title: Dysregulated miR34a/diacylglycerol kinase ζ interaction enhances T-cell activation in acquired aplastic anemia.
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.
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Yuan-Xin
authors.initials: YX
authors.lastname: Sun
authors.affiliation: Department of Rheumatology, People's Hospital of Bao'an, Shenzhen, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Feng
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Yu
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Zhou
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan, China.
authors.forename: Guo-Sheng
authors.initials: GS
authors.lastname: Li
authors.affiliation: Department of Hematology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, China.
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Ma
authors.affiliation: Department of Immunology, Shandong University School of Medicine, Jinan, China.
authors.forename: Cheng-Jiang
authors.initials: CJ
authors.lastname: Gao
authors.affiliation: Department of Hematology, Qilu Hospital, Shandong University, Jinan, China.|Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Jinan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Peng
mesh_terms: D000741:Anemia, Aplastic / Q000235:genetics* / Q000276:immunology; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D017252:CD3 Complex; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C526463:DGKZ protein, human; D019852:Diacylglycerol Kinase
keywords: T cells; aplastic anemia; diacylglycerol kinase ζ; miR34a