The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia

Thrombocytopenia-absent radius (TAR) syndrome is caused by RBM8A insufficiency. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKO(MK)) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, providing evidence that genetic deficiency of Rbm8a causes a disorder o...

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Autores principales: Su, Chun-Hao, Liao, Wei-Ju, Ke, Wei-Chi, Yang, Ruey-Bing, Tarn, Woan-Yuh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593568/
https://www.ncbi.nlm.nih.gov/pubmed/34816104
http://dx.doi.org/10.1016/j.isci.2021.103368
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author Su, Chun-Hao
Liao, Wei-Ju
Ke, Wei-Chi
Yang, Ruey-Bing
Tarn, Woan-Yuh
author_facet Su, Chun-Hao
Liao, Wei-Ju
Ke, Wei-Chi
Yang, Ruey-Bing
Tarn, Woan-Yuh
author_sort Su, Chun-Hao
collection PubMed
description Thrombocytopenia-absent radius (TAR) syndrome is caused by RBM8A insufficiency. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKO(MK)) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, providing evidence that genetic deficiency of Rbm8a causes a disorder of platelet production. Rbm8aKO(MK) mice accumulated low-ploidy immature megakaryocytes in the bone marrow and exhibited defective platelet activation and aggregation. Accordingly, depletion of Y14 (RBM8A) in human erythroleukemia (HEL) cells compromised phorbol-ester-induced polyploidization. Notably, Y14/RBM8A deficiency induced both p53 and p21 in megakaryocytes and HEL cells. Treatment with a p53 inhibitor restored ex vivo differentiation of Rbm8aKO(MK) megakaryocytes and unexpectedly activated Y14 expression in HEL cells. Trp53 knockout partially restored megakaryocyte differentiation by reversing cell-cycle arrest and increased platelet counts of Rbm8aKO(MK), indicating that excess p53 in part accounts for thrombocytopenia in TAR syndrome. This study provides evidence for the role of the Y14-p53 circuit in platelet production and a potential therapeutic strategy.
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spelling pubmed-85935682021-11-22 The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia Su, Chun-Hao Liao, Wei-Ju Ke, Wei-Chi Yang, Ruey-Bing Tarn, Woan-Yuh iScience Article Thrombocytopenia-absent radius (TAR) syndrome is caused by RBM8A insufficiency. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKO(MK)) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, providing evidence that genetic deficiency of Rbm8a causes a disorder of platelet production. Rbm8aKO(MK) mice accumulated low-ploidy immature megakaryocytes in the bone marrow and exhibited defective platelet activation and aggregation. Accordingly, depletion of Y14 (RBM8A) in human erythroleukemia (HEL) cells compromised phorbol-ester-induced polyploidization. Notably, Y14/RBM8A deficiency induced both p53 and p21 in megakaryocytes and HEL cells. Treatment with a p53 inhibitor restored ex vivo differentiation of Rbm8aKO(MK) megakaryocytes and unexpectedly activated Y14 expression in HEL cells. Trp53 knockout partially restored megakaryocyte differentiation by reversing cell-cycle arrest and increased platelet counts of Rbm8aKO(MK), indicating that excess p53 in part accounts for thrombocytopenia in TAR syndrome. This study provides evidence for the role of the Y14-p53 circuit in platelet production and a potential therapeutic strategy. Elsevier 2021-10-29 /pmc/articles/PMC8593568/ /pubmed/34816104 http://dx.doi.org/10.1016/j.isci.2021.103368 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Su, Chun-Hao
Liao, Wei-Ju
Ke, Wei-Chi
Yang, Ruey-Bing
Tarn, Woan-Yuh
The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
title The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
title_full The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
title_fullStr The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
title_full_unstemmed The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
title_short The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
title_sort y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8593568/
https://www.ncbi.nlm.nih.gov/pubmed/34816104
http://dx.doi.org/10.1016/j.isci.2021.103368
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