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Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia

Taylor, Alison M. ; Macari, Elizabeth R. ; Chan, Iris T. ; Blair, Megan C. ; Doulatov, Sergei ; Vo, Linda T. ; Raiser, David M. ; Siva, Kavitha LU ; Basak, Anindita and Pirouz, Mehdi , et al. (2020) In Science Translational Medicine 12(566).
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.... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Translational Medicine
volume
12
issue
566
article number
eabb5831
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:33087503
  • scopus:85094118417
ISSN
1946-6242
DOI
10.1126/scitranslmed.abb5831
language
English
LU publication?
yes
id
724fa8b1-a356-4b36-8a86-8ee640a45ce4
date added to LUP
2020-11-06 08:31:27
date last changed
2024-10-03 11:05:10
@article{724fa8b1-a356-4b36-8a86-8ee640a45ce4,
  abstract     = {{<p>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.</p>}},
  author       = {{Taylor, Alison M. and Macari, Elizabeth R. and Chan, Iris T. and Blair, Megan C. and Doulatov, Sergei and Vo, Linda T. and Raiser, David M. and Siva, Kavitha and Basak, Anindita and Pirouz, Mehdi and Shah, Arish N. and McGrath, Katherine and Humphries, Jessica M. and Stillman, Emma and Alter, Blanche P. and Calo, Eliezer and Gregory, Richard I. and Sankaran, Vijay G. and Flygare, Johan and Ebert, Benjamin L. and Zhou, Yi and Daley, George Q. and Zon, Leonard I.}},
  issn         = {{1946-6242}},
  language     = {{eng}},
  number       = {{566}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Translational Medicine}},
  title        = {{Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia}},
  url          = {{http://dx.doi.org/10.1126/scitranslmed.abb5831}},
  doi          = {{10.1126/scitranslmed.abb5831}},
  volume       = {{12}},
  year         = {{2020}},
}