Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM-Chk1/Chk2-p53/p21(CIP1) checkpoint and cellular senescence at early stages of cellular transformation caused by a regulatable MLL-ENL-ERtm in mice. Furthermore, we identified the transcription program underlying this intrinsic anticancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling toward senescence, thereby modulating the fate of MLL-ENL-immortalized cells in a tissue-environment-dependent manner. Our results indicate that DDR is a rate-limiting event for acquisition of stem cell-like properties in MLL-ENL-ERtm-mediated transformation, as experimental inhibition of the barrier accelerated the transition to immature cell states and acute leukemia development.

Esophageal adenocarcinoma (EAC) is highly aggressive malignancy that frequently develops from Barrett's esophagus (BE), a premalignant pathologic change occurring in the lower end of the esophagus. MicroRNAs (miRNAs) are small, non-coding RNAs that function as posttranscriptional regulators of gene expression and were repeatedly proved to play key roles in pathogenesis of BE as well as EAC. In our study, we used Affymetrix GeneChip miRNA arrays to obtain miRNA expression profiles in total of 119 tissue samples [24 normal esophageal mucosa (EM), 60 BE and 35 EAC]. We identified a number of miRNAs, that showed altered expression progressively in sequence EM, BE and EAC, including for instance miR-21, miR-25, miR-194 and miR-196a with increasing levels (P < 0.0015) and miR-203, miR-205, miR-210 and miR-378 with decreasing levels (P < 0.0001). The subsequent analysis revealed four diagnostic miRNA signatures enabling to distinguish EM and BE [12 miRNAs, area under curve (AUC) = 0.971], EM and EAC (13 miRNAs, AUC = 1.0), BE without and BE with dysplasia (21 miRNAs, AUC = 0.856) and BE without dysplastic changes and BE with dysplasia together with EAC (2 miRNAs, AUC = 0.886). We suggest that miRNA expression profiling expands current knowledge in molecular pathology of Barrett's-based carcinogenesis and enables identification of molecular biomarkers for early detection of BE dysplasia and progression to EAC.

BackgroundBarrett's esophagus (BE) is a disease with a rising prevalence in western countries probably due to the unhealthy lifestyle. In significant number of cases it develops to esophageal adenocarcinoma. Two decades ago, important gene regulators (microRNAs) were discovered and their attendance in the process of malignant transformation was demonstrated (e.g. miR-192, 196a, 203). Our aim was to select the patients with the increased risk of malignant transformation before the cancer develops.Methods71 patients with BE disease were selected, slides from FFPE blocks were prepared, the lesions were microdissected and a qPCR relative expression analysis for selected microRNAs (generally known to be connected with malignant transformation process) was carried out.ResultsWe demonstrated unequivocal statistically significant upregulation of two microRNAs (miR-192, 196a) and downregulation of miR-203 and positive miR-196a correlation with progression from intestinal metaplasia to adenocarcinoma compared to normal individuals.ConclusionsWe hypothetize that there do exist changes of selected microRNAs which can undoubtedly distinguish the patients with BE from normal healthy individuals.

Comparing to OA, aseptic loosening of TKA is associated with upregulated expression of CHIT1, IL-8 and MMP9, dysregulated RANKL:OPG ratio and low levels of inflammatory cytokines. Similar cytokine profiles were associated with primary knee and hip OA. Further research is required to explain the differences in CCL3 and DC-STAMP expression between failed TKA and THA.