{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:36:16Z","timestamp":1787027776254,"version":"build-2736575974"},"reference-count":33,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T00:00:00Z","timestamp":1756425600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["R01CA277493-01"],"award-info":[{"award-number":["R01CA277493-01"]}]},{"name":"NIH","award":["T32CA009213"],"award-info":[{"award-number":["T32CA009213"]}]},{"name":"NIH","award":["T32HL007249"],"award-info":[{"award-number":["T32HL007249"]}]},{"name":"NIH","award":["1T32CA272303-01A1"],"award-info":[{"award-number":["1T32CA272303-01A1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Donor lymphocyte infusion (DLI) is employed to enhance the graft-versus-leukemia (GvL) effect and improve remission rates following allogeneic hematopoietic cell transplantation (alloHCT). However, graft-versus-host disease (GvHD) remains a significant complication of both alloHCT and DLI. Regular exercise has been shown to reduce cancer risk, enhance treatment responses, and mitigate therapy-related toxicities. This study investigated the effects of voluntary wheel running on GvL and GvHD following DLI in a xenogeneic mouse model. Methods: Immunodeficient NSG-IL15 mice were challenged with a luciferase-expressing chronic myelogenous leukemia cell line (K562), and then they received DLI with peripheral blood mononuclear cells (PBMCs) from healthy volunteers (GvL model). Non-tumor bearing mice received DLI to model GvHD. Half of the mice in each group were then given free access to a running wheel. Tumor growth (bioluminescence), GvHD, and body weight were monitored biweekly for ~40 days. Results: In the GvHD model, exercise extended overall survival by 60% and reduced GvHD severity. In the GvL model, exercise significantly lowered tumor burden and extended tumor-free survival in both DLI and vehicle control groups by 44.5% and 37.5%, respectively, suggesting both immune-dependent and immune-independent mechanisms. RNA sequencing of bone marrow from saline-injected mice revealed that genes associated with mitochondrial function, protein synthesis, and metabolic processes were downregulated in tumors from exercised mice. Conclusions: In summary, voluntary wheel running improved DLI outcomes by enhancing GvL and reducing GvHD. These benefits may be mediated, in part, through exercise-induced metabolic reprogramming of leukemia cells.<\/jats:p>","DOI":"10.3390\/cancers17172826","type":"journal-article","created":{"date-parts":[[2025,8,29]],"date-time":"2025-08-29T12:25:57Z","timestamp":1756470357000},"page":"2826","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exercise Delays Human Leukemia Progression and Mitigates Graft-Versus-Host Disease After Donor Lymphocyte Infusion in Xenogeneic Mice"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3410-5973","authenticated-orcid":false,"given":"Helena","family":"Batatinha","sequence":"first","affiliation":[{"name":"School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole A.","family":"Pe\u00f1a","sequence":"additional","affiliation":[{"name":"School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovannah A.","family":"Hoskin","sequence":"additional","affiliation":[{"name":"School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M.","family":"Kistner","sequence":"additional","affiliation":[{"name":"The University of Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglass M.","family":"Diak","sequence":"additional","affiliation":[{"name":"School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace M.","family":"Niemiro","sequence":"additional","affiliation":[{"name":"The University of Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1466-6965","authenticated-orcid":false,"given":"Emmanuel","family":"Katsanis","sequence":"additional","affiliation":[{"name":"The University of Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA"},{"name":"Department of Immunobiology, The University of Arizona, Tucson, AZ 85724, USA"},{"name":"Department of Pediatrics, The University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7064-6881","authenticated-orcid":false,"given":"Richard J.","family":"Simpson","sequence":"additional","affiliation":[{"name":"School of Nutritional Sciences and Wellness, The University of Arizona, Tucson, AZ 85724, USA"},{"name":"The University of Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA"},{"name":"Department of Immunobiology, The University of Arizona, Tucson, AZ 85724, USA"},{"name":"Department of Pediatrics, The University of Arizona, Tucson, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.tmrv.2015.07.001","article-title":"Adoptive Immunotherapies After Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Hematologic Malignancies","volume":"29","author":"Xiong","year":"2015","journal-title":"Transfus. Med. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1182\/asheducation-2015.1.225","article-title":"Graft-versus-Host Disease versus Graft-versus-Leukemia","volume":"2015","author":"Negrin","year":"2015","journal-title":"Hematology"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Maurer, K., and Antin, J.H. (2024). The Graft versus Leukemia Effect: Donor Lymphocyte Infusions and Cellular Therapy. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1328858"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4889","DOI":"10.1158\/0008-5472.CAN-21-1258","article-title":"Effects of Exercise on Cancer Treatment Efficacy: A Systematic Review of Preclinical and Clinical Studies","volume":"81","author":"Yang","year":"2021","journal-title":"Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.semradonc.2018.10.001","article-title":"Exercise as Adjunct Therapy in Cancer","volume":"29","author":"Ashcraft","year":"2019","journal-title":"Semin. Radiat. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Batatinha, H., Diak, D.M., Niemiro, G.M., Baker, F.L., Smith, K.A., Z\u00fa\u00f1iga, T.M., Mylabathula, P.L., Seckeler, M.D., Lau, B., and LaVoy, E.C. (2023). Human Lymphocytes Mobilized with Exercise Have an Anti-Tumor Transcriptomic Profile and Exert Enhanced Graft-versus-Leukemia Effects in Xenogeneic Mice. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1067369"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.bbi.2018.08.017","article-title":"B2-Adrenergic Receptor Signaling Mediates the Preferential Mobilization of Differentiated Subsets of CD8+ T-Cells, NK-Cells and Non-Classical Monocytes in Response to Acute Exercise in Humans","volume":"74","author":"Graff","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/s41577-023-00943-0","article-title":"The Effect of Physical Exercise on Anticancer Immunity","volume":"24","author":"Valenzuela","year":"2024","journal-title":"Nat. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.cmet.2017.09.015","article-title":"Molecular Mechanisms Linking Exercise to Cancer Prevention and Treatment","volume":"27","author":"Hojman","year":"2018","journal-title":"Cell Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.cmet.2016.01.011","article-title":"Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution","volume":"23","author":"Pedersen","year":"2016","journal-title":"Cell Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1158\/2326-6066.CIR-20-0499","article-title":"Exercise Training Improves Tumor Control by Increasing CD8+ T-Cell Infiltration via CXCR3 Signaling and Sensitizes Breast Cancer to Immune Checkpoint Blockade","volume":"9","author":"Amoozgar","year":"2021","journal-title":"Cancer Immunol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/j.bbi.2025.04.040","article-title":"Exercise-Induced \u03922-Adrenergic Receptor Activation Enhances Effector Lymphocyte Mobilization in Humans and Suppresses Lymphoma Growth in Mice through NK-Cells","volume":"128","author":"Smith","year":"2025","journal-title":"Brain Behav. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"100016","DOI":"10.1016\/j.bbih.2019.100016","article-title":"Effects of Combined Exercise Training on the Inflammatory Profile of Older Cancer Patients Treated with Systemic Therapy","volume":"2","author":"Fontvieille","year":"2020","journal-title":"Brain Behav. Immun. Health"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Feng, Y., Feng, X., Wan, R., Luo, Z., Qu, L., and Wang, Q. (2024). Impact of Exercise on Cancer: Mechanistic Perspectives and New Insights. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1474770"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2050312120922657","DOI":"10.1177\/2050312120922657","article-title":"Effects of Exercise Therapy in Cancer Patients Undergoing Radiotherapy Treatment: A Narrative Review","volume":"8","author":"Piraux","year":"2020","journal-title":"SAGE Open Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A Flexible Trimmer for Illumina Sequence Data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.12688\/f1000research.10082.1","article-title":"Disambiguate: An Open-Source Application for Disambiguating Two Species in next Generation Sequencing Data from Grafted Samples","volume":"5","author":"Gray","year":"2016","journal-title":"F1000Research"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast Universal RNA-Seq Aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2943","DOI":"10.1093\/bioinformatics\/btac166","article-title":"Analysing High-Throughput Sequencing Data in Python with HTSeq 2.0","volume":"38","author":"Putri","year":"2022","journal-title":"Bioinformatics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"gkaf018","DOI":"10.1093\/nar\/gkaf018","article-title":"edgeR v4: Powerful Differential Analysis of Sequencing Data with Expanded Functionality and Improved Support for Small Counts and Larger Datasets","volume":"53","author":"Chen","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R Package for Comparing Biological Themes Among Gene Clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1038\/s41409-019-0624-z","article-title":"Death after Hematopoietic Stem Cell Transplantation: Changes over Calendar Year Time, Infections and Associated Factors","volume":"55","author":"Tridello","year":"2020","journal-title":"Bone Marrow Transplant."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2409","DOI":"10.3727\/096368912X658746","article-title":"Effects of Exercise Interventions in Graft-Versus-Host Disease Models","volume":"22","author":"Palacio","year":"2013","journal-title":"Cell Transplant."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1249\/MSS.0b013e31828fa004","article-title":"Exercise Benefits in Chronic Graft versus Host Disease: A Murine Model Study","volume":"45","author":"Palacio","year":"2013","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e1600200","DOI":"10.1126\/sciadv.1600200","article-title":"Fundamentals of Cancer Metabolism","volume":"2","author":"DeBerardinis","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.cell.2016.12.039","article-title":"Understanding the Intersections between Metabolism and Cancer Biology","volume":"168","author":"Heiden","year":"2017","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eaaw5473","DOI":"10.1126\/science.aaw5473","article-title":"Metabolic Reprogramming and Cancer Progression","volume":"368","author":"Faubert","year":"2020","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/s41573-021-00339-6","article-title":"Targeting Cancer Metabolism in the Era of Precision Oncology","volume":"21","author":"Stine","year":"2022","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.1101\/gad.326470.119","article-title":"Metabolic Dependencies and Vulnerabilities in Leukemia","volume":"33","author":"Rashkovan","year":"2019","journal-title":"Genes Dev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41375-021-01416-w","article-title":"Mitochondrial Metabolism as a Potential Therapeutic Target in Myeloid Leukaemia","volume":"36","author":"Himonas","year":"2022","journal-title":"Leukemia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1038\/nm.4399","article-title":"Targeting Mitochondrial Oxidative Phosphorylation Eradicates Therapy-Resistant Chronic Myeloid Leukemic Stem Cells","volume":"23","author":"Kuntz","year":"2017","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/nm.4336","article-title":"Single-Cell Transcriptomics Uncovers Distinct Molecular Signatures of Stem Cells in Chronic Myeloid Leukemia","volume":"23","author":"Giustacchini","year":"2017","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1182\/blood.V45.3.321.321","article-title":"Human Chronic Myelogenous Leukemia Cell-Line with Positive Philadelphia Chromosome","volume":"45","author":"Lozzio","year":"1975","journal-title":"Blood"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/17\/2826\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:35:05Z","timestamp":1760034905000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/17\/2826"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,29]]},"references-count":33,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["cancers17172826"],"URL":"https:\/\/doi.org\/10.3390\/cancers17172826","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,29]]}}}