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.

Aplastic anemia is related to alterations in T cell receptor signaling

“…DGKζ terminates DAG-mediated downstream signals and negatively regulates T cell activation. This finding was confirmed by repressed DGKζ expression, which enhances T cell activation by elevating the miRNA34a level in AA patients (32).…”

Hematopoiesis by iPSC-derived hematopoietic stem cells of aplastic anemia that escape cytotoxic T-cell attack

“…1 cytotoxic T cells, 5 constitutes important biological evidence that supports an autoimmune etiology in this disease. In this model, CTLs that recognize autoantigens presented on HSCs through their class I HLA molecules are considered to play a central role in the autoimmune reactions that ultimately lead to the destruction of HSCs.…”

MicroRNA 34a promotes ionizing radiation–induced DNA damage repair in murine hematopoietic stem cells

“…C57BL/6J mice (CD45.2) were purchased from the Institute of Zoology (Chinese Academy of Sciences, Beijing, China). miR-34a 2/2 mice (CD45.2) were a gift from Professor Jun Peng (Department of Hematology, Qilu Hospital, Shandong University, Jinan, China) (21). miR-34a +/+ mice (wild-type littermates) were used as controls.…”

“…Notably, studies have elucidated the different roles of miR-34a in B-cell maturation (19), megakaryocyte differentiation (20), and T-cell activation (21). These findings suggest that miR-34a can function as an important regulator of hematopoiesis by targeting several critical genes.…”