Probes for LONG

Peripheral enhanced complement activation has long been considered as one of the major pathogenesis of immune thrombocytopenia. Impaired bone marrow microenvironment, especially the dysfunction of mesenchymal stem cells, has been observed in patients with immune thrombocytopenia. However, the potential role of the complement system involved in impaired bone marrow microenvironment remains poorly understood. Here, bone marrow samples of patients were divided into the MSC-ITP-C+ and MSC-ITP-C- groups based on the deposition of the complement components on the surfaces of mesenchymal stem cells. Reduced and dysfunctional mesenchymal stem cells, characterized by reduced proliferation capacity, increased apoptosis as well as abnormal secretion of interleukin-1β and C-X-C motif chemokine ligand 12, were observed in the MSC-ITP-C+ group. In vitro treatment with all-trans retinoic acid quantitatively and functionally improved MSC-ITP-C+ by upregulating DNA hypermethylation of the interleukin-1β promoter. In vivo studies showed that all-trans retinoic acid could rescue the impaired mesenchymal stem cells to support the thrombopoietic niche in both patients and the murine model with immune thrombocytopenia. Taken together, these results indicate that deficient mesenchymal stem cells mediated by the complement-IL-1β loop play a role in the pathogenesis of immune thrombocytopenia. All-trans retinoic acid represents a promising therapeutic approach in patients with immune thrombocytopenia by repairing impaired mesenchymal stem cells.

Abstract

BACKGROUND:

TP53 is frequently mutated across various tissue types of cancers. In normal cells, long interspersed nuclear element-1 (LINE-1, L1) is mostly repressed by DNA methylation in its 5' untranslated region but is activated by DNA demethylation process during tumorigenesis. p53 is indispensable for maintaining genomic stability and plays its role in controlling genomic stability by repressing retrotransposon activity. However, it is unclear whether p53 regulates expression or methylation of L1 differently depending on the mutational status of TP53. Four hundred ninety cases of advanced gastric cancer (AGC) were analyzed for their statuses in p53 expression and L1 methylation using immunohistochemistry and pyrosequencing, respectively. Whether L1 methylation and expression statuses were differently affected by types of TP53 mutants was analyzed in gastric cancer cell line.

RESULTS:

By p53 immunohistochemistry, tumors were classified into 4 groups according to the intensity and extent of stained tumor nuclei. L1 methylation level was significantly higher in p53 expression group 1 than in the other groups in which L1 methylation level was similar (P <  0.001). Although L1 methylation and p53 expression statuses were associated with patient survival, multivariate analysis revealed that L1 methylation was an independent prognostic parameter. In in vitro analysis of AGS cells with the introduction of wild type or mutant types of TP53, L1 methylation level and activity were different depending on types of TP53 mutation.

CONCLUSIONS:

Findings suggest that L1 methylation level is affected by TP53 mutation status; although, L1 methylation status was an independent prognostic parameter in patients with AGC. Further study is required to elucidate the mechanism of how wild type or mutant p53 affects L1 activity and methylation status of L1 CpG island.