Blood Cancer Discovery最新文献

{"title":"Nuclear Export Gone Rogue: XPO1's Chromatin Side Hustle Fuels Leukemia.","authors":"Drew J Adams","doi":"10.1158/2643-3230.BCD-25-0407","DOIUrl":"10.1158/2643-3230.BCD-25-0407","url":null,"abstract":"<p><p>Exportin-1 (XPO1/CRM1) is a validated target in hematologic malignancies best studied for its role in mediating nuclear export. In this issue of Blood Cancer Discovery, Barajas and colleagues reveal that UBTF tandem duplications found in acute myeloid leukemia complete a nuclear export sequence that enables a novel UBTF-XPO1 interaction, particularly at chromatin loci critical for leukemogenesis, thus raising the question: Could XPO1 inhibitors find new use in the UBTF-TD acute myeloid leukemia subtype? See related article by Barajas et al., p. 51.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"15-17"},"PeriodicalIF":12.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145565581","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":"The Global State of Blood Cancers: An Ongoing Challenge.","authors":"Lillian L Siu","doi":"10.1158/2643-3230.BCD-25-0408","DOIUrl":"10.1158/2643-3230.BCD-25-0408","url":null,"abstract":"<p><p>The state of the blood cancer field and its toll on patient mortality and morbidity, adapted from the 15th edition of the annual AACR Cancer Progress Report (https://cancerprogressreport.aacr.org/progress/), is presented to the US Congress and the public.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"25-30"},"PeriodicalIF":12.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145507491","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":"Long-term Therapy Outcomes of CD19/22 CAR T Cell Alone or with Autologous Stem Cell Transplantation for Relapsed/Refractory DLBCL.","authors":"Xiaoying Zhang, Jue Wang, Na Wang, Yang Yang, Jinhuan Xu, Xiaojian Zhu, Gaoxiang Wang, Di Wang, Fankai Meng, Yi Xiao, Miao Zheng, Li Meng, Chunrui Li, Jia Wei, Yang Cao, Yicheng Zhang","doi":"10.1158/2643-3230.BCD-24-0317","DOIUrl":"10.1158/2643-3230.BCD-24-0317","url":null,"abstract":"<p><p>We conducted a comparative analysis of the long-term efficacy and safety of two single-arm trials for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL): CD19/CD22-directed chimeric antigen receptor (CAR19/22) T-cell cocktail therapy alone or combined with autologous stem cell transplantation (ASCT). The study included 124 patients not in remission after bridging therapy. Cytopenia (36.92% vs. 52.54%) and infection (29.68% vs. 28.81%) were the predominant late grade ≥3 adverse events. CAR19/22 T-cell cocktail therapy combined with ASCT achieved a higher overall response rate (best overall response: 78.46% vs. 93.22%, P = 0.023) and superior progression-free survival (median, 5.68 months vs. not reached, P < 0.001) and overall survival (median, 27.61 months vs. not reached, P < 0.001) than CAR19/22 T-cell cocktail therapy alone. Independent predictors of longer progression-free survival and overall survival included achieving a complete response at 3 months and receiving combination therapy. The associations remained statistically significant after adjustment in sensitivity analyses incorporating propensity score matching and inverse probability of treatment weighting.</p><p><strong>Significance: </strong>CAR19/22 T-cell therapy combined with ASCT significantly improves response and survival in R/R DLBCL, including high-risk patients. This approach seems to enhance the efficacy-safety balance and offers a clinically actionable strategy to optimize CAR T-cell combination therapies.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"142-153"},"PeriodicalIF":12.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145356203","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":"Overcoming BTK Inhibitor Resistance in Chronic Lymphocytic Leukemia by Targeting PKCβ.","authors":"Billy Michael Chelliah Jebaraj, Stephan Stilgenbauer","doi":"10.1158/2643-3230.BCD-25-0390","DOIUrl":"10.1158/2643-3230.BCD-25-0390","url":null,"abstract":"<p><p>Resistance of chronic lymphocytic leukemia to BTK inhibitors poses a major clinical challenge; however, there is potential to overcome this obstacle by targeting the downstream protein kinase PKCβ using the novel inhibitor MS-553. By inhibiting PKCβ, MS-553 blocks B-cell receptor signaling and WNT/β-catenin and NF-κB functions, thereby inducing apoptosis in BTK inhibitor-resistant cells. See related article by Gordon et al., p. 85.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"21-24"},"PeriodicalIF":12.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744946","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":"Tandem Duplications in UBTF Create XPO1-Dependent Nuclear Export Signals that Reveal a Leukemic Therapeutic Dependency.","authors":"Juan M Barajas, Aaron H Phillips, Jina Wang, Melvin E Thomas, Lisett Contreras, Masayuki Umeda, Ryan Hiltenbrand, Elizabeth Caldwell, Michael P Walsh, Guangchun Song, Lauren Ezzell, Kelly Churion, Tamara Westover, Emily Xiong, Chandra Rolle, Jamila Moore, Josi Lott, Sandi Radko-Juettner, Amit Kumar, Wenjie Qi, Beisi Xu, Evangelia K Papachristou, Clive S D'Santos, Jing Ma, Burgess B Freeman, Laura J Janke, Richard W Kriwacki, Jeffery M Klco","doi":"10.1158/2643-3230.BCD-25-0112","DOIUrl":"10.1158/2643-3230.BCD-25-0112","url":null,"abstract":"<p><p>UBTF tandem duplications (UBTF-TD) define a high-risk molecular subtype of acute myeloid leukemia (AML). Although menin inhibitors show therapeutic promise in UBTF-TD AMLs, acquired resistance remains a challenge. In this study, we used proteomic, epigenetic, and functional analyses to uncover mechanisms underlying UBTF-TD leukemogenesis. Biochemical studies showed that UBTF-TDs result in structural destabilization and create nuclear export signal (NES) motifs, which mediate direct interactions with exportin-1 (XPO1). In cord blood CD34+ UBTF-TD models, these interactions were shown to drive aberrant chromatin binding and transcriptional activation of genes dysregulated in UBTF-TD tumors. Through mutagenesis, we demonstrated that these NES motifs are critical for localization of UBTF-TD proteins to chromatin, transcriptional dysregulation, and cellular proliferation and differentiation. In preclinical UBTF-TD models of human leukemia, we found that XPO1 inhibition disrupts UBTF-TD chromatin localization, reduces tumor burden, and promotes differentiation. These mechanistic findings highlight XPO1 inhibition as a potential therapy for UBTF-TD AMLs.</p><p><strong>Significance: </strong>UBTF tandem duplications are a high-risk AML subtype. We identified a mechanism in which UBTF-TDs result in the generation of NES motifs, enabling aberrant interaction with XPO1. We found that XPO1 inhibitors block this interaction and impair leukemia growth, identifying a possible therapeutic strategy in UBTF-TD AML. See related commentary by Adams, p. 15.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"51-67"},"PeriodicalIF":12.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12793833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145439070","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":"The Link between Modifiable Risk Factors and Myeloid Disorders-From Plate to Pathogenesis.","authors":"Joshua T Weinreb, Omar Abdel-Wahab, Urvi A Shah","doi":"10.1158/2643-3230.BCD-25-0056","DOIUrl":"10.1158/2643-3230.BCD-25-0056","url":null,"abstract":"<p><p>Clonal hematopoiesis of indeterminate potential, myelodysplastic syndromes, and acute myeloid leukemia are myeloid cell disorders that exist on a spectrum. Modifiable risk factors, including obesity, insulin resistance, physical activity, dietary patterns, smoking, and the microbiome, have been implicated in myeloid cell disorder pathogenesis. Although the connection between these modifiable risk factors and their association with myeloid disorders has been studied, as of September 2025, no clinical trials are ongoing that evaluate whether lifestyle interventions can alter myeloid disorder disease progression. This article reviews myeloid disorders and their association with inflammation and how lifestyle interventions may influence disease progression.</p><p><strong>Significance: </strong>Myeloid disorders are associated with inflammation and metabolic disorders such as obesity and diabetes mellitus. Dietary and lifestyle modifications may directly influence the pathogenesis, development, and survival by addressing inflammatory and metabolic pathways. However, additional preclinical research and large prospective clinical trials are needed to confirm these findings. This review provides an overview on myeloid disorder pathogenesis and modifiable factors that influence it, which may guide future research to reduce the myeloid disorder burden and improve outcomes for patients with clonal hematopoiesis of indeterminate potential, myelodysplastic syndromes, and acute myeloid leukemia.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"31-40"},"PeriodicalIF":12.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13331244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145497045","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":"Intra-Leukemic Interferon Signaling Suppresses Expansion and Mediates Chemoresistance in Human AML.","authors":"Daiki Karigane, Amy C Fan, Toshinobu Nishimura, Kensuke Kayamori, Yusuke Nakauchi, Thomas Köhnke, Athreya Rangavajhula, Asiri Ediriwickrema, Brooks A Benard, Rozario Thomas, Feifei Zhao, Melissa Stafford, Fabian P Suchy, Jonas L Fowler, Mark P Chao, Tian Yi Zhang, Kyle M Loh, Hiromitsu Nakauchi, Ravindra Majeti","doi":"10.1158/2643-3230.BCD-25-0173","DOIUrl":"10.1158/2643-3230.BCD-25-0173","url":null,"abstract":"<p><p>Intratumoral heterogeneity can affect the competitive fitness and chemoresistance of individual cancer cells. In acute myeloid leukemia (AML), both genetic and functional heterogeneity contribute to chemoresistance, resulting in relapse. Whereas the role of cell-extrinsic factors has been described for AML relapse, whether interactions between cancer cells affect chemoresistance is not fully known. In this study, we demonstrated that a dominant leukemic fraction can suppress the proliferation and expansion of other leukemic cells and that this suppression is reversible. This suppression is mediated in part by both type I and type II intra-leukemic interferon signaling and dependent on BST2. Importantly, blocking antibodies to type II interferon receptor activated the cycling of this suppressed cell fraction and sensitized the cells to subsequent chemotherapy treatment. Our findings suggest that interactions between functionally heterogeneous leukemic fractions can affect competitive fitness and treatment response, highlighting interferon signaling as a potential therapeutic target to counter chemoresistance.</p><p><strong>Significance: </strong>AML presents a significant challenge in clinical management due to its poor prognosis and high rates of relapse following chemotherapy. Using multiple models of primary human AML, we demonstrate that competitive interactions between leukemia cells affect clonal dynamics and therapy resistance, thereby identifying a potential strategy to improve patient outcomes. See related commentary by Papaioannou and Aifantis, p. 18.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"68-84"},"PeriodicalIF":12.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12784446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145402183","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":"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 preexisting, undetectable clones. By leveraging chemotherapy mutational signatures as temporal barcodes within whole-genome sequencing data, we could time genomic antigen escape in 4 of 11 patients with RRMM. In all cases, the biallelic loss was driven by genomic events acquired after exposure to BCMA- and GPCR5D-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 GPCR5D, 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><p><strong>Significance: </strong>Multiple myeloma has been demonstrated to recurrently develop resistance to T-cell redirection via genomic antigen escape. By leveraging chemotherapy mutational signatures, we demonstrate that somatic antigen-escape mechanisms are uniformly acquired following treatment initiation and not selected from among preexisting clones, emphasizing the importance of dynamic longitudinal surveillance for their emergence. See related commentary by Kauer et al., p. 532.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"572-579"},"PeriodicalIF":12.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12514755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145001553","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":"Real-World Experience with Teclistamab for Relapsed/Refractory Multiple Myeloma from the US Myeloma Immunotherapy Consortium.","authors":"Beatrice M Razzo, Shonali Midha, Andrew J Portuguese, Ariel F Grajales-Cruz, Andre De Menezes Silva Corraes, Patrick Costello, Yuxin Liu, Adam S Sperling, Omar Nadeem, Danai Dima, Rahul Banerjee, Andrew J Cowan, Aimaz Afrough, Larry D Anderson, Alex Lieberman-Cribbin, Gurbakhash Kaur, Anmol Goyal, Shebli Atrash, Christopher J Ferreri, Peter M Voorhees, Oren Pasvolsky, Hans C Lee, Krina K Patel, Kelley L Julian, Peter A Forsberg, Megan M Herr, Saurabh Chhabra, Ricardo D Parrondo, Yi Lin, Anna Chen, Sandra P Susanibar-Adaniya, Jack Khouri, Shahzad Raza, Faiz Anwer, Mariola Vazquez-Martinez, Omar Castaneda Puglianini, Douglas W Sborov, James A Davis, Adriana Rossi, Leyla Shune, Jenny Bhurtel, Wei-Ting Hwang, Doris K Hansen, Surbhi Sidana, Alfred L Garfall, Shambavi Richard","doi":"10.1158/2643-3230.BCD-24-0354","DOIUrl":"10.1158/2643-3230.BCD-24-0354","url":null,"abstract":"<p><p>Teclistamab is an anti-CD3-/B-cell maturation antigen (BCMA) bispecific antibody approved for use in relapsed/refractory multiple myeloma. We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the US Multiple Myeloma Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≥3) and immune effector cell-associated neurotoxicity syndrome in 11% (2.2% grade ≥3), with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR or better in 45%. With 10.1 months of median follow-up, the estimated median progression-free survival (PFS) was 5.8 months and 12-month overall survival was 61%. Independent predictors of less than very good PR and shorter PFS included BCMA-directed chimeric antigen receptor T-cell therapy in the previous 9 months, high disease burden, lymphopenia, and elevated ferritin.</p><p><strong>Significance: </strong>T cell-engaging bispecific antibodies such as teclistamab represent an important new treatment modality for multiple myeloma and other blood cancers. This study evaluates the real-world safety and efficacy of teclistamab, including its activity in populations not represented in the initial phase I/II study, and identifies clinical variables associated with treatment response. See related commentary by Zweegman et al., p. 542.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"561-571"},"PeriodicalIF":12.2,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144592465","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":"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":"10.1158/2643-3230.BCD-25-0292","url":null,"abstract":"<p><p>The real-world effectiveness of the bispecific antibody teclistamab seems 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 bispecific antibody therapy in high-risk populations and ultimately advancing more personalized treatment strategies while supporting sustainable models of care. See related article by Razzo et al., p. 561.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"542-546"},"PeriodicalIF":12.2,"publicationDate":"2025-11-03","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}