MMP9 inhibition increases erythropoiesis in RPS14-deficient del(5q) MDS models through suppression of TGF-β pathways.

ABSTRACT: The del(5q) myelodysplastic syndrome (MDS) is a distinct subtype of MDS, associated with deletion of the ribosomal protein S14 (RPS14) gene that results in macrocytic anemia. This study sought to identify novel targets for the treatment of patients with del(5q) MDS by performing an in vivo drug screen using an rps14-deficient zebrafish model. From this, we identified the secreted gelatinase matrix metalloproteinase 9 (MMP9). MMP9 inhibitors significantly improved the erythroid defect in rps14-deficient zebrafish. Similarly, treatment with MMP9 inhibitors increased the number of colony forming unit-erythroid colonies and the CD71⁺ erythroid population from RPS14 knockdown human BMCD34⁺ cells. Importantly, we found that MMP9 expression is upregulated in RPS14-def

SUBMITTER: Youn M 

PROVIDER: S-EPMC6759738 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature