{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T15:04:39Z","timestamp":1789571079358,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sumitomo Pharma America"},{"name":"NCI Cancer Center","award":["P30CA076292"],"award-info":[{"award-number":["P30CA076292"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Myelodysplastic syndrome (MDS) is characterized by S100A9-mediated constitutive innate immune activation that leads to the inflammatory death of hematopoietic stem\/progenitor cells (HSPCs). This suppressive microenvironment includes the secretion of TGF\u03b2 and is phenocopied by the S100A9-transgenic (Tg) mice. However, the role of the different ALK\/TGFB receptors in hematopoiesis or in S100A9-mediated inflammation is not understood. Primary low-risk MDS bone marrow mononuclear cells (BM-MNCs) were analyzed in vitro for hematopoietic restoration by an ALK4\/ALK5 inhibitor (Vactosertib), an ALK2 inhibitor (TP-0184\/Itacnosertib) and an ALK5\/TGFBR1-specific inhibitor (TP-6379). Specimens significantly responded to TP-6379 treatment restoring hematopoiesis, with a positive bias for specimens harboring spliceosomal mutations. We previously shown that S100A9 drives phenotypic pathology of MDS, and it has been known to induce and cooperate with TGF\u03b2 in this disease. Hence, we treated healthy BM-MNC with recombinant human (rh) S100A9 where TP-6379 rescued the S100A9-reduced hematopoiesis. The effect of TP-6379 was validated in vivo in S100A9-Tg mice. Similar results were obtained with K562 cells, with or without the knock-in (KI) mutation in SF3B1, with strong sensitivity to rhS100A9 that was overcome by TP-6379. Hence, directly targeting TGFBR1\/ALK5 with TP-6379 restores healthy hematopoiesis in low-risk MDS preclinical models.<\/jats:p>","DOI":"10.3390\/cells15181674","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T13:50:27Z","timestamp":1789566627000},"page":"1674","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting TGFBR1 with the Investigational Inhibitor TP-6379 Improves Hematopoiesis in Low-Risk MDS Ex Vivo"],"prefix":"10.3390","volume":"15","author":[{"given":"Tiffany","family":"Razabdouski","sequence":"first","affiliation":[{"name":"Department of Immunology, Moffitt Cancer Center, Tampa, FL 33621, 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