Cancer research最新文献

{"title":"Intratumoral Fusobacterium nucleatum Recruits Tumor-Associated Neutrophils to Promote Gastric Cancer Progression and Immune Evasion.","authors":"Tianhao Zhang, Ying Li, Ertao Zhai, Risheng Zhao, Yan Qian, Zhixin Huang, Yinan Liu, Zeyu Zhao, Xiang Xu, Jianqiu Liu, Zikang Li, Zhi Liang, Ran Wei, Linying Ye, Jinping Ma, Qingping Wu, Jianhui Chen, Shirong Cai","doi":"10.1158/0008-5472.CAN-24-2580","DOIUrl":"10.1158/0008-5472.CAN-24-2580","url":null,"abstract":"<p><p>Intratumoral microbiota can affect the development and progression of many types of cancer, including gastric cancer. A better understanding of the precise mechanisms by which microbiota support gastric cancer could lead to improved therapeutic approaches. In this study, we investigated the effect of intratumoral microbiota on the tumor immune microenvironment during gastric cancer malignant progression. Analysis of human gastric cancer tissues with 16S rRNA amplicon sequencing revealed that Fusobacterium nucleatum was significantly enriched in gastric cancer tissues with lymph node metastasis and correlated with a poor prognosis. F. nucleatum infection spontaneously induced chronic gastritis and promoted gastric mucosa dysplasia in mice. Furthermore, gastric cancer cells infected with F. nucleatum showed accelerated growth in immunocompetent mice compared with immunodeficient mice. Single-cell RNA sequencing uncovered that F. nucleatum recruited tumor-associated neutrophils (TAN) to reshape the tumor immune microenvironment. Mechanistically, F. nucleatum invaded gastric cancer cells and activated IL17/NF-κB/RelB signaling, inducing TAN recruitment. F. nucleatum also stimulated TAN differentiation into the protumoral subtype and subsequent promotion of PD-L1 expression, further facilitating gastric cancer immune evasion while also enhancing the efficacy of anti-PD-L1 antibody therapy. Together, these data uncover mechanisms by which F. nucleatum affects gastric cancer immune evasion and immunotherapy efficacy, providing insights for developing effective treatment strategies. Significance: Intratumoral F. nucleatum activates NF-κB signaling to facilitate gastric cancer immune evasion by promoting tumor-associated neutrophil recruitment that sensitizes tumors to immune checkpoint blockade therapy.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1819-1841"},"PeriodicalIF":12.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079103/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Retraction: Prostaglandin E2 Enhances Pancreatic Cancer Invasiveness through an Ets-1-Dependent Induction of Matrix Metalloproteinase-2.","authors":"Hiromichi Ito, Mark Duxbury, Eric Benoit, Thomas E Clancy, Michael J Zinner, Stanley W Ashley, Edward E Whang","doi":"10.1158/0008-5472.CAN-25-0887","DOIUrl":"https://doi.org/10.1158/0008-5472.CAN-25-0887","url":null,"abstract":"","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"85 10","pages":"1947"},"PeriodicalIF":12.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Palmitic Acid Accumulation Activates Fibroblasts and Promotes Matrix Stiffness in Colorectal Cancer.","authors":"Shenghe Deng, Jun Wang, Falong Zou, Denglong Cheng, Mian Chen, Junnan Gu, Jianguo Shi, Jia Yang, Yifan Xue, Zhenxin Jiang, Le Qin, Fuwei Mao, Xiaona Chang, Xiu Nie, Li Liu, Yinghao Cao, Kailin Cai","doi":"10.1158/0008-5472.CAN-24-2892","DOIUrl":"10.1158/0008-5472.CAN-24-2892","url":null,"abstract":"<p><p>Obstructions can occur during any stage of colorectal cancer and correspond with poor prognosis. Obstructive colorectal cancer (OCRC) is harder and exhibits increased tumor budding and proliferation of myofibroblasts compared with nonobstructive colorectal cancer, suggesting that the occurrence of obstruction may be related to extracellular matrix (ECM) remodeling. In this study, we found that colorectal cancer and OCRC samples differed substantially in ECM composition, specifically in collagen (newly formed and mature) and proteoglycans (including glycosaminoglycan, hyaluronic acid, and chondroitin sulfate). OCRC also exhibited considerable changes in ECM biomechanics and collagen arrangement. Interestingly, OCRC samples presented a notable increase in matrix cancer-associated fibroblasts (mCAF). The abundance of mCAFs correlated with the accumulation of palmitic acid (PA), and high concentrations of PA increased the secretion of ECM-related proteins by mCAFs. Additionally, PA did not directly affect normal fibroblasts but rather activated the NF-κB pathway in tumor cells to stimulate secretion of CSF1, TGFβ1, and CXCL8, which promoted the activation of normal fibroblasts into mCAFs and exacerbated ECM stiffening. Drug screening with a natural compound library identified vanillylacetone as a potential inhibitor of PA-induced cytokine secretion and ECM stiffening. These findings highlight intratumoral PA accumulation as a key mechanism driving ECM alterations and OCRC progression and suggest that targeting this axis may be useful for treating patients with colorectal cancer with risk of obstruction. Significance: Palmitic acid accumulation activates the NF-κB pathway in colorectal cancer cells to promote cytokine secretion that facilitates the generation of matrix cancer-associated fibroblasts, driving extracellular matrix remodeling and development of obstructions.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"1784-1802"},"PeriodicalIF":12.5,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12079102/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MYLK-AS1 Enhances Glutamine Metabolism to Promote EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer.","authors":"Tianyu Qu,Lei Song,Jiali Xu,Xiyi Lu,Dandan Yin,Jiali Dai,Chen Zhang,Renhua Guo,Erbao Zhang","doi":"10.1158/0008-5472.can-23-3748","DOIUrl":"https://doi.org/10.1158/0008-5472.can-23-3748","url":null,"abstract":"Acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) limits the efficacy of molecular targeted therapy in non-small cell lung cancer (NSCLC). Metabolic reprogramming is a hallmark of lung cancer that could contribute to TKI resistance. Through systematic screening and verification, we identified a role for the long noncoding RNA (lncRNA) MYLK-AS1 supporting acquired TKI resistance in lung cancer. Elevated expression of MYLK-AS1 correlated with TKI resistance in NSCLC patient samples and cell lines. c-Myc mediated transcriptional activation of MYLK-AS1, and m6A modification promoted post transcriptional upregulation. Mechanistically, MYLK-AS1 bound and directly drove phase separation of interleukin enhancer binding factor 3 (ILF3), thus interacting with the 3'UTR of glutamate dehydrogenase 1 (GLUD1) to post-transcriptionally promote its mRNA stability. MYLK-AS1-mediated GLUD1 upregulation accelerated mitochondrial glutamine catabolism, promoting TKI resistance. Inhibition of GLUD1 with the small-molecule inhibitor R162 in TKI resistant models suppressed cell proliferation in vitro and tumor growth in vivo. Moreover, knockdown of MYLK-AS1 also enhanced drug sensitivity in TKI resistant patient-derived xenograft models, suggesting its therapeutic potential. Collectively, these findings offer insights into the regulation of TKI resistance from the perspective of phase separation and metabolism and highlight targeting the MYLK-AS1/ILF3/GLUD1 axis as a potential strategy for improving the efficacy of EGFR TKIs in NSCLC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"55 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tobacco Smoking Rewires Cell Metabolism by Inducing GAPDH Succinylation to Promote Lung Cancer Progression.","authors":"Kun Wang,Jingzhuo Li,Hai Zhang,Hongyan Ma,Hong-Yong Cui,Huai-Qiang Ju,Jing Zhang,Qing-Zhi Ma,Ming Zhao,Qing-Mei Zeng,Jie Zou,Xiu-Xuan Sun,Gang Nan,Meirui Qian,Lin Jing,Yiming Li,Cai-Feng Xiong,Qiu-Zi Yang,Hao Wang,Jian-Li Jiang,Zhi-Nan Chen,Liang Chen,Wan Huang","doi":"10.1158/0008-5472.can-24-3525","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3525","url":null,"abstract":"Patient behavior and physiology can directly affect cancer metabolism. Smoking is the leading risk factor for non-small cell lung cancer (NSCLC). Here, we identified that smoking modulates lung cancer cell metabolism through altered protein post-translational modification. Proteomic analyses identified elevated K251 succinylation (K251-Su) of GAPDH, a key enzyme in glycolysis, in NSCLC samples, and GAPDH K251-Su was significantly higher in patients who smoke compared to non-smokers. Exposure of lung cancer cells to cigarette smoke extract led to increased uptake of glutamine and enhanced GAPDH K251-Su. Glutamine uptake by cancer cells in hypoxic and nutrient-deficient microenvironments provided succinyl-CoA donors for GAPDH succinylation at K251, which was catalyzed by acyltransferase p300. K251-Su increased GAPDH stability by suppressing TRIM4-mediated K254 ubiquitination. GAPDH K251-Su enhanced glycolysis and glutamine reductive carboxylation to meet the demands for cell growth and to support survival in hypoxic and nutrient-depleted conditions, promoting tumor growth and metastasis. These findings indicate that tobacco smoking mediates metabolic reprogramming of cancer cells through succinylation of GAPDH to drive NSCLC progression.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"57 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor Suppressor Genes with Segmental Duplications are Prone to Somatic Deletions and Structural Variations.","authors":"Ziheng Huang,Lin Zhang,Huarong Chen,Xiaodong Liu,Likai Tan,Dan Huang,Yingzhi Liu,Yushan Wang,Xinyi Zhang,Alfred Sze Lok Cheng,Maggie Haitian Wang,Wei Kang,Ka-Fai To,Jun Yu,Ho Ko,Le Yu,Sunny H Wong,Tony Gin,Matthew Tak Vai Chan,Xiansong Wang,William Ka Kei Wu","doi":"10.1158/0008-5472.can-24-2225","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2225","url":null,"abstract":"Segmental duplications (SDs) are blocks of genomic DNA with high sequence homology that are hotspots for chromosomal rearrangements, coinciding with copy-number and single-nucleotide variations in the population. SDs could represent unstable genomic regions that are susceptible to somatic alterations in human cancers. Here, we aimed to elucidate the genomic locations of SDs in relation to cancer-related genes and their propensity for somatic alterations in cancer. The analysis showed that tumor suppressor genes (TSGs) were less associated with SDs compared to non-cancer genes in nearly all mammalian species. TSGs with SDs were larger in size in humans but only modestly conserved among mammals. In humans, the proportion of non-cancer genes with SDs decreased as the gene age increased. However, for TSGs, a loss of association with SDs was apparent among young genes. Pan-cancer analysis revealed that TSGs with SDs were more prone to deletions and structural variations independently of gene size. Re-analysis of publicly available experimental data further revealed that genes with SDs tended to replicate late and were more likely to undergo the error-prone mitotic DNA synthesis upon replication stress. In conclusion, the loss of SDs from TSGs during mammalian evolution protects against tumor formation by reducing somatic alterations.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"96 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SMARCA4 loss increases RNA Polymerase II pausing and elevates R-loops to inhibit BRCA1-mediated repair in ovarian cancer.","authors":"Xianbing Zhu,Zheng Fu,Giulio Aceto,Jonathan St-Germain,Kexin Liu,Azadeh Arabzadeh,Yuxuan Qi,Yibo Xue,Leora Witkowski,Elise Graulich,Jutta Steinberger,Selim Misirlioglu,Nicklas Bassani,Racim Sansal,Amber Yasmeen,Geneviève Morin,Jingjie Guo,Anie Monast,Virginie Pilon,Alica Valachová,Kitty Pavlakis,Lili Fu,Walter H Gotlieb,W Glenn McCluggage,David Huntsman,Alexander J R Bishop,Douglas A Levine,Morag Park,Yemin Wang,Brian Raught,William D Foulkes,Sidong Huang","doi":"10.1158/0008-5472.can-24-3990","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3990","url":null,"abstract":"Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive cancer affecting young women, driven by inactivating mutations in SMARCA4, a key SWI/SNF chromatin remodeling gene. To uncover its druggable vulnerabilities, we performed a compound screen and found that SCCOHT cells and tumors were sensitive to PARP inhibitors. Paradoxically, SCCOHT displayed BRCA-deficient traits despite retaining wild-type BRCA1 expression. Elevated R-loop in SCCOHT sequestered BRCA1, limiting its availability for DNA damage repair. Proximity-dependent biotin identification revealed that wild-type SMARCA4, but not its pathogenic variants, promoted RNA polymerase II (Pol II) elongation by mediating the assembly of the polymerase-associated factor 1 (PAF1) complex. Thus, SMARCA4 loss increased Pol II pausing, resulting in elevated R-loops and BRCA1 redistribution. The suppression of BRCA1 activity sensitized SMARCA4-deficient SCCOHT cells and tumors to PARP inhibitors, which was further enhanced by the addition of a CDK9 inhibitor targeting Pol II elongation. Co-targeting PARP/CDK9 also elicited synergistic effects against other undifferentiated ovarian cancer cells with SMARCA4 loss. These findings link SMARCA4 loss to perturbed Pol II elongation and compromised DNA repair by BRCA1, providing a therapeutic opportunity to target SCCOHT and other SWI/SNF-deficient ovarian cancers.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"68 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systemic Inactivation of TREX1 Induces Selective Inflammation of the Tumor Microenvironment and Invigorated T Cell-Mediated Tumor Control","authors":"Emilija Marinkovic, Minyi Chen, Nadja Schubert, Elif Dogan Dar, Tanja Poth, Janet Y. Leung, Jack Lohre, Jennifer M. Sahni, Christine Tun, Pavithra Rajeswaran, Tanja Mehlo-Jensen, Olivia Perng, C. Mark Hill, Pallavur Sivakumar, Michael J. Barnes, Rohit Malik, Rayk Behrendt, Axel Roers","doi":"10.1158/0008-5472.can-24-2262","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2262","url":null,"abstract":"Therapeutic innate immune stimulation within the tumor microenvironment can potentiate endogenous antitumor T cell immunity. Strategies for controlled activation of cGAS/STING signaling are currently under intense investigation. DNase 3’-repair exonuclease 1 (TREX1) is essential for cellular DNA disposal, which prevents autoimmunity ensuing from cGAS/STING activation by endogenous DNA. TREX1-deficient tumor cells elicit enhanced protective immunity in syngeneic models. Here, we showed that induced inactivation of the Trex1 gene in host (non-cancer) cells yields improved type I IFN- and T cell-dependent control of established TREX1-competent tumors. Host TREX1 deficiency was well tolerated and triggered selective immune cell infiltration into tumors but not into other tissues. Induced systemic loss of TREX1 in tumor-bearing mice resulted in enhanced intra-tumoral T cell proliferation and massive increase in numbers of effector and effector-like ‘exhausted’ cells, enabling complete rejection in combination with checkpoint inhibition. To conclude, systemic TREX1 inhibition is a promising approach to boost anti-tumor immunity and to overcome immune evasion mediated by cancer cell-intrinsic cGAS/STING inactivation.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"38 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Machine Learning-Based Strategy Predicts Selective and Synergistic Drug Combinations for Relapsed Acute Myeloid Leukemia","authors":"Yingjia Chen, Liye He, Aleksandr Ianevski, Kristen Nader, Tanja Ruokoranta, Nora Linnavirta, Juho J. Miettinen, Markus Vähä-Koskela, Ida Vänttinen, Heikki Kuusanmaki, Mika Kontro, Kimmo Porkka, Krister Wennerberg, Caroline A. Heckman, Anil K. Giri, Tero Aittokallio","doi":"10.1158/0008-5472.can-24-3840","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3840","url":null,"abstract":"Combination therapies are one potential approach to improve the outcomes of patients with refractory or relapsed disease. However, comprehensive testing in scarce primary patient material is hampered by the many drug combination possibilities. Furthermore, inter- and intra-patient heterogeneity necessitates personalized treatment optimization approaches that effectively exploit patient-specific vulnerabilities to selectively target both the disease- and resistance-driving cell populations. Here, we developed a systematic combinatorial design strategy that uses machine learning to prioritize the most promising drug combinations for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). The predictive approach leveraged single-cell transcriptomics and single-agent response profiles measured in primary patient samples to identify targeted combinations that co-inhibit treatment resistant cancer cells individually in each AML patient sample. Cell type compositions evolved dynamically between the diagnostic and R/R stages uniquely in each patient, hence requiring personalized drug combination strategies to target therapy-resistant cancer cells. Cell population-specific drug combination assays demonstrated how patient-specific and disease stage-tailored combination predictions led to treatments with synergy and strong potency in R/R AML cells, while the same combinations elicited non-synergistic effects in the diagnostic stage and minimal co-inhibitory effects on normal cells. In preliminary experiments on clinical trial samples, the approach predicted clinical outcomes to venetoclax-azacitidine combination therapy in patients with AML. Overall, the computational-experimental approach provides a rational means to identify personalized combinatorial regimens for individual AML patients with R/R disease that target treatment-resistant leukemic cells, thereby increasing their likelihood for clinical translation.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"27 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling the PAX5P80R Mutation Reveals HIF2α Activation as a Common Feature and Therapeutic Target in B-Cell Acute Lymphoblastic Leukemia","authors":"Manon Bayet, Vincent Fregona, Mathieu Bouttier, Clémence Rouzier, Jérémy Bigot, Laura Jamrog, Sylvie Hebrard, Naïs Prade, Stéphanie Lagarde, Christine Didier, Stéphanie Gachet, Marie Passet, Laetitia Largeaud, Marlène Pasquet, Ahmed Amine Khamlichi, Emmanuelle Clappier, Eric Delabesse, Cyril Broccardo, Bastien Gerby","doi":"10.1158/0008-5472.can-24-1698","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1698","url":null,"abstract":"The transcription factor PAX5 is a major target of genetic alterations in human B-cell precursor acute lymphoblastic leukemia (B-ALL). Among the alterations, the P80R mutation affecting the DNA-binding domain represents the most frequent PAX5 point mutation in B-ALL. In contrast to other somatic PAX5 mutations, PAX5P80R defines a distinct B-ALL subtype characterized by a unique transcriptional program. Here, we aimed to develop a model to elucidate the mechanism by which PAX5P80R perturbs normal B-cell differentiation and the oncogenic relays involved in PAX5P80R-driven malignant progression. A retroviral complementation approach of Pax5-deficient murine fetal liver cells demonstrated at the functional and molecular levels that PAX5P80R failed to rescue definitive B-cell commitment but maintained the repression of T-cell development. Moreover, PAX5P80R eventually led to clonal B-ALL transformation after transplantation through the acquisition of secondary mutations in genes involved in the JAK/STAT and RAS/MAPK pathways. Finally, transcriptomic analyses combined with pharmacological investigation revealed ectopic activation of HIF2α as a common feature of B-ALL and identified acriflavine as a potent drug against B-ALL. Hence, this study provides a strategy to model the multistep process of B-ALL and sheds light on the biological mechanism by which the PAX5P80R mutation leads to leukemia.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"124 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143940631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}