1. The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia.
- Author
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Su CH, Liao WJ, Ke WC, Yang RB, and Tarn WY
- Abstract
Thrombocytopenia-absent radius (TAR) syndrome is caused by RBM8A insufficiency. We generated megakaryocyte-specific Rbm8a knockout ( Rbm8a KO
MK ) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, providing evidence that genetic deficiency of Rbm8a causes a disorder of platelet production. Rbm8a KOMK 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 Rbm8a KOMK 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 Rbm8a KOMK , 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., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)- Published
- 2021
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