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We investigated the erythroid response to either erythropoietin or RAP\u2010011, a \u201cmurinized\u201d ortholog of sotatercept, in C57BL\/6 mice and in <jats:italic>hepcidin antimicrobial peptide 1<\/jats:italic> over expressing mice. Sotatercept, a soluble, activin receptor type IIA ligand trap, is currently being evaluated for the treatment of anemias associated with chronic renal disease, myelodysplastic syndrome, \u03b2\u2010thalassemia, and Diamond Blackfan anemia and acts by inhibiting signaling downstream of activin and other Transforming Growth Factor\u2010\u03b2 superfamily members. We found that erythropoietin and RAP\u2010011 increased hemoglobin concentration in C57BL\/6 mice and in <jats:italic>hepcidin antimicrobial peptide 1<\/jats:italic> over expressing mice. While erythropoietin treatment depleted splenic iron stores in C57BL\/6 mice, RAP\u2010011 treatment did not deplete splenic iron stores in mice of either genotype. Bone marrow erythroid progenitors from erythropoietin\u2010treated mice exhibited iron\u2010restricted erythropoiesis, as indicated by increased median fluorescence intensity of transferrin receptor immunostaining by flow cytometry. In contrast, RAP\u2010011\u2010treated mice did not exhibit the same degree of iron\u2010restricted erythropoiesis. In conclusion, we have demonstrated that RAP\u2010011 can improve hemoglobin concentration in <jats:italic>hepcidin antimicrobial peptide 1<\/jats:italic> transgenic mice. Our data support the hypothesis that RAP\u2010011 has unique biologic effects which prevent or circumvent depletion of mouse splenic iron stores. RAP\u2010011 may, therefore, be an appropriate therapeutic for trials in human anemias characterized by increased expression of hepcidin antimicrobial peptide and iron\u2010restricted erythropoiesis. Am. J. Hematol. 90:8\u201314, 2015. \u00a9 2014 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/ajh.23856","type":"journal-article","created":{"date-parts":[[2014,9,19]],"date-time":"2014-09-19T08:28:53Z","timestamp":1411115333000},"page":"8-14","source":"Crossref","is-referenced-by-count":28,"title":["RAP\u2010011, an activin receptor ligand trap, increases hemoglobin concentration in hepcidin transgenic mice"],"prefix":"10.1002","volume":"90","author":[{"given":"Jacqueline M.","family":"Langdon","sequence":"first","affiliation":[{"name":"Division of Geriatric Medicine and Gerontology Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sangjucta","family":"Barkataki","sequence":"additional","affiliation":[{"name":"Lowe Family Genomics Core Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan E.","family":"Berger","sequence":"additional","affiliation":[{"name":"Lowe Family Genomics Core Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris","family":"Cheadle","sequence":"additional","affiliation":[{"name":"Lowe Family Genomics Core Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian\u2010Li","family":"Xue","sequence":"additional","affiliation":[{"name":"Division of Geriatric Medicine and Gerontology Johns Hopkins University School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria","family":"Sung","sequence":"additional","affiliation":[{"name":"Translational Development Celgene Corporation San Francisco CA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cindy N.","family":"Roy","sequence":"additional","affiliation":[{"name":"Division of Geriatric Medicine and Gerontology Johns Hopkins University School of Medicine Baltimore Maryland"},{"name":"Division of Hematology Johns Hopkins School of Medicine Baltimore Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,10,25]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-07-356006"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.24.012003.132306"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.06.028"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2010.1.276"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2006091034"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-258467"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1104742"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/35001596"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80425-6"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-10-051755"},{"key":"e_1_2_6_12_1","doi-asserted-by":"crossref","unstructured":"NicolasG BennounM PorteuA et al.Severe iron deficiency anemia in transgenic mice expressing liver hepcidin.Proc Natl Acad Sci U S A2002;99:4596\u20134601.","DOI":"10.1073\/pnas.072632499"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-04-1260"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1157121"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.130"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra041809"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-02-139915"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1159\/000253590"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200420945"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-09-245977"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-10-313064"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-03-345066"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-09-456756"},{"key":"e_1_2_6_24_1","unstructured":"Efficacy of NOX\u2010H94 on Anemia of Chronic Disease in Patients With Cancer.Clinical Trials.govidentifier NCT01691040. 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