Dysregulated miR34a/diacylglycerol kinase ζ interaction enhances T-cell activation in acquired aplastic anemia
Yuan-Xin Sun1, Hui Li2, Qi Feng1
1Department of Hematology, Qilu Hospital, Shandong University, Jinan, China.
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.
Insights
MicroRNA-34a (miR34a) overexpression and decreased diacylglycerol kinase zeta (DGKζ) in T cells drive aplastic anemia. Targeting miR34a offers a potential therapeutic strategy for this bone marrow failure syndrome.
Area of Science:
- Immunology
- Hematology
- Molecular Biology
Background:
- Acquired aplastic anemia is a bone marrow failure syndrome caused by cytotoxic T cell destruction of hematopoietic stem cells.
- Aberrant microRNA (miRNA) expression in T cells is implicated in autoimmune diseases.
- The specific role of miRNAs in aplastic anemia pathogenesis requires further elucidation.
Purpose of the Study:
- To investigate the role of miRNA expression in T cells from aplastic anemia patients.
- To identify specific miRNAs and their targets involved in the disease.
- To explore the therapeutic potential of targeting identified molecular pathways.
Main Methods:
- Microarray analysis of miRNA expression in bone marrow CD3+ T cells from aplastic anemia patients and healthy controls.
- Validation of miR34a and diacylglycerol kinase (DGK) ζ expression in patient samples.
- Investigation of miR34a function in a murine model of immune-mediated bone marrow failure using miR34a knockout mice.
Main Results:
- Overexpression of miR34a and underexpression of its target DGKζ were observed in aplastic anemia patients and correlated with disease severity.
- miR34a levels were higher in naive T cells from patients compared to controls.
- In a murine model, miR34a deficiency reduced T cell activation, proliferation, DGKζ downregulation, and ERK phosphorylation, leading to improved bone marrow cellularity upon T cell transfer.
Conclusions:
- Dysregulation of the miR34a/DGKζ axis enhances T cell activation in aplastic anemia.
- Targeting miR34a presents a potential novel molecular therapeutic strategy for aplastic anemia.
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