Blood Cancer Discovery最新文献

{"title":"Perspectives on Newly Diagnosed Myeloma Treatment and Emerging Challenges.","authors":"Cyrille Touzeau, Philippe Moreau","doi":"10.1158/2643-3230.BCD-25-0280","DOIUrl":"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":"538-541"},"PeriodicalIF":12.2,"publicationDate":"2025-11-03","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":"RNA Splicing as a Therapeutic Vulnerability in Therapy-Refractory Multiple Myeloma.","authors":"Maxim I Maron, Omar Abdel-Wahab","doi":"10.1158/2643-3230.BCD-25-0308","DOIUrl":"10.1158/2643-3230.BCD-25-0308","url":null,"abstract":"<p><p>In this issue of Blood Cancer Discovery, Kamiya and colleagues identify aberrant RNA splicing as a targetable vulnerability in multiple myeloma. Using the RBM39 degrader indisulam, they show that therapeutic modulation of RNA splicing factors is a potential treatment strategy for patients with therapy-resistant multiple myeloma. See related article by Kamiya et al., p. 602.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"535-537"},"PeriodicalIF":12.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13229134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276008","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 after CD19 CAR T Cells with Cross-Antigen Resistance and a Gene Signature Predictive of Clinical CAR T-cell Response.","authors":"Fabiana Lüönd, 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":"10.1158/2643-3230.BCD-24-0176","url":null,"abstract":"<p><p>Current understanding of lymphoma cell-intrinsic mechanisms of relapse following chimeric antigen receptor (CAR) T-cell treatment of diffuse large B-cell lymphoma (DLBCL) include antigen loss and apoptosis resistance. Herein, CD19 CAR T-cell response and resistance were modeled, and it was identified that treatment-naïve CD19 expression does not correlate with CAR T-cell sensitivity, but resistance is frequently accompanied by reversible downregulation of CD19 that once restored is not paralleled with restored sensitivity to CAR T cell-mediated killing. Profiling a suite of DLBCL cell lines to CD19 CAR T-cell sensitivity reveals that DLBCL cells become nonresponsive to CAR T cell-killing, including to alternative antigen targeting of CD20 or CD22. Leveraging these resistant models, we identified gene signatures present in the CAR T cell-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 up-front dual-antigen targeting and combined treatment with an Mcl-1 inhibitor, improve CAR T-cell responses.</p><p><strong>Significance: </strong>We demonstrate that DLBCL cells surviving CD19 CAR T-cell treatment develop a resistance phenotype with a \"resistance signature\" predictive of clinical CAR T-cell response, mediating cross-resistance between CAR T cells targeting different antigens. Our findings suggest that up-front dual-antigen targeting and combination therapies could improve clinical outcomes.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"580-601"},"PeriodicalIF":12.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12591092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512584","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":"Acquired and Selected: Tracking Antigen Escape during T Cell-Redirecting Therapies in Multiple Myeloma.","authors":"Joseph Kauer, Niels Weinhold, Marc S Raab","doi":"10.1158/2643-3230.BCD-25-0328","DOIUrl":"10.1158/2643-3230.BCD-25-0328","url":null,"abstract":"<p><p>In this issue of Blood Cancer Discovery, Papadimitriou and colleagues implement a temporal workflow to monitor genomic antigen escape during BCMA- or GPRC5D-directed immunotherapy. Using chemotherapy-induced mutational signatures as barcodes, they provide evidence that these mutations are acquired during therapy rather than being preexisting in newly diagnosed patients. See related article by Papadimitriou et al., p. 572.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"532-534"},"PeriodicalIF":12.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145281056","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":"IRF4 Promotes Immune Evasion and Shapes the Tumor Microenvironment in Follicular Lymphoma.","authors":"Surendra Dasari, Kerstin Wenzl, Geoffrey M Nelson, Emmanuel Contreras Guzman, Zhiquan Wang, Loic Chartier, Zhi-Zhang Yang, Jose C Villasboas, Joshua Olson, Prithviraj Mukherjee, Vaishali Bhardwaj, Xinyi Tang, Brianna J Negaard, Johannes L Zakrzewski, Rebecca L King, Sarah Huet, Bruno Tesson, Matthew J Maurer, Franck Morschhauser, Grzegorz S Nowakowski, Karen L Adelman, Harinder Singh, Laura Pasqualucci, Mark Shlomchik, Anne J Novak, Stephen M Ansell, Patrizia Mondello","doi":"10.1158/2643-3230.BCD-24-0223","DOIUrl":"10.1158/2643-3230.BCD-24-0223","url":null,"abstract":"<p><p>Twenty percent of patients with follicular lymphoma relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multiomic approach, we show that patients with follicular lymphoma with elevated IRF4 expression (IRF4hi) have increased transformation risk, dysregulated immune signaling, and a suppressive tumor microenvironment. Loss- and gain-of-function experiments in IRF4hi lymphoma cells, along with chromatin profiling, demonstrate that IRF4 impairs their interaction with T cells by repressing antigen presentation and co-receptor gene modules while promoting the expression of cytokines that antagonize T-follicular helper cell and regulatory T-cell functions. Additionally, IRF4 rewires tumor metabolism and restricts glucose availability to immune cells. Silencing of IRF4 inhibits tumor cell growth and restores immune surveillance mechanisms, thus representing a promising target for therapy. Our data suggest that IRF4hi lymphoma cells co-opt a developmental mechanism used to exit the germinal center response in promoting a more aggressive cancer via engagement of multiple immune-evasive mechanisms.</p><p><strong>Significance: </strong>We show that IRF4 controls immune and metabolic signaling with functional effects on the cross-talk between B and T cells, resulting in a suppressive immune microenvironment when IRF4 is overexpressed in lymphoma. This underscores the importance of IRF4 as a pivotal therapeutic target to restore antitumor immunosurveillance for IRF4-associated lymphomas.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"623-645"},"PeriodicalIF":12.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12313276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643754","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":"Identification of a CD138-Negative Therapy-Resistant Subpopulation in Multiple Myeloma with Vulnerability to Splicing Factor Inhibition.","authors":"Takahiro Kamiya, Masahiko Ajiro, Motohiko Oshima, Shuhei Koide, Yaeko Nakajima-Takagi, Kazumasa Aoyama, Akiho Tsuchiya, Satoshi Kaito, Naoki Itokawa, Ryoji Ito, Kiyoshi Yamaguchi, Yoichi Furukawa, Bahityar Rahmutulla, Atsushi Kaneda, Takayuki Shimizu, Noriko Doki, Taku Kikuchi, Nobuhiro Tsukada, Masayuki Yamashita, Shinichiro Okamoto, Akihide Yoshimi, Keisuke Kataoka, Atsushi Iwama","doi":"10.1158/2643-3230.BCD-24-0340","DOIUrl":"10.1158/2643-3230.BCD-24-0340","url":null,"abstract":"<p><p>The molecular basis of therapy resistance in multiple myeloma remains poorly understood. In this study, we performed single-cell RNA sequencing coupled with VDJ-targeted sequencing of highly purified primary multiple myeloma cells from patient bone marrow. This approach uncovered cellular heterogeneity and phenotypic plasticity of multiple myeloma cells across a spectrum of CD138 expression, accompanied by drastic epigenetic alterations. Notably, therapy-resistant subpopulations were identified within a minor fraction of CD138- multiple myeloma cells, which were shown via CRISPR/Cas9 screening to be vulnerable to splicing pathway inhibition. Consistently, this fraction of CD138- multiple myeloma cells showed increased differential splicing associated with overexpression of SR protein family splicing factors. Among these splicing factors, RBM39 was overexpressed in therapy-resistant cells and involved in aberrant splicing. Both genetic and pharmacologic RBM39 inhibition exhibited a significant lethal effect on multiple myeloma cells. Collectively, our findings identify distinct therapy-resistant multiple myeloma subpopulations and highlight targeting the splicing pathway as a promising therapeutic strategy.</p><p><strong>Significance: </strong>Single-cell RNA sequencing coupled with VDJ-targeted profiling identified distinct therapy-resistant subpopulations within the minor CD138- fraction of multiple myeloma cells. These subpopulations were characterized by increased differential splicing events associated with overexpression of splicing factors from the SR protein family, with CD138- cells showing selective vulnerability to pharmacologic targeting of the splicing factor RBM39. See related commentary by Maron and Abdel-Wahab, p. 535.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"602-622"},"PeriodicalIF":12.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144972000","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":"Combination Strategies with Menin Inhibitors for Acute Leukemia.","authors":"Ghayas C Issa, Sheng F Cai, Alex Bataller, Hagop M Kantarjian, Eytan M Stein","doi":"10.1158/2643-3230.BCD-24-0212","DOIUrl":"10.1158/2643-3230.BCD-24-0212","url":null,"abstract":"<p><p>Menin inhibitors are targeted therapies for the treatment of genetically defined subsets of acute leukemia. The menin inhibitor revumenib is approved for the treatment of relapsed or refractory leukemia with rearrangement of KMT2A. In addition, multiple menin inhibitors are currently in clinical development aimed at targeting other additional subsets, such as NPM1 mutations, which form up to 30% of acute myeloid leukemia. However, as observed with other targeted therapies for cancer, on-target resistance mutations emerged in advanced cases following monotherapy. Therefore, combination strategies incorporating menin inhibitors are needed to improve durability and depth of remission.</p><p><strong>Significance: </strong>Menin inhibitors have the potential to reshape treatment paradigms in acute leukemia. There are multiple promising preclinical combinations that require careful clinical trial design and implementation for a successful translation into the clinical setting.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"547-560"},"PeriodicalIF":12.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144972031","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":12.2,"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":12.2,"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":12.2,"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}