Luspatercept (RAP-536) modulates oxidative stress without affecting mutation burden in myelodysplastic syndromes - Archive ouverte HAL Access content directly
Journal Articles Annals of Hematology Year : 2022

Luspatercept (RAP-536) modulates oxidative stress without affecting mutation burden in myelodysplastic syndromes

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Abstract

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.
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Dates and versions

inserm-03874959 , version 1 (28-11-2022)

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Cite

Meunier Mathieu, Chloé Friedrich, Nicolas Ducrot, Johanna Zannoni, Tondeur Sylvie, et al.. Luspatercept (RAP-536) modulates oxidative stress without affecting mutation burden in myelodysplastic syndromes. Annals of Hematology, 2022, 101 (12), pp.2633-2643. ⟨10.1007/s00277-022-04993-7⟩. ⟨inserm-03874959⟩
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