Oncotarget

Research Papers:

Dysregulated miR34a/diacylglycerol kinase ζ interaction enhances T-cell activation in acquired aplastic anemia

Yuan-xin Sun, Hui Li, Qi Feng, Xin Li, Ying-yi Yu, Li-wei Zhou, Yan Gao, Guosheng Li, Juan Ren, Chun-hong Ma, Cheng-jiang Gao and Jun Peng _

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Oncotarget. 2017; 8:6142-6154. https://doi.org/10.18632/oncotarget.14046

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Abstract

Yuan-xin Sun1, Hui Li2, Qi Feng1, Xin Li1, Ying-yi Yu1, Li-wei Zhou1, Yan Gao1, Guo-sheng Li3, Juan Ren4, Chun-hong Ma5, Cheng-jiang Gao5, Jun Peng1,6

1Department of Hematology, Qilu Hospital, Shandong University, Jinan, China

2Department of Rheumatology, People’s Hospital of Bao’an, Shenzhen, China

3Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China

4Department of Hematology, First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China

5Department of Immunology, Shandong University School of Medicine, Jinan, China

6Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, China

Correspondence to:

Jun Peng, email: junpeng88@sina.com.cn

Keywords: aplastic anemia, miR34a, diacylglycerol kinase ζ, T cells

Received: November 18, 2016     Accepted: December 13, 2016     Published: December 20, 2016

ABSTRACT

Acquired aplastic anemia is an idiopathic paradigm of human bone marrow failure syndrome, which involves active destruction of hematopoietic stem cells and progenitors by cytotoxic T cells in the bone marrow. Aberrant expression of microRNAs in T cells has been shown to lead to development of certain autoimmune diseases. In the present study, we performed a microarray analysis of miRNA expression in bone marrow CD3+ T cells from patients with aplastic anemia and healthy controls. Overexpression of miR34a and underexpression of its target gene diacylglycerol kinase (DGK) ζ in bone marrow mononuclear cells were validated in 41 patients and associated with the severity of aplastic anemia. Further, the level of miR34a was higher in naïve T cells from patients than from controls. The role of miR34a and DGKζ in aplastic anemia was investigated in a murine model of immune-mediated bone marrow failure using miR34a-/- mice. After T-cell receptor stimulation in vitro, lymph node T cells from miR34a-/- mice demonstrated reduced activation and proliferation accompanied with a less profound down-regulation of DGKζ expression and decreased ERK phosphorylation compared to those from wild-type C57BL6 control mice. Infusion of 5 × 106 miR34a-/- lymph node T cells into sublethally irradiated CB6F1 recipients led to increased Lin-Sca1+CD117+ cells and less vigorous expansion of CD8+ T cells than injection of same number of wild-type lymph node cells. Our study demonstrates that the miR34a/DGKζ dysregulation enhances T-cell activation in aplastic anemia and targeting miR34a may represent a novel molecular therapeutic approach for patients with aplastic anemia.


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