Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia

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

doi:10.1126/scitranslmed.abb5831

Calmodulin inhibitors improve erythropoiesis in Diamond-Blackfan anemia

Sci Transl Med. 2020 Oct 21;12(566):eabb5831. doi: 10.1126/scitranslmed.abb5831.

Authors

Alison M Taylor^{1

2

3}, Elizabeth R Macari^{1

2

3}, Iris T Chan^{1

2}, Megan C Blair^{1

2}, Sergei Doulatov^{1

2

3}, Linda T Vo^{1

2

3}, David M Raiser^{2

3

4}, Kavitha Siva⁵, Anindita Basak^{2

3

6}, Mehdi Pirouz^{1

2

3}, Arish N Shah⁷, Katherine McGrath^{1

2}, Jessica M Humphries^{1

2}, Emma Stillman^{1

2}, Blanche P Alter⁸, Eliezer Calo⁷, Richard I Gregory^{1

2

3}, Vijay G Sankaran^{2

3

6}, Johan Flygare⁵, Benjamin L Ebert^{2

3

6}, Yi Zhou^{1

2}, George Q Daley^{1

2

3}, Leonard I Zon^{9

2

3

10

11}

Affiliations

¹ Stem Cell Program, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA.
² Division of Hematology/Oncology, Boston Children's Hospital and Dana Farber Cancer Institute, Boston, MA 02115, USA.
³ Harvard Medical School, Boston, MA 02115, USA.
⁴ Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁵ Stem Cell Center, Lund University, Lund 22184, Sweden.
⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02139, USA.
⁷ MIT Department of Biology and David H. Koch Institute for Integrative Cancer Research, Cambridge, MA 02139, USA.
⁸ Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Rockville, MD 20850, USA.
⁹ Stem Cell Program, Boston Children's Hospital and Harvard Stem Cell Institute, Boston, MA 02115, USA. [email protected].
¹⁰ Howard Hughes Medical Institute, Boston, MA 02115, USA.
¹¹ Stem Cell and Regenerative Biology Department, Harvard University, Boston, MA 02115, USA.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Anemia, Diamond-Blackfan* / drug therapy
Animals
Apoptosis
Calmodulin
Erythropoiesis
Humans
Tumor Suppressor Protein p53
Zebrafish

Substances

Calmodulin
Tumor Suppressor Protein p53

Abstract

Publication types

MeSH terms

Substances

Grants and funding