Blood最新文献

{"title":"Evaluating the impact of CRBN mutations on response to immunomodulatory drugs and novel cereblon E3 ligase modulators in myeloma.","authors":"Yakinthi Chrisochoidou, Andrea Scarpino, Salomon Morales, Shannon Martin, Sarah Bird, Yigen Li, Brian Walker, John Caldwell, Yann-Vaï Le Bihan, Charlotte Pawlyn","doi":"10.1182/blood.2024025861","DOIUrl":"10.1182/blood.2024025861","url":null,"abstract":"<p><strong>Abstract: </strong>Immunomodulatory drug (IMiD) resistance is a key clinical challenge in myeloma treatment. Previous data suggest almost one-third of myeloma patients acquire genetic alteration of the key IMiD effector cereblon (CRBN) by the time they are pomalidomide refractory. Some events, including stop codons/frameshift mutations and copy loss, have clearly explicable effects on CRBN protein function. Missense mutations have also been reported throughout the length of CRBN but their functional impact has not been systematically studied. This study modeled selected missense mutations and examined their effect on CRBN function also analyzing whether any mutations deleterious to IMiD action could be overcome using the novel cereblon E3 ligase modulators (CELMoDs). Three patterns of response to missense mutations were apparent: mutations that led to complete loss of CRBN function for all agents, those that had no effect on CRBN function, and those with agent-dependent effect on CRBN function. The latter group of 4 mutations were profiled in more detail with confirmatory experiments demonstrating an ability of the more potent CELMoDs to lead to neosubstrate degradation and cell death even though IMiDs were not active. Dynamic modeling based on a newly generated crystal structure of the DDB1/CRBN/lenalidomide complex, with greater resolution than those published to date, helped to understand the impact of these mutations. These results have important implications for the interpretation of CRBN sequencing results from patients for future therapy decisions, particularly differentiating those who may, despite relapsing on IMiDs with CRBN mutations, have the potential to still benefit from the use of CELMoD agents.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2630-2644"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999402","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}

{"title":"I+Ve got a question: how long should we treat relapsed CLL?","authors":"Moritz Fürstenau","doi":"10.1182/blood.2025028679","DOIUrl":"https://doi.org/10.1182/blood.2025028679","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 22","pages":"2536-2538"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172649","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}

{"title":"Venetoclax and decitabine vs intensive chemotherapy as induction for young patients with newly diagnosed AML.","authors":"Jing Lu, Sheng-Li Xue, Ying Wang, Xue-Feng He, Xiao-Hui Hu, Miao Miao, Yang Zhang, Zai-Xiang Tang, Jun-Dan Xie, Xiao-Fei Yang, Ming-Zhu Xu, Yao-Yao Shen, Feng Du, Qian Wu, Meng-Xing Xue, Yun Wang, Ai-Ling Deng, Xue-Qing Dou, Yang Xu, Hai-Ping Dai, De-Pei Wu, Su-Ning Chen","doi":"10.1182/blood.2024027217","DOIUrl":"10.1182/blood.2024027217","url":null,"abstract":"<p><strong>Abstract: </strong>Venetoclax (VEN) combined with hypomethylating agents is approved for frontline therapy in older/unfit patients with acute myeloid leukemia (AML). However, prospective data on this low-intensity therapy in treatment-naive younger patients with AML are lacking. This study investigated the efficacy and safety of VEN plus decitabine (VEN-DEC) as induction in untreated young fit patients with AML in a randomized trial. Patients aged 18 to 59 years eligible for intensive chemotherapy were randomized 1:1 to receive VEN-DEC or IA-12 (idarubicin and cytarabine). All patients achieved composite complete remission (CRc) underwent high-dose cytarabine consolidation. The primary end point was CRc rate after induction. Of 255 screened, 188 were enrolled and randomly assigned, with 94 in each group. In the intention-to-treat population, CRc was 89% (84/94) in the VEN-DEC group vs 79% (74/94) in the IA-12 group (noninferiority P = .0021), with measurable residual disease negativity rates of 80% (67/84) vs 76% (56/74), respectively. VEN-DEC showed superior CRc in patients aged ≥40 years (91% vs 75%) and those with adverse risk (91% vs 42%) or epigenetic mutations (91% vs 67%), but lower CRc in RUNX1::RUNX1T1 fusion cases (44% vs 88%) than IA-12. Patients in the VEN-DEC group experienced fewer grade ≥3 infections (32% vs 67%) and shorter severe thrombocytopenia duration (median, 13 vs 19 days; P < .001). At a median follow-up of 12.1 months, overall and progression-free survival were similar between groups. In conclusion, VEN-DEC demonstrated noninferior response rates with superior safety over IA-12 in young patients with AML. The trial was registered at www.clinicaltrials.gov as #NCT05177731.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2645-2655"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514617","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}

{"title":"Histo-blood group ABO system transferase plasma levels and risk of future venous thromboembolism: the HUNT study.","authors":"Asbjørn L Onsaker, Anna Y Arntzen, David-Alexandre Trégouët, Therese H Nøst, Weihong Tang, Weihua Guan, Christian Jonasson, Pierre-Emmanuel Morange, Kristian D Hindberg, Aaron R Folsom, Kristian Hveem, Vânia M Morelli, John-Bjarne Hansen","doi":"10.1182/blood.2024025923","DOIUrl":"10.1182/blood.2024025923","url":null,"abstract":"<p><strong>Abstract: </strong>The non-O blood group is a well-established risk factor for venous thromboembolism (VTE). However, the association between plasma levels of the histo-blood group ABO system transferase (BGAT), the gene product of the ABO locus, and VTE risk remains unclear. We aimed to investigate the association between plasma BGAT levels and risk of future VTE, and whether this relationship was mediated by plasma von Willebrand factor (VWF) or coagulation factor VIII (FVIII), as VWF is glycosylated by BGAT. Incident VTE-cases (n = 294) and a randomly sampled age- and-sex-weighted subcohort (n = 1066) were derived from the third survey of the Trøndelag Health Study. Baseline plasma samples (2006-2008) were subjected to the SomaScan aptamer-based-7K platform for protein measurements. Weighted Cox regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) across BGAT quartiles. We found that ABO haplotypes (A1/A2/B/O1/O2) explained ≈80% of the BGAT plasma variability. Participants with BGAT levels in the highest quartile had 2-fold higher VTE risk (HR, 2.12; 95% CI, 1.39-3.22) compared with those with BGAT in the lowest quartile in age-, sex-, and sample batch-adjusted models. The associations were particularly pronounced for unprovoked VTE (HR, 3.71; 95% CI, 1.79-7.67) and deep vein thrombosis (HR, 3.28; 95% CI, 1.63-6.59). The HRs were similar after further adjustment for body mass index, C-reactive protein, and estimated glomerular filtration rate, and moderately attenuated when adding VWF or FVIII plasma levels to the models. Our findings indicate that elevated BGAT plasma levels are associated with increased risk of future VTE beyond what is explained by VWF and FVIII.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2656-2665"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of HLA alloimmunization in gene-modified autologous stem cell transplant for transfusion-dependent thalassemia.","authors":"Nora M Gibson, Eugene Khandros, Caitlin W Elgarten, Elizabeth Worster, Dimitrios S Monos, Alexis A Thompson, Janet L Kwiatkowski, Timothy S Olson","doi":"10.1182/blood.2024027034","DOIUrl":"10.1182/blood.2024027034","url":null,"abstract":"<p><strong>Abstract: </strong>We report our single-center experience demonstrating that HLA class I alloimmunization predicts longer time to platelet engraftment, increased bleeding complications, and higher transfusion requirements in patients undergoing gene-modified hematopoietic stem cell transplant for transfusion-dependent β thalassemia.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2666-2670"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639627","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}

{"title":"Guidance on the interpretation of CRBN mutations in myeloma.","authors":"K Martin Kortüm, Hermann Einsele","doi":"10.1182/blood.2024028272","DOIUrl":"https://doi.org/10.1182/blood.2024028272","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"145 22","pages":"2542"},"PeriodicalIF":21.0,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172606","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}

{"title":"RBM15-MKL1 fusion protein promotes leukemia via m6A methylation and WNT pathway activation.","authors":"Madeline Y Mayday, Giulia Biancon, Manyi Wei, Christian Ramirez, Irene Moratti, Andreas P Pintado-Urbanc, Jether Amos Espinosa, Mi Chen, Lin Wang, Matthew D Simon, Yaara Ofir-Rosenfeld, Oliver Rausch, Toma Tebaldi, Stephanie Halene, Diane S Krause","doi":"10.1182/blood.2024027712","DOIUrl":"10.1182/blood.2024027712","url":null,"abstract":"<p><p>Acute megakaryoblastic leukemia driven by the RBM15-MKL1 fusion protein (RM-AMKL) is encoded by the recurrent t(1;22) translocation. Dysregulation of m6A modification affects RNA fate and is linked to oncogenesis. Because RBM15 is critical for bringing the m6A writer complex to specific RNAs, we hypothesized that RM disrupts m6A modification, altering RNA fate to drive leukemogenesis in RM-AMKL. Using a multi-omic approach, we show for the first time that RM retains the RNA-binding and m6A-modifying functions of RBM15 while also selectively regulating distinct mRNA targets including Frizzled genes in the WNT signaling pathway. Treating murine RM-AMKL cells with the METTL3 inhibitor STM3675, which decreases m6A deposition, induced apoptosis in vitro and prolonged survival in transplanted mice. Frizzled genes were upregulated by RM and downregulated upon METTL3 inhibition, implicating an m6A-dependent mechanism for their dysregulation. Direct Frizzled knockdown reduced RM-AMKL growth in vitro and in vivo, highlighting Wnt signaling as a key oncogenic driver. Elevated Wnt pathway and Frizzled expression in multiple forms of human AMKL underscores the relevance of our findings. Together, our results establish RM-specific m6A modifications and Wnt pathway activation as critical drivers of RM-AMKL, identifying these pathways as potential therapeutic targets.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172595","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}

{"title":"Differentiation-dependent EBF1 Activity Determines CD22 Transcription and Leukemia Sensitivity to Inotuzumab Ozogamicin.","authors":"Carolin S Escherich, Zhenhua Li, Kelly R Barnett, Yizhen Li, Megan Walker, Satoshi Yoshimura, Wenjian Yang, Xin Huang, Jiyang Yu, Wendy Stock, Elisabeth Paietta, Marina Y Konopleva, Steven M Kornblau, Elias Jabbour, Mark R Litzow, Hiroto Inaba, Ching-Hon Pui, Mignon L Loh, William E Evans, Daniel Savic, Jun J Yang","doi":"10.1182/blood.2024028215","DOIUrl":"https://doi.org/10.1182/blood.2024028215","url":null,"abstract":"<p><p>Inotuzumab Ozogamicin (InO) is an antibody-calicheamicin conjugate with high efficacy in lymphoid malignancies. It targets the B-cell surface protein CD22, which is expressed in most B-ALL cases, albeit with variable intensity. However, factors governing CD22 expression and thus leukemia sensitivity to InO remain incompletely understood. Using multi-omic characterization of 196 human B-ALL samples, coupled with ex vivo InO sensitivity profiling, we show that early leukemia differentiation arrest at the Pre-pro-B stage is associated with resistance to InO. Screening 1,639 transcription factor genes prioritized Early B-cell Factor 1 (EBF1) as a key regulator of CD22 expression (false discovery rate=7.1×10-4). Comparing the ATAC-seq profiling results of the most InO-sensitive and -resistant cases (LC50 <10th vs. >90th percentile, n=18), the binding motif for EBF1 was strikingly enriched in regions with differential open chromatin status (P=8×10-174). CRISPR interference targeting EBF1 binding sites at the CD22 locus led to ~ 50-fold reduction in cell surface CD22 expression, and consequently ~ 22-fold increase in InO resistance in ALL cell lines. Interestingly, within BCR::ABL1 ALL, we observed intra-subtype heterogeneity linked to EBF1 transcriptional downregulation (P=1.1×10-15) and/or somatic alteration (P=0.004), which led to reduced CD22 expression (P=8.3×10-11) and ex vivo and in vivo resistance to InO. Collectively, these findings point to the direct impact of EBF1 on CD22 expression during B-cell development, which in turn contributes to inter-patient variability in InO response, even within the same subtype of B-ALL.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172307","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}

{"title":"PERK Maintains Hematopoietic Stem Cell Pool Integrity under Endoplasmic Reticulum Stress by Promoting Proliferation.","authors":"Manxi Zheng, Qinlu Peng, Erin M Kropp, Zhejuan Shen, Suxuan Liu, Zhengyou Yin, Sho Matono, Takao Iwawaki, Xiang Wang, Ken Inoki, Yang Mei, Qing Li, Lu Liu","doi":"10.1182/blood.2024027846","DOIUrl":"10.1182/blood.2024027846","url":null,"abstract":"<p><p>The integrity of the hematopoietic stem cell (HSC) pool depends on effective long-term self-renewal and the timely elimination of damaged or differentiation-prone HSCs. While the PERK branch of the unfolded protein response (UPR) has been shown to initiate pro-apoptotic signaling in response to ER stress in vitro, its role in regulating HSC fate in vivo remains incompletely understood. Here, we demonstrate that PERK is dispensable for steady-state hematopoiesis and HSC self-renewal under homeostatic conditions. However, under ER stress induced by disruption of ER-associated degradation (ERAD), via knockout of key components such as Sel1L or Hrd1, PERK becomes activated and drives HSC proliferation and depletion. Notably, deletion of PERK or expression of a kinase-dead PERK mutant significantly rescues the HSC defects caused by Sel1L or Hrd1 loss. Mechanistically, ERAD deficiency does not lead to increased HSC apoptosis or elevated reactive oxygen species (ROS), and PERK knockout has minimal impact on HSC apoptosis. Instead, PERK activation promotes aberrant mTOR signaling and HSC hyperproliferation, ultimately compromising self-renewal capacity. This PERK-driven elimination of stressed HSCs may function as a protective mechanism to maintain overall HSC pool integrity. Collectively, our findings reveal a previously unrecognized, proliferative, and apoptosis-independent role for PERK in regulating HSC fate under ER stress, highlighting a novel mechanism for preserving HSC homeostasis.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172483","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}

{"title":"Dual biological role and clinical impact of de novo chromatin activation in chronic lymphocytic leukemia.","authors":"Vicente Chapaprieta, Alba Maiques-Diaz, Ferran Nadeu, Guillem Clot, Ramon Massoni-Badosa, Pablo Mozas, Judith Mateos-Jaimez, Anna Vidal, Stella Charalampopoulou, Martí Duran-Ferrer, Romina Royo, Núria Russiñol, Laura Llaó-Cid, Juan A Piñeyroa, Neus Villamor, Holger Heyn, Sophie A Herbst, Junyan Lu, Dean J Bryant, Jonathan C Strefford, Sascha Dietrich, Thorsten Zenz, Julio Delgado, Armando López-Guillermo, Elias Campo, Jose I Martin-Subero","doi":"10.1182/blood.2024025396","DOIUrl":"10.1182/blood.2024025396","url":null,"abstract":"<p><strong>Abstract: </strong>Previous studies have reported that chronic lymphocytic leukemia (CLL) shows a de novo chromatin activation pattern compared with normal B cells. Here, we explored whether the level of chromatin activation is related to the clinical behavior of CLL. We identified that, in some regulatory regions, increased de novo chromatin activation is linked to clinical progression, whereas, in other regions, it is associated with an indolent course. We next developed 2 prognostic scores for progressive and indolent disease, respectively, calculated a single score representing the balance between them, and further generated surrogate scores based on gene and protein expression of the target genes. The balance score outperformed the clinical impact of the 2 individual scores, because it seemed to capture the prognostic information provided by each of them. Biologically, CLLs with higher balance score showed increased activation of tumor necrosis factor alpha (TNF-α)/NF-κB and mTOR signaling pathways. Regulatory programs related to progression were predominantly activated in the lymph node microenvironment, whereas those linked to indolent disease appeared to be microenvironment independent. Finally, we thoroughly validated the balance score as a powerful and independent quantitative prognostic factor for time to first treatment across independent CLL cohorts and data modalities, such as chromatin, transcriptome, or proteome data. Our findings support the concept that de novo acquisition of chromatin changes in CLL cells plays a dual biological role, and the balance between proprogression and proindolence is a strong independent determinant of CLL prognosis.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2473-2487"},"PeriodicalIF":21.0,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999362","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}