Research ArticleBlood Disorders

Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia

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Science Translational Medicine  21 Oct 2020:
Vol. 12, Issue 566, eabb5831
DOI: 10.1126/scitranslmed.abb5831

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Fishing for treatment

Diamond-Blackfan anemia is an inherited blood disorder associated with a block in red blood cell development. It is most commonly caused by ribosomal protein abnormalities and associated with increased activity of p53, which is best known for its role as a tumor suppressor but in this case promotes red blood cell death. Taylor et al. first performed a chemical screen in zebrafish and identified calmodulin inhibitors as a potentially useful intervention. The authors then focused on the approved drug trifluoperazine, which suppressed the buildup of excess p53 and reversed hematopoietic abnormalities in zebrafish and mouse models, as well as cells from human patients.

Abstract

Diamond-Blackfan anemia (DBA) is a rare hematopoietic disease characterized by a block in red cell differentiation. Most DBA cases are caused by mutations in ribosomal proteins and characterized by higher than normal activity of the tumor suppressor p53. Higher p53 activity is thought to contribute to DBA phenotypes by inducing apoptosis during red blood cell differentiation. Currently, there are few therapies available for patients with DBA. We performed a chemical screen using zebrafish ribosomal small subunit protein 29 (rps29) mutant embryos that have a p53-dependent anemia and identified calmodulin inhibitors that rescued the phenotype. Our studies demonstrated that calmodulin inhibitors attenuated p53 protein amount and activity. Treatment with calmodulin inhibitors led to decreased p53 translation and accumulation but does not affect p53 stability. A U.S. Food and Drug Administration–approved calmodulin inhibitor, trifluoperazine, rescued hematopoietic phenotypes of DBA models in vivo in zebrafish and mouse models. In addition, trifluoperazine rescued these phenotypes in human CD34+ hematopoietic stem and progenitor cells. Erythroid differentiation was also improved in CD34+ cells isolated from a patient with DBA. This work uncovers a potential avenue of therapeutic development for patients with DBA.

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