{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T12:15:33Z","timestamp":1791375333117,"version":"4.3.1"},"reference-count":55,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T00:00:00Z","timestamp":1588118400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Acceleron Pharmaceuticals"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Cellular Molecular Medi"],"published-print":{"date-parts":[[2020,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    In \u03b2\u2010thalassaemia, anaemia results from ineffective erythropoiesis characterized by inhibition of late\u2010stage erythroid differentiation. We earlier used luspatercept and RAP\u2010536 protein traps for certain Smad2\/3\u2010pathway ligands to implicate Smad2\/3\u2010pathway overactivation in dysregulated erythroid differentiation associated with murine \u03b2\u2010thalassaemia and myelodysplasia. Importantly, luspatercept alleviates anaemia and has been shown to reduce transfusion burden in patients with \u03b2\u2010thalassaemia or myelodysplasia. Here, we investigated the molecular mechanisms underlying luspatercept action and pSmad2\/3\u2010mediated inhibition of erythroid differentiation. In murine erythroleukemic (MEL) cells in vitro, ligand\u2010mediated overactivation of the Smad2\/3 pathway reduced nuclear levels of GATA\u20101 (GATA\u2010binding factor\u20101) and its transcriptional activator TIF1\u03b3 (transcription intermediary factor 1\u03b3), increased levels of reactive oxygen species, reduced cell viability and haemoglobin levels, and inhibited erythroid differentiation. Co\u2010treatment with luspatercept in MEL cells partially or completely restored each of these. In \u03b2\u2010thalassaemic mice, RAP\u2010536 up\u2010regulated\n                    <jats:italic>Gata1<\/jats:italic>\n                    and its target gene signature in erythroid precursors determined by transcriptional profiling and gene set enrichment analysis, restored nuclear levels of GATA\u20101 in erythroid precursors, and nuclear distribution of TIF1\u03b3 in erythroblasts. Bone marrow cells from \u03b2\u2010thalassaemic mice treated with luspatercept also exhibited restored nuclear availability of GATA\u20101 ex vivo. Our results implicate GATA\u20101, and likely TIF1\u03b3, as key mediators of luspatercept\/RAP\u2010536 action in alleviating ineffective erythropoiesis.\n                  <\/jats:p>","DOI":"10.1111\/jcmm.15243","type":"journal-article","created":{"date-parts":[[2020,4,29]],"date-time":"2020-04-29T20:51:44Z","timestamp":1588193504000},"page":"6162-6177","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Smad2\/3\u2010pathway ligand trap luspatercept enhances erythroid differentiation in murine \u03b2\u2010thalassaemia by increasing GATA\u20101 availability"],"prefix":"10.1111","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1489-9689","authenticated-orcid":false,"given":"Pedro A.","family":"Martinez","sequence":"first","affiliation":[{"name":"Acceleron Pharma Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Li","sequence":"additional","affiliation":[{"name":"Acceleron Pharma Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harish N.","family":"Ramanathan","sequence":"additional","affiliation":[{"name":"Acceleron Pharma Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj","family":"Bhasin","sequence":"additional","affiliation":[{"name":"BIDMC Beth Israel Deaconess Medical Center, Harvard Medical School Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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