with investigator-selected TKIs (IS-TKIs) in newly diagnosed CML-CP, asciminib demonstrated superior efficacy vs all IS-TKIs and vs imatinib in the imatinib stratum, meeting both primary objectives. In the secondary analysis (2.2 years median follow-up), major molecular response (MMR) rate at week 96 was 74.1% with asciminib vs 52.0% with IS-TKIs (treatment difference, 22.4%; 95% CI, 13.6%-31.3%; 1-sided P<.001), and 76.2% with asciminib vs 47.1% with imatinib in the imatinib stratum (treatment difference, 29.7%; 95% CI, 17.6%-41.8%; 1-sided P<.001), meeting both key secondary objectives. MMR rate was 72.0% with asciminib vs 56.9% with second-generation (2G) TKIs (treatment difference, 15.1%; 95% CI, 2.3%-28.0%; 1-sided P<.05), suggesting possible clinical benefit although the study was not designed to formally confirm statistical significance for this secondary endpoint. Safety/tolerability remained favorable with asciminib vs IS-TKIs. Dose reductions and interruptions, respectively, occurred with asciminib (18.5% and 46.5%), imatinib (23.2% and 47.5%), and 2G TKIs (54.9% and 63.7%). The hazard ratio for time to discontinuation of treatment due to AEs for asciminib vs 2G TKIs was 0.46 (95% CI, 0.215%-0.997%). With longer follow-up, asciminib continued to demonstrate a favorable benefit-risk profile over IS-TKIs and imatinib, supporting its potential as a treatment option for newly diagnosed CML-CP.
{"title":"Asciminib Demonstrates Superior Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia in the ASC4FIRST Trial.","authors":"Jorge E Cortes,Timothy P Hughes,Jianxiang Wang,Dong-Wook Kim,Dennis Dong Hwan Kim,Jiri Mayer,Yoew-Tee Goh,Philipp le Coutre,Gabriel Etienne,Inho Kim,David Andorsky,Felice Bombaci,Ghayas C Issa,Naoto Takahashi,Shruti Kapoor,Rajendra Jinwal,Kamel Malek,Tracey McCulloch,Lillian Yau,Richard A Larson,Andreas Hochhaus","doi":"10.1182/blood.2025029210","DOIUrl":"https://doi.org/10.1182/blood.2025029210","url":null,"abstract":"Many patients receiving frontline tyrosine kinase inhibitors (TKIs) for chronic phase chronic myeloid leukemia (CML-CP) experience inadequate disease control and/or adverse events (AEs) that impair quality of life. Treatments offering optimal efficacy, safety, and tolerability will support long-term therapy. In the primary analysis from ASC4FIRST, a phase 3 randomized trial comparing asciminib with investigator-selected TKIs (IS-TKIs) in newly diagnosed CML-CP, asciminib demonstrated superior efficacy vs all IS-TKIs and vs imatinib in the imatinib stratum, meeting both primary objectives. In the secondary analysis (2.2 years median follow-up), major molecular response (MMR) rate at week 96 was 74.1% with asciminib vs 52.0% with IS-TKIs (treatment difference, 22.4%; 95% CI, 13.6%-31.3%; 1-sided P<.001), and 76.2% with asciminib vs 47.1% with imatinib in the imatinib stratum (treatment difference, 29.7%; 95% CI, 17.6%-41.8%; 1-sided P<.001), meeting both key secondary objectives. MMR rate was 72.0% with asciminib vs 56.9% with second-generation (2G) TKIs (treatment difference, 15.1%; 95% CI, 2.3%-28.0%; 1-sided P<.05), suggesting possible clinical benefit although the study was not designed to formally confirm statistical significance for this secondary endpoint. Safety/tolerability remained favorable with asciminib vs IS-TKIs. Dose reductions and interruptions, respectively, occurred with asciminib (18.5% and 46.5%), imatinib (23.2% and 47.5%), and 2G TKIs (54.9% and 63.7%). The hazard ratio for time to discontinuation of treatment due to AEs for asciminib vs 2G TKIs was 0.46 (95% CI, 0.215%-0.997%). With longer follow-up, asciminib continued to demonstrate a favorable benefit-risk profile over IS-TKIs and imatinib, supporting its potential as a treatment option for newly diagnosed CML-CP.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"152 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145759961","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 : 2025-12-15DOI: 10.1182/blood.2025031454
Min Lu,Md Babu Mia,Lijuan Xia,Gohar Mosoyan,Momina Hayat,Christoph Schaniel,Ronald Hoffman
Cancer develops through the interactions between cancer stem cells and the components of tumor microenvironment (TME). To model in vivo cancer stem cell/TME interactions and elucidate their functional consequences, we focused on myelofibrosis (MF), a stem cell driven myeloproliferative neoplasm. We co-cultured MF hematopoietic stem and progenitor cells (HSPCs) with normal donor endothelial cells (ECs) and mesenchymal stromal cells (MSCs) to investigate the consequences of interactions between malignant MF HSPCs and non-malignant microenvironmental cells. This tri-cultivation system proved to be a simple and reproducible platform, which promoted malignant clone dominance and the persistence of MF HSPCs that recapitulate the MF phenotype upon transplantation into immunodeficient mice, including splenomegaly and marrow fibrosis. Transcriptional profiling revealed extensive reprogramming of not only the co-cultured MF HSPCs, but also MSCs and ECs. Although numerous disease-relevant pathways were upregulated, the pro-inflammatory response stood out as a key consequence of MF HSPC/TME interactions. We validated these findings through quantitation of pro-inflammatory transcript upregulation and cytokine production. This human multicellular model system has proven useful in demonstrating the multidirectional interactions of MF HSPCs with TME cells that are essential for sustaining fully functional MF stem cells.
{"title":"Microenvironmental cell interactions are essential for sustaining functionality of myelofibrosis malignant stem cells.","authors":"Min Lu,Md Babu Mia,Lijuan Xia,Gohar Mosoyan,Momina Hayat,Christoph Schaniel,Ronald Hoffman","doi":"10.1182/blood.2025031454","DOIUrl":"https://doi.org/10.1182/blood.2025031454","url":null,"abstract":"Cancer develops through the interactions between cancer stem cells and the components of tumor microenvironment (TME). To model in vivo cancer stem cell/TME interactions and elucidate their functional consequences, we focused on myelofibrosis (MF), a stem cell driven myeloproliferative neoplasm. We co-cultured MF hematopoietic stem and progenitor cells (HSPCs) with normal donor endothelial cells (ECs) and mesenchymal stromal cells (MSCs) to investigate the consequences of interactions between malignant MF HSPCs and non-malignant microenvironmental cells. This tri-cultivation system proved to be a simple and reproducible platform, which promoted malignant clone dominance and the persistence of MF HSPCs that recapitulate the MF phenotype upon transplantation into immunodeficient mice, including splenomegaly and marrow fibrosis. Transcriptional profiling revealed extensive reprogramming of not only the co-cultured MF HSPCs, but also MSCs and ECs. Although numerous disease-relevant pathways were upregulated, the pro-inflammatory response stood out as a key consequence of MF HSPC/TME interactions. We validated these findings through quantitation of pro-inflammatory transcript upregulation and cytokine production. This human multicellular model system has proven useful in demonstrating the multidirectional interactions of MF HSPCs with TME cells that are essential for sustaining fully functional MF stem cells.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"56 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145760191","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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