PUBLICATION

Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia

Authors
Taylor, A.M., Macari, E.R., Chan, I.T., Blair, M.C., Doulatov, S., Vo, L.T., Raiser, D.M., Siva, K., Basak, A., Pirouz, M., Shah, A.N., McGrath, K., Humphries, J.M., Stillman, E., Alter, B.P., Calo, E., Gregory, R.I., Sankaran, V.G., Flygare, J., Ebert, B.L., Zhou, Y., Daley, G.Q., Zon, L.I.
ID
ZDB-PUB-201023-2
Date
2020
Source
Science Translational Medicine   12(566): (Journal)
Registered Authors
Taylor, Alison, Zhou, Yi, Zon, Leonard I.
Keywords
none
MeSH Terms
  • Anemia, Diamond-Blackfan*/drug therapy
  • Animals
  • Apoptosis
  • Calmodulin
  • Erythropoiesis
  • Humans
  • Tumor Suppressor Protein p53
  • Zebrafish
PubMed
33087503 Full text @ Sci. Transl. Med.
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.
Genes / Markers
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping