Mmp9 Inhibition Rescues The Erythroid Defect In Rps14-Deficient Del(5q) Mds Models

The del(5q) myelodysplastic syndrome (MDS) is a unique subtype of MDS characterized by an interstitial deletion of the long arm of chromosome 5 with macrocytic anemia, normal to increased platelet count, and hypoloblated megakaryocytes. Although haploinsufficiency of several genes encoded within the commonly deleted region have been implicated in the hematologic phenotype of del (5q) MDS, the deletion of the RPS14 gene, which encodes a component of the 40S ribosomal subunit, is a key determinant of the severe macrocytic anemia seen in patients. Lenalidomide is FDA-approved and highly effective for the treatment for del(5q) MDS. However, there are rare resistant cases resulting from p53 mutations in del(5q) MDS patients and 50% of patients acquire resistance within 2 to 3 years. Given these limitations of lenalidomide treatment, as well as frequent side effects, we sought to identify novel targets for the treatment of del(5q) MDS patients by performing an in vivo drug screening assay using a zebrafish model of MDS.