{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T15:50:10Z","timestamp":1762703410908,"version":"build-2065373602"},"reference-count":42,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004710","name":"Fondazione Umberto Veronesi","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004710","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007461","name":"Fondazione Pezcoller","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007461","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020581","name":"Fondazione AIRC per la ricerca sul cancro ETS","doi-asserted-by":"publisher","award":["IG23607"],"award-info":[{"award-number":["IG23607"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009888","name":"Regione Toscana","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009888","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Chronic myeloid leukemia (CML) is a stem cell\u2010driven neoplasia characterized by the expression of the constitutively active tyrosine kinase (TK) BCR\/Abl. Under low oxygen, a condition that characterizes stem cell niches (SCNs)\n                    <jats:italic>in vivo<\/jats:italic>\n                    , the oncogenic BCR\/Abl\n                    <jats:sub>protein<\/jats:sub>\n                    is suppressed. Consequently, leukemia stem cells (LSCs) residing within SCNs show resistance to TK inhibitors (TKIs), the first\u2010line therapy for CML, due to the lack of their molecular target. It is therefore important to deepen understanding of the mechanisms driving BCR\/Abl\n                    <jats:sub>protein<\/jats:sub>\n                    suppression to design new strategies able to repress TKI\u2010resistant LSCs. Our previous studies showed that BCR\/Abl\n                    <jats:sub>protein<\/jats:sub>\n                    suppression occurred when glucose approaches completed exhaustion in culture medium. As lactate is the main byproduct of glucose catabolism in low oxygen, in this study we addressed the role of lactate in regulating BCR\/Abl\n                    <jats:sub>protein<\/jats:sub>\n                    expression. We found that treatment of CML cells with 2\u2010DG, which blocks glycolysis and thereby lactate production, or monocarboxylate transporter (MCT) inhibitors, which reduce lactate excretion, enhanced BCR\/Abl\n                    <jats:sub>protein<\/jats:sub>\n                    expression and promoted maintenance of a BCR\/Abl\u2010dependent\/TKI\u2010sensitive stem cell phenotype. The effects of MCT inhibition were abolished when exogenous lactate was added to culture medium, resulting in the suppression of BCR\/Abl\n                    <jats:sub>protein<\/jats:sub>\n                    expression. Treatment with 3\u2010hydroxy\u2010butyrate acid, an antagonist of the GPR81 plasma membrane \u2018lactate\u2019 receptor, prevented lactate\u2010driven BCR\/Abl\n                    <jats:sub>protein<\/jats:sub>\n                    suppression, while the selective GPR81 agonist 3\u2010chloro\u20105\u2010hydroxy\u2010BA counteracted the maintenance of BCR\/Abl\n                    <jats:sub>protein<\/jats:sub>\n                    induced by MCT inhibition. Our results indicate that GPR81 engagement by extracellular lactate determines BCR\/Abl\n                    <jats:sub>protein<\/jats:sub>\n                    suppression in low oxygen environments. \u00a9 2025 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.6492","type":"journal-article","created":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T12:56:03Z","timestamp":1761224163000},"page":"399-409","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lactate\u2010mediated activation of\n                    <scp>GPR81<\/scp>\n                    regulates\n                    <scp>BCR<\/scp>\n                    \/Abl protein expression in chronic myeloid leukemia cells selected under low oxygen tension"],"prefix":"10.1002","volume":"267","author":[{"given":"Giulio","family":"Menegazzi","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences Universit\u00e0 degli Studi di Firenze  Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dayana","family":"Desideri","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences Universit\u00e0 degli Studi di Firenze  Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessio","family":"Biagioni","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences Universit\u00e0 degli Studi di Firenze  Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabetta","family":"Rovida","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences Universit\u00e0 degli Studi di Firenze  Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Persio","family":"Dello Sbarba","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences Universit\u00e0 degli Studi di Firenze  Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6459-0458","authenticated-orcid":false,"given":"Silvia","family":"Peppicelli","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Biomedical Sciences Universit\u00e0 degli Studi di Firenze  Florence Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,10,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25792"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-015-0143-7"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-09-696013"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0229104"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13194820"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-69194-7_3"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13174372"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2404224"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2010.029082"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-10-745588"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.4161\/15384101.2014.964107"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13319"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3727\/096504022X16442289212164"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.01143"},{"key":"e_1_2_9_16_1","first-page":"5726","article-title":"Increased lactate in AML blasts upregulates TOX expression, leading to exhaustion of CD8+ cytolytic T cells","volume":"11","author":"Chen Y","year":"2021","journal-title":"Am J Cancer Res"},{"key":"e_1_2_9_17_1","doi-asserted-by":"crossref","unstructured":"SotoCA Leschm BeckerJL et al.Elevated lactate in the AML bone marrow microenvironment polarizes leukemia\u2010associated macrophages via GPR81 signaling bioRxiv2023; 2023.11.13.566874. 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