Taylor AM, Macari ER, Chan IT, Blair MC, Doulatov S, Vo LT, Raiser DM, Siva K, Basak A, Pirouz M, Shah AN, McGrath K, Humphries JM, Stillman E, Alter BP, Calo E, Gregory RI, Sankaran VG, Flygare J, Ebert BL, Zhou Y, Daley GQ, Zon LI. 2020. Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia. Science translational medicine. 12(566). Pubmed: 33087503 DOI:10.1126/scitranslmed.abb5831


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 () 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.
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Related Faculty

Photo of Len Zon

The Zon laboratory aims to dissect how assaults to the hematopoietic system cause severe diseases such as leukemias, lymphomas, and anemias. They investigate hematopoietic development and disease using chemical screens, genetic screens, and analysis of novel transgenic lines in zebrafish.

Search Menu