%0 Journal Article %T Luspatercept (RAP-536) modulates oxidative stress without affecting mutation burden in myelodysplastic syndromes %+ CHU Grenoble %+ Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB) %+ Institut Cochin (IC UM3 (UMR 8104 / U1016)) %+ Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)) %+ Hôpital Cochin [AP-HP] %+ Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity) %A Mathieu, Meunier %A Friedrich, Chloé %A Ducrot, Nicolas %A Zannoni, Johanna %A Sylvie, Tondeur %A Jerraya, Nelly %A Rousseaux, Sophie %A Chuffart, Florent %A Kosmider, Olivier %A Karim, Zoubida %A Park, Sophie %< avec comité de lecture %@ 0939-5555 %J Annals of Hematology %I Springer Verlag %V 101 %N 12 %P 2633-2643 %8 2022-12 %D 2022 %R 10.1007/s00277-022-04993-7 %M 36195681 %K Luspatercept %K Myelodysplastic syndromes %K PDX mice model %K RAP-536 %Z Life Sciences [q-bio]/Genetics/Human genetics %Z Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] %Z Life Sciences [q-bio]/Human health and pathology/Hematology %Z Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism %Z Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology %Z Life Sciences [q-bio]/Human health and pathology/Infectious diseases %Z Life Sciences [q-bio]/Human health and pathology/Urology and NephrologyJournal articles %X In low-risk myelodysplastic syndrome (LR-MDS), erythropoietin (EPO) is widely used for the treatment of chronic anemia. However, initial response to EPO has time-limited effects. Luspatercept reduces red blood cell transfusion dependence in LR-MDS patients. Here, we investigated the molecular action of luspatercept (RAP-536) in an in vitro model of erythroid differentiation of MDS, and also in a in vivo PDX murine model with primary samples of MDS patients carrying or not SF3B1 mutation. In our in vitro model, RAP-536 promotes erythroid proliferation by increasing the number of cycling cells without any impact on apoptosis rates. RAP-536 promoted late erythroid precursor maturation while decreasing intracellular reactive oxygen species level. RNA sequencing of erythroid progenitors obtained under RAP-536 treatment showed an enrichment of genes implicated in positive regulation of response to oxidative stress and erythroid differentiation. In our PDX model, RAP-536 induces a higher hemoglobin level. RAP-536 did not modify variant allele frequencies in vitro and did not have any effect against leukemic burden in our PDX model. These results suggest that RAP-536 promotes in vivo and in vitro erythroid cell differentiation by decreasing ROS level without any remarkable impact on iron homeostasis and on mutated allele burden. %G English %L inserm-03874959 %U https://inserm.hal.science/inserm-03874959 %~ INSERM %~ UNIV-TLSE3 %~ UGA %~ CNRS %~ APHP %~ UNIV-PARIS %~ UNIVERSITE-PARIS %~ UP-SANTE %~ UGA-EPE %~ INFINITY %~ UNIV-UT3 %~ UT3-INP %~ UT3-TOULOUSEINP