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ResearchIn-Press PreviewDevelopmentHematology Open Access | 10.1172/JCI154839

Relieving Dyrk1a repression of MKL1 confers an adult-like phenotype to human infantile megakaryocytes

Kamaleldin E. Elagib,1 Ashton Brock,1 Cara M. Clementelli,2 Gohar Mosoyan,2 Lorrie L. Delehanty,1 Ranjit K. Sahu,1 Alexandra Pacheco-Benichou,3 Corinne Fruit,3 Thierry Besson,3 Stephan W. Morris,4 Koji Eto,5 Chintan Jobaliya,6 Deborah L. French,6 Paul Gadue,6 Sandeep Singh,1 Xinrui Shi,1 Fujun Qin,7 Robert Cornelison,1 Hui Li,1 Camelia Iancu-Rubin,2 and Adam N. Goldfarb1

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Elagib, K. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Brock, A. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Clementelli, C. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Mosoyan, G. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Delehanty, L. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Sahu, R. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Pacheco-Benichou, A. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Fruit, C. in: JCI | PubMed | Google Scholar |

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Besson, T. in: JCI | PubMed | Google Scholar |

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Morris, S. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Eto, K. in: JCI | PubMed | Google Scholar |

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Jobaliya, C. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by French, D. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Gadue, P. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Singh, S. in: JCI | PubMed | Google Scholar |

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Shi, X. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Qin, F. in: JCI | PubMed | Google Scholar |

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Cornelison, R. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Li, H. in: JCI | PubMed | Google Scholar |

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Iancu-Rubin, C. in: JCI | PubMed | Google Scholar

1Department of Pathology, University of Virginia School of Medicine, Charlottesville, United States of America

2Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States of America

3UNIROUEN, Normandie University, Rouen, France

4Medical Oncology, Memphis Bioworks Foundation, Memphis, United States of America

5Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan

6Center of Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, United States of America

7Academy of Medical Sciences, Zhengzhou University, Henan, China

Find articles by Goldfarb, A. in: JCI | PubMed | Google Scholar

Published August 4, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI154839.
Copyright © 2022, Elagib et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 4, 2022 - Version history
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Abstract

Infantile (fetal and neonatal) megakaryocytes have a distinct phenotype consisting of hyperproliferation, limited morphogenesis, and low platelet production capacity. These properties contribute to clinical problems that include thrombocytopenia in neonates, delayed platelet engraftment in recipients of cord blood stem cell transplants, and inefficient ex vivo platelet production from pluripotent stem cell-derived megakaryocytes. The infantile phenotype results from deficiency of the actin-regulated coactivator, MKL1, which programs cytoskeletal changes driving morphogenesis. As a strategy to complement this molecular defect, we screened pathways with potential to affect MKL1 function and found that Dyrk1a kinase inhibition dramatically enhanced megakaryocyte morphogenesis in vitro and in vivo. Dyrk1 inhibitors rescued enlargement, polyploidization, and thrombopoiesis in human neonatal megakaryocytes. Megakaryocytes derived from induced pluripotent stem cells responded in a similar manner. Progenitors undergoing Dyrk1 inhibition demonstrated filamentous actin assembly, MKL1 nuclear translocation, and modulation of MKL1 target genes. Loss of function studies confirmed MKL1 involvement in this morphogenetic pathway. Ablim2, a stabilizer of filamentous actin, increased with Dyrk1 inhibition, and Ablim2 knockdown abrogated the actin, MKL1, and morphogenetic responses to Dyrk1 inhibition. These results thus delineate a pharmacologically tractable morphogenetic pathway whose manipulation may alleviate clinical problems associated with the limited thrombopoietic capacity of infantile megakaryocytes.

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