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Luspatercept (RAP-536) modulates oxidative stress without affecting mutation burden in myelodysplastic syndromes.
- Source :
-
Annals of hematology [Ann Hematol] 2022 Dec; Vol. 101 (12), pp. 2633-2643. Date of Electronic Publication: 2022 Oct 05. - Publication Year :
- 2022
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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.<br /> (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Details
- Language :
- English
- ISSN :
- 1432-0584
- Volume :
- 101
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Annals of hematology
- Publication Type :
- Academic Journal
- Accession number :
- 36195681
- Full Text :
- https://doi.org/10.1007/s00277-022-04993-7