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
{"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":"https://doi.org/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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144643754","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}
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 Benitez-Ribas, Núria Amigó, Andrea Vergara, Valentin Ortiz-Maldonado, Luis Gerardo Rodríguez-Lobato, Julio Delgado, Iñaki Ortiz de Landazuri, Veronica Gonzalez-Calle, Valentin Cabañas, Beatriz Martin-Antonio, Lorena Pérez-Amill, Juan Luis Reguera-Ortega, Paula Rodriguez-Otero, Bruno Paiva, Joaquin Martinez-Lopez, Maria-Victoria Mateos, Mariona Pascal, Álvaro Urbano-Ispizua, Europa Azucena González-Navarro, Carlos Fernández de Larrea, Manel Juan
{"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 Benitez-Ribas, Núria Amigó, Andrea Vergara, Valentin Ortiz-Maldonado, Luis Gerardo Rodríguez-Lobato, Julio Delgado, Iñaki Ortiz de Landazuri, Veronica Gonzalez-Calle, Valentin Cabañas, Beatriz Martin-Antonio, Lorena Pérez-Amill, Juan Luis Reguera-Ortega, Paula Rodriguez-Otero, Bruno Paiva, Joaquin Martinez-Lopez, 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":"https://doi.org/10.1158/2643-3230.BCD-24-0203","url":null,"abstract":"<p><p>Multiple myeloma remains incurable despite advances in immunotherapies like CAR-T cell therapy. This study investigates the role of metabolites and gut microbiota in clinical outcomes in patients treated with the humanized 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 day 100 and 180 post-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>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144609689","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}
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
{"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":"https://doi.org/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}
Cuijuan Han, Zhiping Zhang, Edie I Crosse, Sogand Sajedi, Bin Lu, Xiyue Wang, Sadik Karma, Mitch Kostich, Sakthi Harini Rajendran, Dylan B Udy, Steven Chen, Alexander Arnuk, Abimbola Eunice Lawal, Kayla R Koenig, Meryl McKenna, Patrick K Reville, Hussein A Abbas, Omar Abdel-Wahab, Pedro Miura, Robert K Bradley, Eric Wang
{"title":"An isoform-specific RUNX1C-BTG2 axis governs AML quiescence and chemoresistance.","authors":"Cuijuan Han, Zhiping Zhang, Edie I Crosse, Sogand Sajedi, Bin Lu, Xiyue Wang, Sadik Karma, Mitch Kostich, Sakthi Harini Rajendran, Dylan B Udy, Steven Chen, Alexander Arnuk, Abimbola Eunice Lawal, Kayla R Koenig, Meryl McKenna, Patrick K Reville, Hussein A Abbas, Omar Abdel-Wahab, Pedro Miura, Robert K Bradley, Eric Wang","doi":"10.1158/2643-3230.BCD-24-0327","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-24-0327","url":null,"abstract":"<p><p>Aberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet its role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in AML patients before therapy and at relapse post-chemotherapy, identifying and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long isoform RUNX1C through its alternative distal promoter. The N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. BTG2 promoted ribosomal RNA deadenylation, resulting in decreased mRNA expression and stability. Deletion of ribosomal RNA's increased cellular quiescence. Moreover, RNA-based targeting of RUNX1C reactivated quiescent leukemia cells and enhanced chemotherapy efficacy. These findings delineate an isoform-specific transcriptional circuit that governs chemotherapy response, providing a potential therapeutic strategy to mitigate AML recurrence.</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":"144592464","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}
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 Jp Huntly, Robert P Hasserjian, Eva Hellström-Lindberg, Elli Papaemmanuil, Sanam Loghavi
{"title":"Multi-Modal 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 Jp Huntly, Robert P Hasserjian, Eva Hellström-Lindberg, Elli Papaemmanuil, Sanam Loghavi","doi":"10.1158/2643-3230.BCD-25-0047","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-25-0047","url":null,"abstract":"<p><p>The World Health Organization (WHO) 5th edition and International Consensus Classification (ICC) 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 WHO 5th and ICC for classification of SF3B1-mutated (SF3B1m) myelodysplastic neoplasms (MDS), NPM1m acute myeloid leukemia (AML), and oligomonocytic-chronic myelomonocytic leukemia (O-CMML). Our analysis demonstrated the clonal burden of SF3B1m in MDS informs biological classification and prognosis, supported the notion that NPM1 mutation should be AML-defining regardless of blast percentage, highlighted the prognostic impact of the cumulative number of myelodysplasia-related mutations in NPM1-mutated AML, and provided evidence that integrating specific molecular signatures could improve accuracy of O-CMML classification.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144561337","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}
Jaeyong Jung, Sining Zhu, Almin Lalani, Judith Shakarchi, Brygida Matracz, Guojun Gary Wu, Wei-Xing Zong, Liping Zhao, Ping Xie
{"title":"Commensal bacteria drive B-cell lymphomagenesis in the setting of innate immunodeficiency.","authors":"Jaeyong Jung, Sining Zhu, Almin Lalani, Judith Shakarchi, Brygida Matracz, Guojun Gary Wu, Wei-Xing Zong, Liping Zhao, Ping Xie","doi":"10.1158/2643-3230.BCD-24-0279","DOIUrl":"10.1158/2643-3230.BCD-24-0279","url":null,"abstract":"<p><p>Myeloid cells are central players in innate immunity and inflammation. Their function is regulated by the adaptor protein TRAF3. We previously reported that aging myeloid cell-specific TRAF3-deficient (M-Traf3-/-) mice spontaneously develop chronic inflammation and B-cell lymphoma (BCL). Here we aimed to identify the internal trigger of this disease phenotype in these mice. We first detected gut microbiota dysbiosis and transmigration of commensal bacteria (CB) to the liver in aging M-Traf3-/- mice. Interestingly, depletion of CB using antibiotics effectively prevented BCL development in these mice. Systemic IgG responses against CB were induced and the IgH CDR3 sequences of malignant B-cell clones of M-Traf3 /- mice showed high homology to prevalent bacteria-reactive Ig clonotypes. Furthermore, M-Traf3-/- mice with BCL exhibited high serum titers of antibodies against CB. Together, our findings offer insights into the mechanisms underlying increased risks of B-cell lymphomagenesis observed in patients with compromised innate immunity.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12279395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144561336","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}
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
{"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}
Shruti Sridhar, Allison S Y Chan, Anand D Jeyasekharan
{"title":"Single-cell Resolved Oncogene Co-expression: From Principles to Clinical Impact.","authors":"Shruti Sridhar, Allison S Y Chan, Anand D Jeyasekharan","doi":"10.1158/2643-3230.BCD-25-0064","DOIUrl":"10.1158/2643-3230.BCD-25-0064","url":null,"abstract":"<p><p>This commentary explores the concept and utility of studying oncogene co-expression at single-cell resolution and its clinical and biological implications. We emphasize the importance of scalable methods, mathematically driven quantification models, and artificial intelligence integration to enhance the clinical utility of this approach.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"288-292"},"PeriodicalIF":11.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144022289","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}
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
{"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":"10.1158/2643-3230.BCD-24-0240","url":null,"abstract":"<p><p>The genetic subtypes of Burkitt lymphoma have been defined, but 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 the Epstein-Barr virus 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 patients with Burkitt lymphoma who may experience inferior outcomes.</p><p><strong>Significance: </strong>Burkitt lymphoma can be divided into two epigenetic subtypes (epitypes), each carrying distinct biological, transcriptomic, genomic, and clinical features. Epitype is more strongly associated with clinical and mutational features than the Epstein-Barr virus status or genetic subtype, highlighting an important additional layer of Burkitt lymphoma pathogenesis.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"325-342"},"PeriodicalIF":11.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12209777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144062378","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}
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