{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:33:23Z","timestamp":1790728403107,"version":"4.1.0"},"reference-count":54,"publisher":"American Society of Hematology","issue":"26","license":[{"start":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T00:00:00Z","timestamp":1660780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,12,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Relapse is a leading cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). However, the underlying mechanisms remain poorly understood. Natural killer (NK) cells play a crucial role in tumor surveillance and cancer immunotherapy, and NK cell dysfunction has been observed in various tumors. Here, we performed ex\u00a0vivo experiments to systematically characterize the mechanisms underlying the dysfunction of bone marrow\u2212derived NK (BMNK) cells isolated from AML patients experiencing early relapse after allo-HSCT. We demonstrated that higher levels of active transforming growth factor \u03b21 (TGF-\u03b21) were associated with impaired effector function of BMNK cells in these AML patients. TGF-\u03b21 activation was induced by the overexpression of glycoprotein A repetitions predominant on the surface of CD4+ T cells. Active TGF-\u03b21 significantly suppressed mTORC1 activity, mitochondrial oxidative phosphorylation, the proliferation, and cytotoxicity of BMNK cells. Furthermore, pretreatment with the clinical stage TGF-\u03b21 pathway inhibitor, galunisertib, significantly restored mTORC1 activity, mitochondrial homeostasis, and cytotoxicity. Importantly, the blockade of the TGF-\u03b21 signaling improved the antitumor activity of NK cells in a leukemia xenograft mouse model. Thus, our findings reveal a mechanism explaining BMNK cell dysfunction and suggest that targeted inhibition of TGF-\u03b21 signaling may represent a potential therapeutic intervention to improve outcomes in AML patients undergoing allo-HSCT or NK cell\u2212based immunotherapy.<\/jats:p>","DOI":"10.1182\/blood.2022015474","type":"journal-article","created":{"date-parts":[[2022,8,18]],"date-time":"2022-08-18T22:02:49Z","timestamp":1660860169000},"page":"2788-2804","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":57,"title":["GARP-mediated active TGF-\u03b21 induces bone marrow NK cell dysfunction in AML patients with early relapse post\u2013allo-HSCT"],"prefix":"10.1182","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1720-1135","authenticated-orcid":false,"given":"Dongyao","family":"Wang","sequence":"first","affiliation":[{"name":"1Division of Life Sciences and Medicine, Department of Hematology, the First 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