Blood Cancer Discovery最新文献

{"title":"The Silence of the Lambdas: Hidden Complexities in the Evolution of Double-Hit Lymphomas.","authors":"Galina Shevchenko, Daniel J Hodson","doi":"10.1158/2643-3230.BCD-25-0160","DOIUrl":"10.1158/2643-3230.BCD-25-0160","url":null,"abstract":"<p><p>In this issue of Blood Cancer Discovery, Varano and colleagues uncover a substantial fraction of high-grade B-cell lymphoma with MYC and BCL2(-BCL6) translocations (so called \"double-hit\" lymphomas or high-grade B-cell lymphoma-double-hit-BCL2) that lack detectable expression of the B-cell receptor. MYC translocation in these cells is mediated by RAG enzymes, induced in response to silencing of the B-cell receptor in a precursor cell, a feature that renders them resistant to polatuzumab vedotin. See related article by Varano et al., p. 364.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"284-287"},"PeriodicalIF":11.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144318128","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":"Putting AML Differentiation States on the BoneMarrowMap.","authors":"Jonas Berger, Livius Penter","doi":"10.1158/2643-3230.BCD-25-0083","DOIUrl":"10.1158/2643-3230.BCD-25-0083","url":null,"abstract":"<p><p>This article presents a novel computational tool, \"BoneMarrowMap,\" that enables the mapping of leukemic single-cell RNA sequencing datasets to hematopoietic differentiation states. By utilizing BoneMarrowMap for a large-scale single-cell RNA sequencing reanalysis, the authors discover 12 recurrent acute myeloid leukemia differentiation patterns linked to prognosis and treatment and dissect leukemic clonal architectures within individual patients. See related article by Zeng and colleagues, p. 307.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"280-283"},"PeriodicalIF":11.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209771/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986234","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":"Overcoming B-ALL Resistance to Targeted and Immune Therapies by Rational Combination Strategies.","authors":"Miguel Quijada-Álamo, Grace Freed, Elvin Wagenblast","doi":"10.1158/2643-3230.BCD-25-0036","DOIUrl":"10.1158/2643-3230.BCD-25-0036","url":null,"abstract":"<p><p>Despite the remarkable efficacy of targeted therapies and immunotherapies in B-cell acute lymphoblastic leukemia (B-ALL), relapsed and refractory cases remain a major challenge. In this review, we discuss how integrating targeted agents with immunotherapy could help overcome resistance and improve long-term patient outcomes in B-ALL.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"293-297"},"PeriodicalIF":11.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209775/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144054055","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":"Enhancer Hijacking Discovery in Acute Myeloid Leukemia by Pyjacker Identifies MNX1 Activation via Deletion 7q.","authors":"Etienne Sollier, Anna Riedel, Umut H Toprak, Justyna A Wierzbinska, Dieter Weichenhan, Jan Philipp Schmid, Mariam Hakobyan, Aurore Touzart, Ekaterina Jahn, Binje Vick, Fiona Brown-Burke, Katherine Kelly, Simge Kelekçi, Anastasija Pejkovska, Ashish Goyal, Marion Bähr, Kersten Breuer, Mei-Ju May Chen, Maria Llamazares-Prada, Mark Hartmann, Maximilian Schönung, Nadia Correia, Andreas Trumpp, Yomn Abdullah, Ursula Klingmüller, Sadaf S Mughal, Benedikt Brors, Frank Westermann, Elias Ulrich, Robert J Autry, Matthias Schlesner, Sebastian Vosberg, Tobias Herold, Philipp A Greif, Dietmar Pfeifer, Michael Lübbert, Thomas Fischer, Florian H Heidel, Claudia Gebhard, Wencke Walter, Torsten Haferlach, Ann-Kathrin Eisfeld, Krzysztof Mrózek, Deedra Nicolet, Lars Bullinger, Leonie Smeenk, Claudia Erpelinck-Verschueren, Roger Mulet-Lazaro, Ruud Delwel, Aurélie Ernst, Michael Scherer, Pavlo Lutsik, Irmela Jeremias, Konstanze Döhner, Hartmut Döhner, Daniel B Lipka, Christoph Plass","doi":"10.1158/2643-3230.BCD-24-0278","DOIUrl":"10.1158/2643-3230.BCD-24-0278","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) with complex karyotype is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. Genomic rearrangements can reposition active enhancers near proto-oncogenes, leading to their aberrant expression; however, a comprehensive understanding of these events in AML is still incomplete. To facilitate the discovery of such \"enhancer hijacking\" events, we developed Pyjacker, a computational tool, and applied it to 39 AML samples with complex karyotype. Pyjacker identified several enhancer hijacking events in AML patient samples, including aberrant expression of MNX1, which can result from del(7)(q22q36) and is associated with hijacking of a CDK6 enhancer. MNX1 activation occurred in 1.4% of patients with AML and showed significant co-occurrence with BCOR mutations. Through a xenograft mouse model, we demonstrated that MNX1 is required for leukemia cell fitness. Pyjacker is an easy-to-use, accurate, and broadly applicable tool for identifying consequences of genomic events driving tumorigenesis, especially when germline genomic data are missing.</p><p><strong>Significance: </strong>This study examines the consequences of structural alterations in AML and demonstrates that proto-oncogene activation by enhancer hijacking is an understudied pathomechanism. MNX1 overexpression demonstrates that deletions on chromosome 7q can not only lead to haploinsufficiency but also to activation of oncogenes by enhancer hijacking.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"343-363"},"PeriodicalIF":11.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143754715","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":"B-cell Receptor Silencing Reveals the 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 J P Bonnal, Cristina Lopez Gonzalez, Euplio Visco, Pasquale Capaccio, Sara Torretta, Lorenzo Pignataro, Camillo Almici, Mario Varasi, Luigi M Larocca, Reiner Siebert, Brunangelo Falini, Andres 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":"10.1158/2643-3230.BCD-25-0099","url":null,"abstract":"<p><p>The B-cell receptor (BCR) is critical for mature B-cell lymphomas (BCL), serving as a therapeutic target. We show that high-grade BCLs with MYC and BCL2 rearrangements [HGBCL-double-hit (DH)-BCL2] predominantly exhibit immunoglobulin heavy (IGH) chain silencing, leading to BCR shutdown. IGH-silenced HGBCL-DH-BCL2 (IGHUND) tumors differ from IGH+ counterparts in germinal center (GC) zone programs, MYC expression, and immune infiltrate. Whereas IGH+ HGBCL-DH-BCL2 tumors favor IGM/IG-κ expression, IGHUND counterparts complete IGH isotype switching and IG-λ 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)+ GC B cells, which edit IG light chains, fueling intraclonal diversification, BCR extinction, and t(8;22) while maintaining IGH dependence, with clinical implications.</p><p><strong>Significance: </strong>These findings link BCR silencing in IGH isotype-switched t(14;18)+ GC B cells to RAG1/2 expression, which triggers IG light chain editing and predisposes to IGL::MYC translocations, promoting HGBCL. In HGBCL with MYC and BCL2 rearrangements, BCR silencing protects from polatuzumab vedotin killing. See related commentary by Shevchenko and Hodson, p. 284.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"364-393"},"PeriodicalIF":11.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144121079","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":"Q&A: Louis Staudt on Molecular Classification of Cancer.","authors":"","doi":"10.1158/2643-3230.BCD-25-0133","DOIUrl":"10.1158/2643-3230.BCD-25-0133","url":null,"abstract":"","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"276-279"},"PeriodicalIF":11.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050649","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":"DLBCL cells emerge post CD19 CAR-T with cross-antigen resistance and a gene signature predictive of clinical CAR-T response.","authors":"Fabiana Lϋӧnd, Jeanne Whalen, Youngchul Song, Kalyn Schriefer, Rick Newcombe, Elena J Orlando, Sarah M Choi, Marco Ruella, Joseph A Fraietta, Stephen J Schuster, Jennifer L Brogdon, Matthew J Niederst, Louise M Treanor","doi":"10.1158/2643-3230.BCD-24-0176","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-24-0176","url":null,"abstract":"<p><p>Current understanding of lymphoma cell-intrinsic mechanisms of relapse following CAR-T cell treatment of diffuse large B-cell lymphoma (DLBCL) include antigen-loss and apoptosis resistance. Herein, CD19 CAR-T response and resistance were modeled and it was identified that treatment-naïve CD19 expression does not correlate with CAR-T sensitivity, but resistance is frequently accompanied by reversible downregulation of CD19, that once restored is not paralleled with restored sensitivity to CAR-T mediated killing. Profiling a suite of DLBCL cell lines to CD19 CAR-T sensitivity, reveals that DLBCL cells become non-responsive to CAR-T mediated killing, including to alternative antigen-targeting of CD20 or CD22. Leveraging these resistant models, we identified gene signatures present in the CAR-T resistant DLBCL cell lines that correlate with patient response to CTL019 in two independent clinical trials. Finally, we show that combination strategies to overcome this resistance, including upfront dual antigen-targeting and combined treatment with an Mcl-1 inhibitor, improve CAR-T responses.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512584","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":"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":"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":"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-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}