{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T14:49:04Z","timestamp":1778942944845,"version":"3.51.4"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T00:00:00Z","timestamp":1639699200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013076","name":"National Major Science and Technology Projects of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013076","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>SAMHD1 (sterile alpha motif domain and histidine-aspartate domain-containing protein 1) is a deoxynucleoside triphosphate triphosphohydrolase regulating innate immune and modulating DNA damage signaling. It plays an important role in the development of some tumors. SAMHD1 was also reported as a barrier to cytarabine, a common chemotherapy drug for mantle cell lymphoma (MCL), and as a biomarker of grim prognosis for acute myelocytic leukemia (AML) patients. However, SAMHD1 expression and function in MCL have not been well-defined. In the present study, we evaluated SAMHD1 expression by immunohistochemistry and its gene structure by Sanger sequencing in MCL. Our results showed that SAMHD1 was positive in 36 (62.1%) patients. Importantly, SAMHD1-positive patients were associated with lower chemotherapy response rate (<jats:italic>p<\/jats:italic> = 0.023) and shorter overall survival (<jats:italic>p<\/jats:italic> = 0.039) than SAMHD1-negative cases. These results suggest that SAMHD1 is an adverse biomarker for MCL patients, which is due to the high expression of SAMHD1 and rapid cell proliferation. These findings were confirmed in an <jats:italic>in vitro<\/jats:italic> study using the <jats:italic>si<\/jats:italic>RNA technique. Silencing the <jats:italic>SAMHD1<\/jats:italic> gene in the MCL cell line Jeko-1 significantly decreased cell proliferation and increased cell apoptosis. The MCL cell line with <jats:italic>SAMHD1<\/jats:italic> knockdown showed lower Ki-67 proliferation index, higher caspase-3, and higher sensitivity to cytarabine. Furthermore, for the first time, four previously unreported missense mutations (S302Y, Y432C, E449G, and R451H) in exon 8 and exon 12 of the <jats:italic>SAMHD1<\/jats:italic> gene were discovered by sequencing. The mutations had not been found to corelate with SAMHD1 protein expression detected by immunohistochemistry. The biological functions of this mutated SAMHD1 remain to be investigated.<\/jats:p>","DOI":"10.3389\/fonc.2021.763151","type":"journal-article","created":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T05:12:28Z","timestamp":1639717948000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["SAMHD1 Mutations and Expression in Mantle Cell Lymphoma Patients"],"prefix":"10.3389","volume":"11","author":[{"given":"Tao","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenqin","family":"Yue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gusheng","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingyu","family":"Ye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiechen","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lijuan","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuefei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuyi","family":"Yin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianmin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miaoxia","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.373","article-title":"Mutations Involved in Aicardi-Goutieres Syndrome Implicate SAMHD1 as Regulator of the Innate Immune Response","volume":"41","author":"Rice","year":"2009","journal-title":"Nat Genet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10117","article-title":"SAMHD1 Is the Dendritic- and Myeloid-Cell-Specific HIV-1 Restriction Factor Counteracted by Vpx","volume":"474","author":"Laguette","year":"2011","journal-title":"Nature"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nature10623","article-title":"HIV-1 Restriction Factor SAMHD1 Is a Deoxynucleoside Triphosphate Triphosphohydrolase","volume":"480","author":"Goldstone","year":"2011","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.03.017","article-title":"Phosphorylation of SAMHD1 by Cyclin A2\/CDK1 Regulates its Restriction Activity Toward HIV-1","volume":"3","author":"Cribier","year":"2013","journal-title":"Cell Rep"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1312033110","article-title":"The Deoxynucleotide Triphosphohydrolase SAMHD1 Is a Major Regulator of DNA Precursor Pools in Mammalian Cells","volume":"110","author":"Franzolin","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.08.008","article-title":"SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination","volume":"20","author":"Daddacha","year":"2017","journal-title":"Cell Rep"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1519128113","article-title":"Heterozygous Colon Cancer-Associated Mutations of SAMHD1 Have Functional Significance","volume":"113","author":"Rentoft","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2014.10.153","article-title":"SAMHD1 Is Down Regulated in Lung Cancer by Methylation and Inhibits Tumor Cell Proliferation","volume":"455","author":"Wang","year":"2014","journal-title":"Biochem Biophys Res Commun"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-04-490847","article-title":"SAMHD1 Is Mutated Recurrently in Chronic Lymphocytic Leukemia and Is Involved in Response to DNA Damage","volume":"123","author":"Clifford","year":"2014","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.ccell.2017.05.008","article-title":"Chromatin Accessibility Landscape of Cutaneous T Cell Lymphoma and Dynamic Response to HDAC Inhibitors","volume":"32","author":"Qu","year":"2017","journal-title":"Cancer Cell"},{"key":"B11","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s41408-017-0036-5","article-title":"SAMHD1 Is Recurrently Mutated in T-Cell Prolymphocytic Leukemia","volume":"8","author":"Johansson","year":"2018","journal-title":"Blood Cancer J"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e1287554","DOI":"10.1080\/23723556.2017.1287554","article-title":"SAMHD1 Is a Barrier to Antimetabolite-Based Cancer Therapies","volume":"4","author":"Rudd","year":"2017","journal-title":"Mol Cell Oncol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1038\/nm0617-788a","article-title":"Corrigendum: SAMHD1 Is a Biomarker for Cytarabine Response and a Therapeutic Target in Acute Myeloid Leukemia","volume":"23","author":"Schneider","year":"2017","journal-title":"Nat Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4265","article-title":"Targeting SAMHD1 With the Vpx Protein to Improve Cytarabine Therapy for Hematological Malignancies","volume":"23","author":"Herold","year":"2017","journal-title":"Nat Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-08-236570","article-title":"The Mantle Cell Lymphoma International Prognostic Index (MIPI) Is Superior to the International Prognostic Index (IPI) in Predicting Survival Following Intensive First-Line Immunochemotherapy and Autologous Stem Cell Transplantation (ASCT)","volume":"115","author":"Geisler","year":"2010","journal-title":"Blood"},{"key":"B16","doi-asserted-by":"publisher","first-page":"3407","DOI":"10.1182\/blood-2005-10-4079","article-title":"The Ki67 Proliferation Index Is a Quantitative Indicator of Clinical Risk in Mantle Cell Lymphoma","volume":"107","author":"Katzenberger","year":"2006","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2014.07.017","article-title":"R-CHOP or R-HyperCVAD With or Without Autologous Stem Cell Transplantation for Older Patients With Mantle Cell Lymphoma","volume":"15","author":"Frosch","year":"2015","journal-title":"Clin Lymphoma Myeloma Leukemia"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2011.08958.x","article-title":"Rituximab Plus HyperCVAD Alternating With High Dose Cytarabine and Methotrexate for the Initial Treatment of Patients With Mantle Cell Lymphoma, A Multicentre Trial From Gruppo Italiano Studio Linfomi","volume":"156","author":"Merli","year":"2012","journal-title":"Br J Haematol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1053\/sonc.2002.30143","article-title":"Immunotherapy With Rituximab Following High-Dose Therapy and Autologous Stem-Cell Transplantation for Mantle Cell Lymphoma","volume":"29","author":"Mangel","year":"2002","journal-title":"Semin Oncol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2011.08820.x","article-title":"VcR-CVAD Induction Chemotherapy Followed by Maintenance Rituximab in Mantle Cell Lymphoma: A Wisconsin Oncology Network Study","volume":"155","author":"Chang","year":"2011","journal-title":"Br J Haematol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1023\/A:1008325212484","article-title":"Treatment of Mantle-Cell Lymphomas With Intermittent Two-Hour Infusion of Cladribine as First-Line Therapy or in First Relapse","volume":"10","author":"Rummel","year":"1999","journal-title":"Ann Oncol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.23537","article-title":"Long-Term Results of the Treatment of Patients With Mantle Cell Lymphoma With Cladribine (2-CDA) Alone (95-80-53) or 2-CDA and Rituximab (N0189) in the North Central Cancer Treatment Group","volume":"113","author":"Inwards","year":"2008","journal-title":"Cancer"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.08.133","article-title":"Immunochemotherapy With Rituximab and Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Significantly Improves Response and Time to Treatment Failure, But Not Long-Term Outcome in Patients With Previously Untreated Mantle Cell Lymphoma: Results of a Prospective Randomized Trial of the German Low Grade Lymphoma Study Group (GLSG)","volume":"23","author":"Lenz","year":"2005","journal-title":"J Clin Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdt070","article-title":"A Phase II Multicenter Trial of hyperCVAD MTX\/Ara-C and Rituximab in Patients With Previously Untreated Mantle Cell Lymphoma; SWOG 0213","volume":"24","author":"Bernstein","year":"2013","journal-title":"Ann Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3109\/10428194.2011.575489","article-title":"Cladribine Plus Rituximab Is an Effective Therapy for Newly Diagnosed Mantle Cell Lymphoma","volume":"52","author":"Spurgeon","year":"2011","journal-title":"Leuk Lymphoma"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdg414","article-title":"Limited-Stage Mantle-Cell Lymphoma","volume":"14","author":"Leitch","year":"2003","journal-title":"Ann Oncol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdp495","article-title":"Prognostic Impact of Proliferative Index Determined by Quantitative Image Analysis and the International Prognostic Index in Patients With Mantle Cell Lymphoma","volume":"21","author":"Schaffel","year":"2010","journal-title":"Ann Oncol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.22.2554","article-title":"Immunochemotherapy and Autologous Stem-Cell Transplantation for Untreated Patients With Mantle-Cell Lymphoma: CALGB 59909","volume":"27","author":"Damon","year":"2009","journal-title":"J Clin Oncol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.11838","article-title":"Long-Term Follow-Up of Autologous Stem Cell Transplantation in Patients With Diffuse Mantle Cell Lymphoma in First Disease Remission: The Prognostic Value of Beta2-Microglobulin and the Tumor Score","volume":"98","author":"Khouri","year":"2003","journal-title":"Cancer"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61763-2","article-title":"Bendamustine Plus Rituximab Versus CHOP Plus Rituximab as First-Line Treatment for Patients With Indolent and Mantle-Cell Lymphomas: An Open-Label, Multicentre, Randomised, Phase 3 Non-Inferiority Trial","volume":"381","author":"Rummel","year":"2013","journal-title":"Lancet"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdn045","article-title":"Intensive Treatment Strategies may Not Provide Superior Outcomes in Mantle Cell Lymphoma: Overall Survival Exceeding 7 Years With Standard Therapies","volume":"19","author":"Martin","year":"2008","journal-title":"Ann Oncol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65399-0","article-title":"Detection of Translocation T(11;14)(Q13;Q32) in Mantle Cell Lymphoma by Fluorescence In Situ Hybridization","volume":"154","author":"Li","year":"1999","journal-title":"Am J Pathol"},{"key":"B33","article-title":"WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues","author":"Swerdlow","year":"2017"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-08-452284","article-title":"CCND2 Rearrangements Are the Most Frequent Genetic Events in Cyclin D1(-) Mantle Cell Lymphoma","volume":"121","author":"Salaverria","year":"2013","journal-title":"Blood"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-07-862151","article-title":"CCND2 and CCND3 Hijack Immunoglobulin Light-Chain Enhancers in Cyclin D1(-) Mantle Cell Lymphoma","volume":"133","author":"Mart\u00edn-Garcia","year":"2019","journal-title":"Blood"},{"key":"B36","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.chom.2012.01.004","article-title":"The Ability of Primate Lentiviruses to Degrade the Monocyte Restriction Factor SAMHD1 Preceded the Birth of the Viral Accessory Protein Vpx","volume":"11","author":"Lim","year":"2012","journal-title":"Cell Host Microbe"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2020005289","article-title":"Genomic and Epigenomic Insights Into the Origin, Pathogenesis, and Clinical Behavior of Mantle Cell Lymphoma Subtypes","volume":"136","author":"Nadeu","year":"2020","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12030713","article-title":"The dNTPase Activity of SAMHD1 Is Important for its Suppression of Innate Immune Responses in Differentiated Monocytic Cells","volume":"295","author":"Clotet","year":"2020","journal-title":"Cancers (Basel)"},{"key":"B39","doi-asserted-by":"publisher","first-page":"101170","DOI":"10.1016\/j.jbc.2021.101170","article-title":"Structural and Functional Characterization Explains Loss of Dntpase Activity of the Cancer-Specific R366C\/H Mutant SAMHD1 Proteins","author":"Bowen","year":"2021","journal-title":"J Biol Chem"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2013.311","article-title":"Downregulation of SAMHD1 Expression Correlates With Promoter DNA Methylation in S\u00e9zary Syndrome Patients","volume":"134","author":"de Silva","year":"2014","journal-title":"J Invest Dermatol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.19704","article-title":"SAMHD1 Acetylation Enhances its Deoxynucleotide Triphosphohydrolase Activity and Promotes Cancer Cell Proliferation","volume":"8","author":"Lee","year":"2017","journal-title":"Oncotarget"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.763151\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,17]],"date-time":"2021-12-17T05:12:33Z","timestamp":1639717953000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2021.763151\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,17]]},"references-count":41,"alternative-id":["10.3389\/fonc.2021.763151"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2021.763151","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,17]]},"article-number":"763151"}}