Calmodulin Inhibitors Improve Erythropoiesis in Diamond-Blackfan Anemia

Overview

Journal Sci Transl Med

Specialties General Medicine
Science

Date 2020 Oct 22

PMID 33087503

Citations 17

Authors

Alison M Taylor

Elizabeth R Macari

Iris T Chan

Megan C Blair

Sergei Doulatov

Linda T Vo

David M Raiser

Kavitha Siva

Anindita Basak

Mehdi Pirouz

Arish N Shah

Katherine McGrath

Jessica M Humphries

Emma Stillman

Blanche P Alter

Eliezer Calo

Richard I Gregory

Vijay G Sankaran

Johan Flygare

Benjamin L Ebert

Yi Zhou

George Q Daley

Leonard I Zon

Affiliations

Soon will be listed here.

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 () 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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