NAR cancer最新文献_第2页

CSDE1: a versatile regulator of gene expression in cancer CSDE1：癌症基因表达的多功能调节器

NAR cancer Pub Date : 2024-04-10 DOI: 10.1093/narcan/zcae014

Annagiulia Ciocia, N. Mestre-Farràs, Ignacio Vicent-Nacht, Tanit Guitart, Fátima Gebauer

引用次数: 0

HDAC10 inhibition represses melanoma cell growth and BRAF inhibitor resistance via upregulating SPARC expression 抑制 HDAC10 可通过上调 SPARC 的表达抑制黑色素瘤细胞的生长和 BRAF 抑制剂的抗药性

NAR cancer Pub Date : 2024-04-08 DOI: 10.1093/narcan/zcae018

Hongbo Ling, Yixuan Li, Changmin Peng, Shengyu Yang, Edward Seto

{"title":"HDAC10 inhibition represses melanoma cell growth and BRAF inhibitor resistance via upregulating SPARC expression","authors":"Hongbo Ling, Yixuan Li, Changmin Peng, Shengyu Yang, Edward Seto","doi":"10.1093/narcan/zcae018","DOIUrl":"https://doi.org/10.1093/narcan/zcae018","url":null,"abstract":"Abstract Secreted protein acidic and rich in cysteine (SPARC), a conserved secreted glycoprotein, plays crucial roles in regulating various biological processes. SPARC is highly expressed and has profound implications in several cancer types, including melanoma. Understanding the mechanisms that govern SPARC expression in cancers has the potential to lead to improved cancer diagnosis, prognosis, treatment strategies, and patient outcomes. Here, we demonstrate that histone deacetylase 10 (HDAC10) is a key regulator of SPARC expression in melanoma cells. Depletion or inhibition of HDAC10 upregulates SPARC expression, whereas overexpression of HDAC10 downregulates it. Mechanistically, HDAC10 coordinates with histone acetyltransferase p300 to modulate the state of acetylation of histone H3 at lysine 27 (H3K27ac) at SPARC regulatory elements and the recruitment of bromodomain-containing protein 4 (BRD4) to these regions, thereby fine-tuning SPARC transcription. HDAC10 depletion and resultant SPARC upregulation repress melanoma cell growth primarily by activating AMPK signaling and inducing autophagy. Moreover, SPARC upregulation due to HDAC10 depletion partly accounts for the resensitization of resistant cells to a BRAF inhibitor. Our work reveals the role of HDAC10 in gene regulation through indirect histone modification and suggests a potential therapeutic strategy for melanoma or other cancers by targeting HDAC10 and SPARC.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140729495","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}

引用次数: 0

The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities 子宫内膜癌的 DNA 损伤反应 (DDR) 情况定义了不同的疾病亚型，并揭示了治疗机会

NAR cancer Pub Date : 2024-04-08 DOI: 10.1093/narcan/zcae015

Xingyuan Zhang, Sayali Joseph, Di Wu, Jessica L. Bowser, Cyrus Vaziri

{"title":"The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities","authors":"Xingyuan Zhang, Sayali Joseph, Di Wu, Jessica L. Bowser, Cyrus Vaziri","doi":"10.1093/narcan/zcae015","DOIUrl":"https://doi.org/10.1093/narcan/zcae015","url":null,"abstract":"Abstract Genome maintenance is an enabling characteristic that allows neoplastic cells to tolerate the inherent stresses of tumorigenesis and evade therapy-induced genotoxicity. Neoplastic cells also deploy many mis-expressed germ cell proteins termed Cancer Testes Antigens (CTAs) to promote genome maintenance and survival. Here, we present the first comprehensive characterization of the DNA Damage Response (DDR) and CTA transcriptional landscapes of endometrial cancer in relation to conventional histological and molecular subtypes. We show endometrial serous carcinoma (ESC), an aggressive endometrial cancer subtype, is defined by gene expression signatures comprising members of the Replication Fork Protection Complex (RFPC) and Fanconi Anemia (FA) pathway and CTAs with mitotic functions. DDR and CTA-based profiling also defines a subset of highly aggressive endometrioid endometrial carcinomas (EEC) with poor clinical outcomes that share similar profiles to ESC yet have distinct characteristics based on conventional histological and genomic features. Using an unbiased CRISPR-based genetic screen and a candidate gene approach, we confirm that DDR and CTA genes that constitute the ESC and related EEC gene signatures are required for proliferation and therapy-resistance of cultured endometrial cancer cells. Our study validates the use of DDR and CTA-based tumor classifiers and reveals new vulnerabilities of aggressive endometrial cancer where none currently exist.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140729240","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}

引用次数: 0

TDP2 is a regulator of estrogen-responsive oncogene expression TDP2 是雌激素反应性癌基因表达的调节器

NAR cancer Pub Date : 2024-04-08 DOI: 10.1093/narcan/zcae016

N. Manguso, Minhyung Kim, Neeraj Joshi, Md Rasel Al Mahmud, Juan Aldaco, Ryusuke Suzuki, Felipe Cortés-Ledesma, Xiaojiang Cui, Shintaro Yamada, Shunichi Takeda, Armando Giuliano, Sungyong You, Hisashi Tanaka

{"title":"TDP2 is a regulator of estrogen-responsive oncogene expression","authors":"N. Manguso, Minhyung Kim, Neeraj Joshi, Md Rasel Al Mahmud, Juan Aldaco, Ryusuke Suzuki, Felipe Cortés-Ledesma, Xiaojiang Cui, Shintaro Yamada, Shunichi Takeda, Armando Giuliano, Sungyong You, Hisashi Tanaka","doi":"10.1093/narcan/zcae016","DOIUrl":"https://doi.org/10.1093/narcan/zcae016","url":null,"abstract":"Abstract With its ligand estrogen, the estrogen receptor (ER) initiates a global transcriptional program, promoting cell growth. This process involves topoisomerase 2 (TOP2), a key protein in resolving topological issues during transcription by cleaving a DNA duplex, passing another duplex through the break, and repairing the break. Recent studies revealed the involvement of various DNA repair proteins in the repair of TOP2-induced breaks, suggesting potential alternative repair pathways in cases where TOP2 is halted after cleavage. However, the contribution of these proteins in ER-induced transcriptional regulation remains unclear. We investigated the role of tyrosyl-DNA phosphodiesterase 2 (TDP2), an enzyme for the removal of halted TOP2 from the DNA ends, in the estrogen-induced transcriptome using both targeted and global transcription analyses. MYC activation by estrogen, a TOP2-dependent and transient event, became prolonged in the absence of TDP2 in both TDP2-deficient cells and mice. Bulk and single-cell RNA-seq analyses defined MYC and CCND1 as oncogenes whose estrogen response is tightly regulated by TDP2. These results suggest that TDP2 may inherently participate in the repair of estrogen-induced breaks at specific genomic loci, exerting precise control over oncogenic gene expression.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140730859","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}

引用次数: 0

XPA tumor variant leads to defects in NER that sensitize cells to cisplatin. XPA 肿瘤变体导致 NER 缺陷，使细胞对顺铂敏感。

IF 3.4

NAR cancer Pub Date : 2024-03-18 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae013

Alexandra M Blee, Kaitlyn S Gallagher, Hyun-Suk Kim, Mihyun Kim, Suhas S Kharat, Christina R Troll, Areetha D'Souza, Jiyoung Park, P Drew Neufer, Orlando D Schärer, Walter J Chazin

{"title":"XPA tumor variant leads to defects in NER that sensitize cells to cisplatin.","authors":"Alexandra M Blee, Kaitlyn S Gallagher, Hyun-Suk Kim, Mihyun Kim, Suhas S Kharat, Christina R Troll, Areetha D'Souza, Jiyoung Park, P Drew Neufer, Orlando D Schärer, Walter J Chazin","doi":"10.1093/narcan/zcae013","DOIUrl":"10.1093/narcan/zcae013","url":null,"abstract":"Nucleotide excision repair (NER) reduces efficacy of treatment with platinum (Pt)-based chemotherapy by removing Pt lesions from DNA. Previous study has identified that missense mutation or loss of the NER genes Excision Repair Cross Complementation Group 1 and 2 (ERCC1 and ERCC2) leads to improved patient outcomes after treatment with Pt-based chemotherapies. Although most NER gene alterations found in patient tumors are missense mutations, the impact of mutations in the remaining nearly 20 NER genes is unknown. Towards this goal, we previously developed a machine learning strategy to predict genetic variants in an essential NER protein, Xeroderma Pigmentosum Complementation Group A (XPA), that disrupt repair. In this study, we report in-depth analyses of a subset of the predicted variants, including in vitro analyses of purified recombinant protein and cell-based assays to test Pt agent sensitivity in cells and determine mechanisms of NER dysfunction. The most NER deficient variant Y148D had reduced protein stability, weaker DNA binding, disrupted recruitment to damage, and degradation. Our findings demonstrate that tumor mutations in XPA impact cell survival after cisplatin treatment and provide valuable mechanistic insights to improve variant effect prediction. Broadly, these findings suggest XPA tumor variants should be considered when predicting chemotherapy response.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10946055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140159805","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}

引用次数: 0

The impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues. tRNA 修饰对癌症翻译的影响：确定新的治疗途径。

NAR cancer Pub Date : 2024-03-12 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae012

Ana M Añazco-Guenkova, Borja Miguel-López, Óscar Monteagudo-García, Raquel García-Vílchez, Sandra Blanco

{"title":"The impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues.","authors":"Ana M Añazco-Guenkova, Borja Miguel-López, Óscar Monteagudo-García, Raquel García-Vílchez, Sandra Blanco","doi":"10.1093/narcan/zcae012","DOIUrl":"10.1093/narcan/zcae012","url":null,"abstract":"Recent advancements have illuminated the critical role of RNA modifications in post-transcriptional regulation, shaping the landscape of gene expression. This review explores how tRNA modifications emerge as critical players, fine-tuning functionalities that not only maintain the fidelity of protein synthesis but also dictate gene expression and translation profiles. Highlighting their dysregulation as a common denominator in various cancers, we systematically investigate the intersection of both cytosolic and mitochondrial tRNA modifications with cancer biology. These modifications impact key processes such as cell proliferation, tumorigenesis, migration, metastasis, bioenergetics and the modulation of the tumor immune microenvironment. The recurrence of altered tRNA modification patterns across different cancer types underscores their significance in cancer development, proposing them as potential biomarkers and as actionable targets to disrupt tumorigenic processes, offering new avenues for precision medicine in the battle against cancer.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10928989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140112604","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}

引用次数: 0

The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest. 模拟 DSB 的 AsiDNA™ 诱饵通过 DNA-PK/p53/p21 依赖性 G1/S 停顿保护正常组织免受辐射毒性的伤害。

IF 3.4

NAR cancer Pub Date : 2024-03-12 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae011

Anouk Sesink, Margaux Becerra, Jia-Ling Ruan, Sophie Leboucher, Maxime Dubail, Sophie Heinrich, Wael Jdey, Kristoffer Petersson, Charles Fouillade, Nathalie Berthault, Marie Dutreix, Pierre-Marie Girard

{"title":"The AsiDNA™ decoy mimicking DSBs protects the normal tissue from radiation toxicity through a DNA-PK/p53/p21-dependent G1/S arrest.","authors":"Anouk Sesink, Margaux Becerra, Jia-Ling Ruan, Sophie Leboucher, Maxime Dubail, Sophie Heinrich, Wael Jdey, Kristoffer Petersson, Charles Fouillade, Nathalie Berthault, Marie Dutreix, Pierre-Marie Girard","doi":"10.1093/narcan/zcae011","DOIUrl":"10.1093/narcan/zcae011","url":null,"abstract":"AsiDNA™, a cholesterol-coupled oligonucleotide mimicking double-stranded DNA breaks, was developed to sensitize tumour cells to radio- and chemotherapy. This drug acts as a decoy hijacking the DNA damage response. Previous studies have demonstrated that standalone AsiDNA™ administration is well tolerated with no additional adverse effects when combined with chemo- and/or radiotherapy. The lack of normal tissue complication encouraged further examination into the role of AsiDNA™ in normal cells. This research demonstrates the radioprotective properties of AsiDNA™. In vitro, AsiDNA™ induces a DNA-PK/p53/p21-dependent G1/S arrest in normal epithelial cells and fibroblasts that is absent in p53 deficient and proficient tumour cells. This cell cycle arrest improved survival after irradiation only in p53 proficient normal cells. Combined administration of AsiDNA™ with conventional radiotherapy in mouse models of late and early radiation toxicity resulted in decreased onset of lung fibrosis and increased intestinal crypt survival. Similar results were observed following FLASH radiotherapy in standalone or combined with AsiDNA™. Mechanisms comparable to those identified in vitro were detected both in vivo, in the intestine and ex vivo, in precision cut lung slices. Collectively, the results suggest that AsiDNA™ can partially protect healthy tissues from radiation toxicity by triggering a G1/S arrest in normal cells.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10928987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140112552","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}

引用次数: 0

Singleton mutations in large-scale cancer genome studies: uncovering the tail of cancer genome. 大规模癌症基因组研究中的单突变：揭开癌症基因组的尾巴。

NAR cancer Pub Date : 2024-03-12 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae010

Sanket Desai, Suhail Ahmad, Bhargavi Bawaskar, Sonal Rashmi, Rohit Mishra, Deepika Lakhwani, Amit Dutt

{"title":"Singleton mutations in large-scale cancer genome studies: uncovering the tail of cancer genome.","authors":"Sanket Desai, Suhail Ahmad, Bhargavi Bawaskar, Sonal Rashmi, Rohit Mishra, Deepika Lakhwani, Amit Dutt","doi":"10.1093/narcan/zcae010","DOIUrl":"10.1093/narcan/zcae010","url":null,"abstract":"Singleton or low-frequency driver mutations are challenging to identify. We present a domain driver mutation estimator (DOME) to identify rare candidate driver mutations. DOME analyzes positions analogous to known statistical hotspots and resistant mutations in combination with their functional and biochemical residue context as determined by protein structures and somatic mutation propensity within conserved PFAM domains, integrating the CADD scoring scheme. Benchmarked against seven other tools, DOME exhibited superior or comparable accuracy compared to all evaluated tools in the prediction of functional cancer drivers, with the exception of one tool. DOME identified a unique set of 32 917 high-confidence predicted driver mutations from the analysis of whole proteome missense variants within domain boundaries across 1331 genes, including 1192 noncancer gene census genes, emphasizing its unique place in cancer genome analysis. Additionally, analysis of 8799 TCGA (The Cancer Genome Atlas) and in-house tumor samples revealed 847 potential driver mutations, with mutations in tyrosine kinase members forming the dominant burden, underscoring its higher significance in cancer. Overall, DOME complements current approaches for identifying novel, low-frequency drivers and resistant mutations in personalized therapy.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10939354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140133687","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}

引用次数: 0

METTL3 as a master regulator of translation in cancer: mechanisms and implications. METTL3 作为癌症翻译的主调节器：机制与影响。

NAR cancer Pub Date : 2024-03-05 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae009

Margalida Esteva-Socias, Francesca Aguilo

{"title":"METTL3 as a master regulator of translation in cancer: mechanisms and implications.","authors":"Margalida Esteva-Socias, Francesca Aguilo","doi":"10.1093/narcan/zcae009","DOIUrl":"10.1093/narcan/zcae009","url":null,"abstract":"Translational regulation is an important step in the control of gene expression. In cancer cells, the orchestration of both global control of protein synthesis and selective translation of specific mRNAs promote tumor cell survival, angiogenesis, transformation, invasion and metastasis. N6-methyladenosine (m6A), the most prevalent mRNA modification in higher eukaryotes, impacts protein translation. Over the past decade, the development of m6A mapping tools has facilitated comprehensive functional investigations, revealing the involvement of this chemical mark, together with its writer METTL3, in promoting the translation of both oncogenes and tumor suppressor transcripts, with the impact being context-dependent. This review aims to consolidate our current understanding of how m6A and METTL3 shape translation regulation in the realm of cancer biology. In addition, it delves into the role of cytoplasmic METTL3 in protein synthesis, operating independently of its catalytic activity. Ultimately, our goal is to provide critical insights into the interplay between m6A, METTL3 and translational regulation in cancer, offering a deeper comprehension of the mechanisms sustaining tumorigenesis.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10914372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140041211","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}

引用次数: 0

SAMHD1 expression contributes to doxorubicin resistance and predicts survival outcomes in diffuse large B-cell lymphoma patients. SAMHD1 的表达会导致多柔比星耐药，并预测弥漫大 B 细胞淋巴瘤患者的生存结果。

IF 3.4

NAR cancer Pub Date : 2024-02-24 eCollection Date: 2024-03-01 DOI: 10.1093/narcan/zcae007

Waaqo Daddacha, Dominique Monroe, Ashley J Schlafstein, Allison E Withers, Elizabeth B Thompson, Diana Danelia, Nho C Luong, Fatmata Sesay, Sandip K Rath, Edidiong R Usoro, Mark E Essien, Andrew T Jung, Jinmeng G Jiang, Jiaxuan Hu, Bijan Mahboubi, Arilyn Williams, Julia E Steinbeck, Xiaofeng Yang, Zachary S Buchwald, William S Dynan, Jeffrey M Switchenko, Baek Kim, Mohammad K Khan, David L Jaye, David S Yu

{"title":"SAMHD1 expression contributes to doxorubicin resistance and predicts survival outcomes in diffuse large B-cell lymphoma patients.","authors":"Waaqo Daddacha, Dominique Monroe, Ashley J Schlafstein, Allison E Withers, Elizabeth B Thompson, Diana Danelia, Nho C Luong, Fatmata Sesay, Sandip K Rath, Edidiong R Usoro, Mark E Essien, Andrew T Jung, Jinmeng G Jiang, Jiaxuan Hu, Bijan Mahboubi, Arilyn Williams, Julia E Steinbeck, Xiaofeng Yang, Zachary S Buchwald, William S Dynan, Jeffrey M Switchenko, Baek Kim, Mohammad K Khan, David L Jaye, David S Yu","doi":"10.1093/narcan/zcae007","DOIUrl":"10.1093/narcan/zcae007","url":null,"abstract":"Diffuse large B-cell lymphoma (DLBCL) is a commonly diagnosed, aggressive non-Hodgkin's lymphoma. While R-CHOP chemoimmunotherapy is potentially curative, about 40% of DLBCL patients will fail, highlighting the need to identify biomarkers to optimize management. SAMHD1 has a dNTPase-independent role in promoting resection to facilitate DNA double-strand break (DSB) repair by homologous recombination. We evaluated the relationship of SAMHD1 levels with sensitivity to DSB-sensitizing agents in DLBCL cells and the association of SAMHD1 expression with clinical outcomes in 79 DLBCL patients treated with definitive therapy and an independent cohort dataset of 234 DLBCL patients. Low SAMHD1 expression, Vpx-mediated, or siRNA-mediated degradation/depletion in DLBCL cells was associated with greater sensitivity to doxorubicin and PARP inhibitors. On Kaplan-Meier log-rank survival analysis, low SAMHD1 expression was associated with improved overall survival (OS), which on subset analysis remained significant only in patients with advanced stage (III-IV) and moderate to high risk (2-5 International Prognostic Index (IPI)). The association of low SAMHD1 expression with improved OS remained significant on multivariate analysis independent of other adverse factors, including IPI, and was validated in an independent cohort. Our findings suggest that SAMHD1 expression mediates doxorubicin resistance and may be an important prognostic biomarker in advanced, higher-risk DLBCL patients.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10894040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139975172","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}

引用次数: 0