Blood Cancer Discovery最新文献

{"title":"Food for Thought: Addressing a Research Gap for Dietary Trials in Hematologic Malignancies.","authors":"Akash Patel, Shireen Kassam, Urvi A Shah","doi":"10.1158/2643-3230.BCD-25-0141","DOIUrl":"10.1158/2643-3230.BCD-25-0141","url":null,"abstract":"<p><p>There is growing interest from both patients and clinicians in understanding the role nutrition plays across hematologic malignancies. In this study, we highlight key unanswered questions related to studying dietary interventions in hematologic malignancies, including questions about how to conduct research, trial design considerations, and integrating dietary interventions into hematologic cancer care and policy.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"406-411"},"PeriodicalIF":11.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405862/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800478","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":"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":"https://doi.org/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 currently approved for relapsed or refractory leukemia with rearrangement of lysine methyltransferase 2 A (KMT2A). However, multiple other menin inhibitors are currently in clinical development aimed at targeting additional subsets such as nucleophosmin 1 (NPM1) mutations which form up to 30% of acute myeloid leukemia. 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>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-03","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":"Microbiota Shape Metabolic and Immune Determinants of CAR-T Therapy and Correlate with Outcomes in Myeloma.","authors":"Mireia Uribe-Herranz, Aina Oliver-Caldés, Neus Martínez-Micaelo, Marta Español-Rego, Maria Val-Casals, Roberto Martínez-Soler, Elisa Rubio-Garcia, Valeria Brunello, Erik Z Mihelic, Nela Klein-González, Daniel Benítez-Ribas, Núria Amigó, Andrea Vergara, Valentin Ortiz-Maldonado, Luis Gerardo Rodríguez-Lobato, Julio Delgado, Iñaki Ortiz de Landazuri, Verónica González-Calle, Valentín Cabañas, Beatriz Martin-Antonio, Lorena Pérez-Amill, Juan Luis Reguera-Ortega, Paula Rodríguez-Otero, Bruno Paiva, Joaquín Martínez-López, Maria-Victoria Mateos, Mariona Pascal, Álvaro Urbano-Ispizua, Europa Azucena González-Navarro, Carlos Fernández de Larrea, Manel Juan","doi":"10.1158/2643-3230.BCD-24-0203","DOIUrl":"10.1158/2643-3230.BCD-24-0203","url":null,"abstract":"<p><p>Multiple myeloma remains incurable despite advances in immunotherapies like chimeric antigen receptor (CAR) T-cell therapy. This study investigates the role of metabolites and gut microbiota in clinical outcomes in patients treated with the humanized B-cell maturation antigen (BCMA)-directed CAR-T therapy ARI0002h. Stool metabolites, particularly succinate, were associated with CAR T-cell phenotypes and persistence in patients. In CAR T-cell culture, succinate supplementation enhanced CD4+ central memory phenotype and respiratory capacity. In a murine myeloma model, a succinate-enhancing diet significantly improved CAR T-cell persistence and showed a trend toward better tumor control. Furthermore, Acidaminococcaceae, Monoglobaceae, or Akkermansiaceae, along with specific metabolites, were associated with CAR T-cell clinical outcomes. These multimodal profiles were integrated into response models, including one that identified patients likely to achieve a complete response by days 100 and 180 after infusion. These findings suggest that metabolites and gut microbiota correlate with CAR T-cell therapy responses and can be a valuable tool for risk assessment.</p><p><strong>Significance: </strong>This study integrates microbial profiles into response models, providing a tool to identify patients with multiple myeloma who may benefit from BCMA-directed CAR T-cell therapy optimization by identifying bacterial taxa and metabolites associated with CAR T-cell persistence and therapeutic outcomes.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"484-504"},"PeriodicalIF":11.5,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12405848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144609689","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":"https://doi.org/10.1158/2643-3230.BCD-24-0340","url":null,"abstract":"<p><p>The molecular basis of therapy resistance in multiple myeloma (MM) remains poorly understood. Here, we performed single-cell RNA sequencing coupled with VDJ-targeted sequencing of highly purified primary MM cells from patient bone marrow. This approach uncovered cellular heterogeneity and phenotypic plasticity along the CD138 axis, accompanied by drastic epigenetic alterations. Notably, therapy-resistant subpopulations were identified within a minor fraction of CD138- MM cells, and were shown via CRISPR/Cas9 screening to be vulnerable to splicing pathway inhibition. Consistently, this fraction of CD138- MM cells showed increased differential splicing associated with overexpression of SR protein family splicing factors. Among these splicing factors, RNA-binding protein 39 (RBM39) was specifically overexpressed in therapy-resistant cells and involved in aberrant splicing. Both genetic and pharmacological RBM39 inhibition exhibited a significant selective lethal effect on therapy-resistant CD138- MM cells. Collectively, our findings identify distinct therapy-resistant MM subpopulations and highlight the splicing pathway as a promising therapeutic target.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-09-02","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":"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 multiomic alterations, survival outcomes, and risk stratification. Among 1,309 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 was nonprognostic among patients of African ancestry. Integrating genetic ancestry with published T-ALL risk classifiers, we identified that an X01 penalized Cox regression classifier stratified patients regardless of ancestry, whereas a European multigene 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><p><strong>Significance: </strong>There is a lack of studies examining the prognostic significance of genomic features by genetic ancestry in T-ALL, especially in non-European ancestral groups. In this study, we demonstrate how the prognostic value of individual alterations differs by genetic ancestry, warranting future studies to identify germline alleles affecting these associations. See related commentary by de Smith, p. xxx.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"OF1-OF13"},"PeriodicalIF":11.5,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800479","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":"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":"https://doi.org/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 postapproval, 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.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"OF1-OF11"},"PeriodicalIF":11.5,"publicationDate":"2025-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144800430","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 follicular lymphoma (FL) patients relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multi-omics approach, we show that FL patients 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 TFH and Treg functions. Additionally, IRF4 rewires tumor metabolism which 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>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-16","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":"Real-World Experience with Teclistamab for Relapsed/ Refractory Multiple Myeloma from the U.S. 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-CD3xBCMA bispecific antibody approved for use in relapsed/refractory multiple myeloma (MM). We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the U.S. MM 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 (VGPR) or better in 45%. With 10.1 months median follow-up, estimated median progression-free survival (PFS) was 5.8 months, and 12-month overall survival was 61%. Independent predictors of <VGPR and shorter PFS included BCMA-directed CAR T cell therapy in the previous 9 months, high disease burden, lymphopenia, and elevated ferritin.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-09","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":"Single-cell Transcriptional Atlas of Human Hematopoiesis Reveals Genetic and Hierarchy-Based Determinants of Aberrant AML Differentiation.","authors":"Andy G X Zeng, Ilaria Iacobucci, Sayyam Shah, Amanda Mitchell, Gordon Wong, Suraj Bansal, David Chen, Qingsong Gao, Hyerin Kim, James A Kennedy, Andrea Arruda, Mark D Minden, Torsten Haferlach, Charles G Mullighan, John E Dick","doi":"10.1158/2643-3230.BCD-24-0342","DOIUrl":"10.1158/2643-3230.BCD-24-0342","url":null,"abstract":"<p><p>Therapeutic targeting of acute myeloid leukemia (AML) is hampered by intra- and inter-tumoral cell state heterogeneity. To develop a more precise understanding of AML cell states, we constructed a reference atlas of human hematopoiesis from 263,159 single-cell transcriptomes spanning 55 cellular states. Using this atlas, we mapped more than 1.2 million cells spanning 318 leukemia samples, revealing 12 recurrent patterns of aberrant differentiation in AML. Notably, this uncovered unexpected AML cell states resembling lymphoid and erythroid progenitors that were prognostic within the clinically heterogeneous context of normal karyotype AML, independent of genomic classifications. Systematic mapping of genotype-to-phenotype associations revealed specific differentiation landscapes associated with more than 45 genetic drivers. Importantly, distinct cellular hierarchies can arise from samples sharing the same genetic driver, potentially reflecting distinct cellular origins for disease-sustaining leukemia stem cells. Thus, precise mapping of malignant cell states provides insights into leukemogenesis and refines disease classification in acute leukemia.</p><p><strong>Significance: </strong>We present a single-cell reference atlas of human hematopoiesis and a computational tool for rapid mapping and classification of healthy and leukemic cells. Applied to AML, this has enabled single-cell analysis at the scale of hundreds of patient samples, revealing the full breadth of derailment of differentiation in AML. See related commentary by Berger and Penter, p. 280.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"307-324"},"PeriodicalIF":11.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144031382","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":"Clinical Significance of TP53-Mutant Clonal Hematopoiesis Across Diseases.","authors":"Yoshiaki Usui, Mikiko Endo, Yusuke Iwasaki, Hanae Iijima, Hidewaki Nakagawa, Koichi Matsuda, Yukihide Momozawa","doi":"10.1158/2643-3230.BCD-24-0355","DOIUrl":"10.1158/2643-3230.BCD-24-0355","url":null,"abstract":"<p><p>Clonal hematopoiesis of indeterminate potential (CHIP) has broad clinical relevance, and TP53 plays various roles within cells. However, the gene-specific and cross-disease significance of CHIP with TP53 mutations (TP53-CHIP) remains unclear. In this study, we evaluated TP53-CHIP using targeted sequencing data of 140,597 individuals without hematologic neoplasms in BioBank Japan. We identified 1,157 individuals with TP53-CHIP and clarified the characteristics of mutations and carriers. TP53-CHIP was associated with poor overall survival, especially because of lymphoid neoplasms and respiratory disease, in addition to myeloid neoplasms. Significant interactions accompanied by excess risks were observed between TP53-CHIP and lifestyle factors for disease-specific mortality: acetaldehyde exposure (resulting from the interaction between drinking and the germline variant of ALDH2) for myeloid neoplasms and smoking for respiratory disease. The clinical significance of TP53-CHIP was sometimes largely independent of variant allele fractions. These findings elucidate aspects of disease pathogenesis and inform personalized risk management.</p><p><strong>Significance: </strong>TP53-CHIP contributed to a wide range of outcomes besides myeloid neoplasm mortality. TP53-CHIP, when combined with environmental factors, showed a remarkably higher risk for disease-specific mortality, accompanied by excess risks.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"298-306"},"PeriodicalIF":11.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144318127","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}