The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia

Chun-Hao Su; Wei-Ju Liao; Wei-Chi Ke; Ruey-Bing Yang; Woan-Yuh Tarn

doi:10.1016/j.isci.2021.103368

The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia

iScience. 2021 Oct 29;24(11):103368. doi: 10.1016/j.isci.2021.103368. eCollection 2021 Nov 19.

Authors

Chun-Hao Su¹, Wei-Ju Liao¹, Wei-Chi Ke¹, Ruey-Bing Yang¹, Woan-Yuh Tarn¹

Affiliation

¹ Institute of Biomedical Sciences, Academia Sinica, 128 Academia Road, Section 2, Nangang, Taipei 11529, Taiwan.

Abstract

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.

Keywords: Biological sciences; Cell biology; Functional aspects of cell biology.