Blood Cancer Discovery最新文献

{"title":"The Two Sides of Bispecific Antibodies in Multiple Myeloma: Where Trial Promise Meets Real-World Practice.","authors":"Sonja Zweegman, Febe Smits, Niels W C J van de Donk","doi":"10.1158/2643-3230.BCD-25-0292","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-25-0292","url":null,"abstract":"<p><p>The real-world effectiveness of the bispecific antibody (BsAb) teclistamab appears to be lower than the efficacy observed in pivotal registration trials. Understanding the drivers of this effectiveness - efficacy gap is essential for guiding the rational selection of patients most likely to benefit, optimizing BsAb therapy in high-risk populations, and ultimately advancing more personalized treatment strategies while supporting sustainable models of care.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perspectives on Newly Diagnosed Myeloma Treatment and Emerging Challenges.","authors":"Cyrille Touzeau, Philippe Moreau","doi":"10.1158/2643-3230.BCD-25-0280","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-25-0280","url":null,"abstract":"<p><p>This commentary explores new challenges in the management of newly diagnosed multiple myeloma and strategies for sustaining improvements in patient outcomes. We highlight the need for risk-adapted approaches, the potential future incorporation of T cell-redirecting immunotherapies in first-line treatment, and the challenge of access to care.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"OF1-OF4"},"PeriodicalIF":11.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145076208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Timing genomic antigen loss in multiple myeloma treated with T-cell redirecting immunotherapies.","authors":"Marios Papadimitriou, Sungwoo Ahn, Benjamin T Diamond, Holly Lee, John B McIntyre, Marietta Truger, Michael A Durante, Bachisio Ziccheddu, Katalin Osz, Ola Landgren, Leo Rasche, Nizar J Bahlis, Paola Neri, Francesco Maura","doi":"10.1158/2643-3230.BCD-25-0005","DOIUrl":"10.1158/2643-3230.BCD-25-0005","url":null,"abstract":"<p><p>Genomic antigen loss is a recurring mechanism of resistance to chimeric antigen receptor T-cell (CAR-T) and T-cell engagers (TCE) in relapsed/refractory multiple myeloma (RRMM). Yet, it remains unclear whether these events are acquired under treatment or merely selected from pre-existing, undetectable clones. By leveraging chemotherapy mutational signatures as temporal barcodes within whole genome sequencing data, we could time genomic antigen escape in 4 out of 11 RRMM patients. In all cases, the biallelic loss was driven by genomic events acquired after exposure to BCMA- and GPRC5D-targeted CAR-T/TCE, and not present at baseline. Longitudinal digital PCR analysis corroborated that resistance mutations were undetectable at therapy initiation but emerged preceding relapse. Among 752 newly diagnosed patients only 2.7% and 9% had monoallelic inactivation of TNFRSF17 and GPRC5D, respectively, with no biallelic loss. Our findings suggest limited utility of mutational screening prior to CAR-T/TCE, while underscoring the importance of dynamic surveillance during therapy.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward Equitable Risk Classification for All Patients with T-ALL.","authors":"Adam J de Smith","doi":"10.1158/2643-3230.BCD-25-0221","DOIUrl":"10.1158/2643-3230.BCD-25-0221","url":null,"abstract":"<p><p>In this issue of Blood Cancer Discovery, Newman and colleagues investigated the impact of genetic ancestry on molecular subtypes, genomic alterations, and survival outcomes in a diverse cohort of patients with T-cell acute lymphoblastic leukemia. They demonstrated that the prognostic utility of genomic alterations varied by ancestry, in particular, with NOTCH1 mutations having no prognostic utility in patients of predominantly African ancestry, and their findings highlight the importance of considering genetic ancestry in the risk stratification of patients with T-ALL. See related article by Newman et al., p. 412.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"400-402"},"PeriodicalIF":11.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405836/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A FABulous Couple: Adding PHENotype to GENotype Improves HMA/VEN Response Prediction in AML.","authors":"Simon Renders, Alexander Waclawiczek, Andreas Trumpp","doi":"10.1158/2643-3230.BCD-25-0174","DOIUrl":"10.1158/2643-3230.BCD-25-0174","url":null,"abstract":"<p><p>In a large retrospective multicenter study of patients with acute myeloid leukemia treated with hypomethylating agents and venetoclax, Lachowiez and colleagues examine the interplay among genetic mutations, disease phenotype, and clinical outcomes. They show that within genetic subgroups-particularly NPM1 wild-type cases-monocytic differentiation is linked to poor treatment response and inferior long-term prognosis, adding a phenotypic layer to genetics-based response prediction. See related article by Lachowiez et al., p. 437.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"403-405"},"PeriodicalIF":11.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multimodal and Data-Driven Assessment of Myeloid Neoplasms Refines Classification across Disease States.","authors":"Curtis A Lachowiez, Georgios Asimomitis, Elsa Bernard, Sean M Devlin, Yanis Tazi, Maria Creignou, Ulrich Germing, Norbert Gattermann, Amanda Gilkes, Ian Thomas, Lars Bullinger, Konstanze Döhner, Luca Malcovati, Jad Othman, Richard Dillon, Ann-Kathrin Eisfeld, Deedra Nicolet, Ghayas C Issa, Naval Daver, Tapan M Kadia, Courtney D DiNardo, Farhad Ravandi, Guillermo Garcia-Manero, Guillermo Montalban-Bravo, Nigel Russell, Mario Cazzola, Hartmut Döhner, Brian J P Huntly, Robert P Hasserjian, Eva Hellström-Lindberg, Elli Papaemmanuil, Sanam Loghavi","doi":"10.1158/2643-3230.BCD-25-0047","DOIUrl":"10.1158/2643-3230.BCD-25-0047","url":null,"abstract":"<p><p>The World Health Organization fifth edition and International Consensus Classification for myeloid neoplasms both incorporate empirical numerical thresholds to morphologic and molecular features defining certain disease entities. However, the clinical implications of these thresholds remain unclear. We analyzed a large cohort (N = 6,976) of patients with myeloid neoplasms to evaluate the impact of proposed yet different numerical thresholds for variant allele frequency of genetic mutations or hematologic parameters set forth by the World Health Organization fifth edition and International Consensus Classification for classification of SF3B1-mutated myelodysplastic neoplasms, NPM1-mutated acute myeloid leukemia (AML), and oligomonocytic chronic myelomonocytic leukemia. Our analysis demonstrated that the clonal burden of SF3B1 mutation in myelodysplastic neoplasms informs classification and prognosis. Our findings support the notion that NPM1 mutation should be AML-defining regardless of blast percentage and highlight the adverse prognostic impact of the cumulative number of myelodysplasia-related mutations in NPM1-mutated AML. Finally, we provide evidence that integrating specific molecular signatures could improve the accuracy of oligomonocytic chronic myelomonocytic leukemia classification.</p><p><strong>Significance: </strong>Using comprehensive clinical and molecular profiling, this study provides a data-driven approach for evaluating numerical thresholds of variant allele frequency or hematologic parameters (i.e., blast percentage and absolute monocyte count) included in current classification schemas across a spectrum of myeloid malignancies, enabling refinement of disease classification and prognostication.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"425-436"},"PeriodicalIF":11.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12294350/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144561337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and Phenotypic Correlates of Clinical Outcomes with Venetoclax in Acute Myeloid Leukemia: The GEN-PHEN-VEN Study.","authors":"Curtis A Lachowiez, Mael Heiblig, Gaspar Aspas Requena, Emmanuelle Tavernier-Tardy, Fangyan Dai, Amenech B Ashango, Daniel T Peters, Jacob Fang, Andy Kaempf, Nicola Long, Christopher A Eide, Stephen E Kurtz, Wei Xie, Anupriya Agarwal, Aishwarya Sahasrabudhe, Christine M McMahon, Maria L Amaya, Gabrielle Meyers, Arpita Gandhi, Jessica Leonard, Brandon Hayes-Lattin, Richard T Maziarz, Elie Traer, Rachel J Cook, Ronan Swords, Theodore P Braun, Jennifer N Saultz, Ashley M Eckel, Michael R Loken, Joshua F Zeidner, Jeffrey W Tyner, Daniel A Pollyea","doi":"10.1158/2643-3230.BCD-24-0256","DOIUrl":"10.1158/2643-3230.BCD-24-0256","url":null,"abstract":"<p><p>Resistance to venetoclax (VEN)-based therapy in acute myeloid leukemia (AML) includes genetic (i.e., mutations in N/KRAS, FLT3-ITD, TP53) and phenotypic (i.e., monocytic differentiation) features. Whether monocytic differentiation contributes to clinical VEN resistance secondary to a genetic bias remains unknown. This multimodal, multicenter, international analysis, inclusive of 678 patients, comprehensively characterized the prognostic role of monocytic differentiation in patients with AML treated with hypomethylating agents combined with VEN. AML genetics and monocytic differentiation (HR = 1.89; 95% confidence interval, 1.35-2.66; P < 0.001) in NPM1 wild-type cases correlated with an increased risk of death, clustering of centralized quantitative multiparameter flow cytometry data, evaluation of RNA sequencing-derived AML maturation stage, and single-cell proteogenomics linked driver mutations with AML phenotype and antiapoptotic gene expression. This comprehensive analysis of AML genetics, phenotype, and antiapoptotic protein expression highlights the complementary role these factors impart following VEN-based therapy.</p><p><strong>Significance: </strong>AML with monocytic differentiation often occurs in the context of co-occurring mutations within signaling pathways. In certain AML subgroups (such as NPM1 wild-type and signaling pathway gene-mutated), a monocytic phenotype is associated with decreased overall survival following VEN-based therapy. See related commentary by Renders, p. 403.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"437-449"},"PeriodicalIF":11.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutagenic Impact and Evolutionary Influence of Chemoradiotherapy in Hematologic Malignancies.","authors":"Benjamin Diamond, Dhanvantri Chahar, Michael D Jain, Alexandra M Poos, Michael A Durante, Bachisio Ziccheddu, Marcella Kaddoura, Marios Papadimitriou, Kylee H Maclachlan, Tomas Jelinek, Faith E Davies, Nicholas B Figura, Gareth J Morgan, Elias K Mai, Katja Weisel, Roland Fenk, Marc S Raab, Saad Usmani, Ola Landgren, Frederick L Locke, Hartmut Goldschmidt, Jonathan Harry Schatz, Niels Weinhold, Francesco Maura","doi":"10.1158/2643-3230.BCD-24-0328","DOIUrl":"10.1158/2643-3230.BCD-24-0328","url":null,"abstract":"<p><p>Ionizing radiotherapy (RT) is a widely used treatment strategy for malignancies. In solid tumors, RT-induced double-strand breaks lead to the accumulation of insertion-deletions (indels; ID), and their repair by nonhomologous end joining has been linked to the ID8 mutational signature in surviving cells. However, the extent of RT-induced mutagenesis in hematologic malignancies and its impact on their mutational profiles and interplay with commonly used chemotherapies has not yet been explored. In this study, we interrogated 580 whole-genome sequence (WGS) samples from patients with large B-cell lymphoma, multiple myeloma, and myeloid neoplasms and identified ID8 only in relapsed disease. Yet ID8 was detected after exposure to both RT and mutagenic chemotherapy (i.e., platinum and melphalan). Using WGS of single-cell colonies derived from treated lymphoma cells, we revealed a dose-response relationship between RT and platinum and ID8. Finally, using ID8 as a genomic barcode, we demonstrate that a single RT-surviving cell may seed distant relapse.</p><p><strong>Significance: </strong>RT and the ID8 indel signature are related, but their genomic impact on hematologic malignancies is unclear. Leveraging WGS, we linked ID8 to both RT and mutagenic chemotherapy and validated that platinum can induce ID8. We used ID8 as a genomic barcode to reveal that RT-resistant cells may seed systemic relapse.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"450-463"},"PeriodicalIF":11.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405863/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Isoform-Specific RUNX1C-BTG2 Axis Governs AML Quiescence and Chemoresistance.","authors":"Cuijuan Han, Zhiping Zhang, Edie I Crosse, Sogand Sajedi, Bin Lu, Xiyue Wang, Sadik Karma, Mitch Kostich, Sakthi Harini Rajendran, Dylan B Udy, Steven Chen, Alexander Arnuk, Abimbola Eunice Lawal, Kayla R Koenig, Meryl McKenna, Patrick K Reville, Hussein A Abbas, Omar Abdel-Wahab, Pedro Miura, Robert K Bradley, Eric Wang","doi":"10.1158/2643-3230.BCD-24-0327","DOIUrl":"10.1158/2643-3230.BCD-24-0327","url":null,"abstract":"<p><p>Aberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet their role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in patients with AML before therapy and at relapse after chemotherapy and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long-isoform RUNX1C through its alternative distal promoter. The unique N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. BTG2 promoted rRNA deadenylation, resulting in decreased mRNA expression and stability. Deletion of rRNAs increased cellular quiescence. Moreover, RNA-based targeting of RUNX1C reactivated quiescent leukemia cells and enhanced chemotherapy efficacy. These findings delineated an isoform-specific transcriptional circuit that governed chemotherapy response, providing a potential therapeutic strategy to mitigate AML recurrence.</p><p><strong>Significance: </strong>This study identifies RUNX1C as a contributor to AML chemoresistance and an inducer of quiescence through BTG2. Targeting RUNX1C with RNA-based approaches disrupts this state and improves chemotherapy response, highlighting RUNX1C inhibition as a promising strategy to overcome resistance and enhance treatment efficacy in AML.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"464-483"},"PeriodicalIF":11.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Commensal Bacteria Drive B-cell Lymphomagenesis in the Setting of Innate Immunodeficiency.","authors":"Jaeyong Jung, Sining Zhu, Almin Lalani, Judith Shakarchi, Brygida Matracz, Guojun Gary Wu, Wei-Xing Zong, Liping Zhao, Ping Xie","doi":"10.1158/2643-3230.BCD-24-0279","DOIUrl":"10.1158/2643-3230.BCD-24-0279","url":null,"abstract":"<p><p>Myeloid cells are central players in innate immunity and inflammation. Their function is regulated by the adapter protein TRAF3. We previously reported that aging myeloid cell-specific TRAF3-deficient (M-Traf3-/-) mice spontaneously develop chronic inflammation and B-cell lymphoma (BCL). In this study, we aimed to identify the internal trigger of this disease phenotype in these mice. We first detected gut microbiota dysbiosis and transmigration of commensal bacteria (CB) to the liver in aging M-Traf3-/- mice. Interestingly, depletion of CB using antibiotics effectively prevented BCL development in these mice. Systemic IgG responses against CB were induced and the IgH CDR3 sequences of malignant B-cell clones of M-Traf3-/- mice showed high homology to prevalent bacteria-reactive Ig clonotypes. Furthermore, M-Traf3-/- mice with BCL exhibited high serum titers of antibodies against CB. Together, our findings offer insights into the mechanisms underlying increased risks of B-cell lymphomagenesis observed in patients with compromised innate immunity.</p><p><strong>Significance: </strong>We present evidence that microbiota dysbiosis in animals with compromised innate immunity increases risk of intestinal bacteria transmigration to internal organs, which subsequently induces malignant transformation of CB-reactive B-cell clones. Accordingly, antibiotic treatment or blocking CB transmigration may serve as a strategy for preventing BCL in patients with innate immunodeficiency.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"505-525"},"PeriodicalIF":11.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144561336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}