Blood Cancer Discovery最新文献

{"title":"Impact of Genetic Ancestry on Genomics and Survival Outcomes in T-cell Acute Lymphoblastic Leukemia.","authors":"Haley Newman, Shawn H R Lee, Petri Pölönen, Rawan Shraim, Yimei Li, Hongyan Liu, Richard Aplenc, Shovik Bandyopadhyay, Changya Chen, Meenakshi Devidas, Caroline Diorio, Kimberly Dunsmore, Omar Elghawy, Amira Elhachimi, Tori Fuller, Sumit Gupta, Junior Hall, Andrew D Hughes, Stephen P Hunger, Mignon L Loh, Zachary Martinez, Michael F McCoy, Cassidy G Mullen, Stanley B Pounds, Elizabeth Raetz, Anna Eames Seffernick, Gongping Shi, Jonathan Sussman, Kai Tan, Lahari Uppuluri, Tiffaney L Vincent, Ruth Wang'ondu, Lena E Winestone, Stuart S Winter, Brent L Wood, Gang Wu, Jason Xu, Wenjian Yang, Charles G Mullighan, Jun J Yang, Kira Bona, David T Teachey","doi":"10.1158/2643-3230.BCD-25-0049","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-25-0049","url":null,"abstract":"<p><p>The influence of genetic ancestry on genomics in T-cell Acute Lymphoblastic Leukemia (T-ALL) has not been fully explored. We examined the impact of genetic ancestry on multi-omic alterations, survival outcomes, and risk stratification. Among 1309 children and young adults with T-ALL treated on the Children's Oncology Group trial AALL0434, the prognostic value of five commonly altered T-ALL genes varied by ancestry-including NOTCH1, which was associated with superior overall survival for patients of European ancestry but non-prognostic among patients of African ancestry. Integrating genetic ancestry with published T-ALL risk classifiers, we identified that a X01 Penalized Cox Regression classifier stratified patients regardless of ancestry, whereas a European multi-gene classifier misclassified patients of certain ancestries. Overall, 80% of patients harbored a genomic alteration in at least one gene with differential prognostic impact in an ancestry-specific manner. These data demonstrate the importance of incorporating genetic ancestry into genomic risk classification.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144162472","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":"Mutagenic impact and evolutionary influence of chemo-radiotherapy 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 indels, and their repair by non-homologous 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. Here, we interrogated 580 whole-genome sequence samples (WGS) 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>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121083","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":"B cell receptor silencing reveals origin and dependencies of high-grade B cell lymphomas with MYC and BCL2 rearrangements.","authors":"Gabriele Varano, Silvia Lonardi, Paola Sindaco, Ilaria Pietrini, Gaia Morello, Piera Balzarini, Filippo Vit, Hadas Neuman, Giorgio Bertolazzi, Silvia Brambillasca, Nicara C Parr, Marco Chiarini, Silvia Bellesi, Elena Maiolo, Sabrina Giampaolo, Federica Mainoldi, Viveka Selvarasa, Hiroshi Arima, Vilma Pellegrini, Chiara Pagani, Mattia Bugatti, Cecilia Ranise, Tommaso M Taddei, Takashi Sonoki, Hajdica Thanasi, Elena Morlacchi, Daniel Segura-Garzon, Emma Albertini, Rosa Daffini, Anojan Sivacegaram, Henry Yang, Ying Li, Valeria Cancila, Giada Cicio, Michela Robusto, Brian Leuzzi, Adrian Andronache, Paolo Trifiro, Mirko Riboni, Simone P Minardi, Raoul Jp Bonnal, Cristina Lopez Gonzalez, Euplio Visco, Pasquale Capaccio, Sara Torretta, Lorenzo Pignataro, Camillo Almici, Mario Varasi, Luigi M Larocca, Reiner Siebert, Brunangelo Falini, Andrés J M Ferreri, Alessandra Tucci, Daniele Lorenzini, Antonello D Cabras, Giancarlo Pruneri, Arianna Di Napoli, Marco Ungari, Marco Pizzi, Stefan Hohaus, Ciro Mercurio, Joo Y Song, Wing C Chan, Luisa Lorenzi, Riccardo Bomben, Maurilio Ponzoni, Ramit Mehr, Claudio Tripodo, Fabio Facchetti, Stefano Casola","doi":"10.1158/2643-3230.BCD-25-0099","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-25-0099","url":null,"abstract":"<p><p>The B cell receptor (BCR) is critical for mature B cell lymphomas, serving as a therapeutic target. We show that high-grade B cell lymphomas with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. IGH-silenced HGBCL-DH-BCL2 (IGHUND) differ from IGH+ counterparts in germinal center-zone programs, MYC expression, and immune infiltrate. While IGH+ HGBCL-DH-BCL2 favor IGM/IG-Kappa expression, IGHUND counterparts complete IGH isotype switching and IG-Lambda rearrangements. IGHUND lymphomas retain productive IGHV rearrangements and require IGH for optimal fitness. BCR silencing, caused by accelerated IGH turnover and reduced IGH expression, precedes HGBCL-DH-BCL2 onset, inducing RAG1/2-dependent IG light chain editing and facilitating t(8;22)/IGL::MYC translocations. IGHUND HGBCL-DH-BCL2 models exhibit reduced sensitivity to the CD79B-targeting antibody-drug conjugate Polatuzumab-vedotin. Collectively, HGBCL-DH-BCL2 commonly arises from isotype-switched t(14;18)+ germinal center B cells, which edit IG light chains, fueling intra-clonal diversification, BCR extinction, and t(8;22) while maintaining IGH dependence, with clinical implications.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121079","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":"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":"https://doi.org/10.1158/2643-3230.BCD-24-0256","url":null,"abstract":"<p><p>Resistance to venetoclax-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 venetoclax 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 AML patients treated with hypomethylating agents combined with venetoclax. AML genetics and monocytic differentiation (HR: 1.89, 95% CI: 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 anti-apoptotic gene expression. This comprehensive analysis of AML genetics, phenotype, and anti-apoptotic protein expression highlights the complementary role these factors impart following venetoclax-based therapy.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112165","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":"DNA methylation epitypes of Burkitt lymphoma with distinct molecular and clinical features.","authors":"Nicole Thomas, Carlos A García-Prieto, Kostiantyn Dreval, Laura K Hilton, Jeremy S Abramson, Nancy L Bartlett, Jeffrey Bethony, Jay Bowen, Anthony C Bryan, Corey Casper, Maureen A Dyer, Julie M Gastier-Foster, Alina S Gerrie, Timothy C Greiner, Nicholas B Griner, Thomas G Gross, Nancy Harris, John D Irvin, Elaine S Jaffe, Fabio E Leal, Sam M Mbulaiteye, Charles G Mullighan, Andrew J Mungall, Karen L Mungall, Constance Namirembe, Ariela Noy, Martin D Ogwang, Jackson Orem, German Ott, Hilary Petrello, Steven J Reynolds, Steven H Swerdlow, Alexandra Traverse-Glehen, Wyndham H Wilson, Marco A Marra, Louis M Staudt, David W Scott, Manel Esteller, Ryan D Morin","doi":"10.1158/2643-3230.BCD-24-0240","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-24-0240","url":null,"abstract":"<p><p>The genetic subtypes of Burkitt Lymphoma (BL) have been defined, whereas the role of epigenetics remains to be comprehensively characterized. We searched genomic DNA from 218 patients across four continents, for recurrent DNA methylation patterns and their associations with clinical and molecular features. We identified DNA methylation patterns that were not fully explained by EBV status or mutation status, leading to two epitypes, described here as HypoBL and HyperBL. Each is characterized by distinct genomic and clinical features including global methylation, mutation burden, aberrant somatic hypermutation, and survival outcomes. Methylation, gene expression and mutational differences between the epitypes support a model in which each arises from a distinct cell-of-origin. These results, pending validation in external cohorts, point to a refined risk assessment for BL patients who may experience inferior outcomes.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062378","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":"High-Dose Methotrexate, Ibrutinib, and Temozolomide in the Treatment of Newly Diagnosed Primary CNS Lymphoma: A Multicenter, Prospective Phase II Study.","authors":"Yan Gao, Liqin Ping, Changguo Shan, He Huang, Zhiming Li, Hui Zhou, Mingyao Lai, Linbo Cai, Bing Bai, Cheng Huang, Haoqing Chen, Xiaoyu Hong, Xiaoxiao Wang, Huiqiang Huang","doi":"10.1158/2643-3230.BCD-24-0156","DOIUrl":"10.1158/2643-3230.BCD-24-0156","url":null,"abstract":"<p><strong>Significance: </strong>We report promising efficacy and good tolerability of Bruton tyrosine kinase (BTK) inhibitor ibrutinib in treatment of newly diagnosed PCNSL. Additionally, we explored the contribution of ctDNA profiling to predictive potential in this prospective study. The consistency of ctDNA clearance from CSF/plasma was associated with more sustained treatment response and survival.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"191-202"},"PeriodicalIF":11.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12050966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256865","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":"Beyond Trial and Error: A Mathematical Model Wrangles DLBCL Heterogeneity Toward Optimizing Combination Therapy.","authors":"Jordan S Goldstein, Nick A Phillips, Ash A Alizadeh","doi":"10.1158/2643-3230.BCD-25-0071","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-25-0071","url":null,"abstract":"<p><p>In this issue of Blood Cancer Discovery, Pomeroy and Palmer present a new mathematical model, incorporating both inter- and intra-patient heterogeneity, to accurately predict outcomes for first-line combination therapies in diffuse large B-cell lymphoma. Their quantitative framework opens a range of possibilities for optimizing trial design and lymphoma therapy with potential to expedite clinical development. See related article by Pomeroy and Palmer, p. 254.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":"6 3","pages":"153-156"},"PeriodicalIF":11.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12050974/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050691","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":"Unleashing the Full Potential of Metabolic Interventions in T-ALL.","authors":"Victoria da Silva-Diz, Daniel Herranz","doi":"10.1158/2643-3230.BCD-25-0012","DOIUrl":"10.1158/2643-3230.BCD-25-0012","url":null,"abstract":"<p><p>Drugs targeting metabolism have been effectively used in patients with T-cell acute lymphoblastic leukemia (T-ALL) for decades; still, the full therapeutic potential of targeting metabolism has not been completely exploited yet. Here, we highlight the critical need for metabolic biomarkers to advance precision medicine in T-ALL, explore the identification of novel metabolic vulnerabilities, and discuss the potential of targeted therapies and dietary interventions to optimize treatment outcomes.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"163-167"},"PeriodicalIF":11.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12050939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664582","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":"Brexucabtagene Autoleucel versus Allogeneic Hematopoietic Cell Transplantation in Relapsed and Refractory Mantle Cell Lymphoma.","authors":"Nora Liebers, Ariane Boumendil, Hervé Finel, Dominic Edelmann, Guido Kobbe, Ben-Niklas Baermann, Yasmina Serroukh, Didier Blaise, Dietrich Wilhelm Beelen, Carlos Solano, Maija Itälä-Remes, Tom van Meerten, Goda Choi, Susanne Anna Christine Schmidt, Nicolaus Kröger, Jenny Byrne, Jean-Jacques Tudesq, Anna Ossami Saidy, Ana Nunes, Rubina Siddiqi, Elande Baro, Dan Zheng, Ioana Kloos, Peter Dreger, Anna Sureda, Bertram Glass, Sascha Dietrich","doi":"10.1158/2643-3230.BCD-24-0178","DOIUrl":"10.1158/2643-3230.BCD-24-0178","url":null,"abstract":"<p><strong>Significance: </strong>Patients aged ≥50 years with r/r MCL had superior OS and lower nonrelapse mortality 1 year after receiving brexu-cel compared with alloHCT. However, the long-term PFS and OS are similar for both treatments. Individual risk-benefit evaluation is essential to guide optimal treatment decisions.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"182-190"},"PeriodicalIF":11.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12050943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143365781","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":"Immune Escape of Acute Myeloid Leukemia after Transplantation.","authors":"Nguyen Huong Jenny Giang Ho, Nana Talvard-Balland, Natalie Köhler, Robert Zeiser","doi":"10.1158/2643-3230.BCD-24-0063","DOIUrl":"10.1158/2643-3230.BCD-24-0063","url":null,"abstract":"<p><strong>Significance: </strong>We discuss the mechanisms of AML immune evasion including loss or downregulation of MHC class I and II, reduced TRAIL receptor expression, inhibitory metabolite production, inhibitory ligand expression, impaired proinflammatory cytokine production, and AML niche alterations.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"168-181"},"PeriodicalIF":11.5,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12050969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764910","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}