Long non-coding RNAs (lncRNAs) are transcripts characterized by >200 nucleotides, without validated protein production. Previous studies have demonstrated that certain lncRNAs have a critical role in the initiation and development of acute myeloid leukemia (AML). In the present study, the subtype-specific lncRNAs in AML was identified. Following the exclusion of the subtype-specific lncRNAs, the prognostic value of lncRNAs was investigated and a three-lncRNA expression-based risk score [long intergenic non-protein coding RNA 926, family with sequence similarity 30 member A and LRRC75A antisense RNA 1 (LRRC75A-AS1)] was developed for AML patient prognosis prediction by analyzing the RNA-seq data of AML patients from Therapeutically Available Research to Generate Effective Treatments (TARGET) and The Cancer Genome Atlas (TCGA) projects. In the training set obtained from TARGET, patients were divided into poor and favorable prognosis groups by the median risk score. The prognostic effectiveness of this lncRNA risk score was confirmed in the validation set obtained from TCGA by the same cut-off. Furthermore, the lncRNA risk score was identified as an independent prognostic factor in the multivariate analysis. As further verification of the independent prognostic power of the lncRNA risk score, stratified analysis was performed by a cytogenetics risk group and revealed a consistent result. The prognostic predictive ability of the risk score was compared with the cytogenetics risk group by time-dependent receiver operating characteristic curves analysis. It was revealed that the combination of the lncRNA risk score and cytogenetics risk group provided a higher prognostic value than a single prognostic factor. The present study also performed co-expression analysis to predict the potential regulatory mechanisms of these lncRNAs in a cis/trans/competing endogenous RNA manner. The results suggested that LRRC75A-AS1 was highly associated with the target genes of transcription factors tumor protein 53 and ETS variant 6. Overall, these results highlighted the use of the three-lncRNA expression-based risk score as a potential molecular biomarker to predict the prognosis in AML patients.

Background/Aims: Adult T-cell leukemia-lymphoma (ATL) is an aggressive disease which is highly resistant to chemotherapy. Studies show that enhanced ability of DNA damage repair (DDR) in cancer cells plays a key role in chemotherapy resistance. Here, we suggest that defect in DDR related genes might be a promising target to destroy the genome stability of tumor cells. Methods: Since KU70 is highly expressed in Jurkat cells, one of the most representative cell lines of ATL, we knocked down KU70 by shRNA and analyzed the impact of KU70 deficiency in Jurkat cells as well as in NOD-SCID animal models by western blot, immunofluorescence, flow cytometry and measuring DNA repair efficiency. Results: It is observed that silencing of KU70 resulted in accumulated DNA damage and impaired DDR in Jurkat cells, resulting in more apoptosis, decreased cell proliferation and cell cycle arrest. DNA damage leads to DNA double-strand breaks (DSBs), which are processed by either non-homologous end joining(NHEJ) or homologous recombination(HR). In our study, both NHEJ and HR are impaired because of KU70 defect, accompanied with increased protein level of SHP-1, a dephosphorylation enzyme. In turn, SHP-1 led to dephosphorylation of SIRT1, which further impaired HR repair efficiency. Moreover, KU70 deficiency prolonged survival of Jurkat-xenografted mice. Conclusion: These findings suggest that targeting KU70 is a promising target for ATL and might overcome the existing difficulties in chemotherapy.

Most chemotherapy drugs used for the treatment of adult T-cell leukemia-lymphoma (ATL) cause cell death directly by inducing DNA damage, which can be repaired via several DNA repair pathways. Enhanced activity of DNA damage repair systems contributes to ATL resistance to chemotherapies. Targeting DNA repair pathways is a promising strategy for the sensitization of ATL cells to chemotherapeutic drugs. in the present study, inhibition of SIRT1 deacetylase by shRNA sensitized Jurkat cells to etoposide by reducing the activity of non-homologous end joining (NHEJ) and homologous recombination (HR). Silencing of SIRT1 deacetylase by shRNA resulted in enhanced apoptosis and cell cycle arrest, while reduced colony formation of Jurkat cells after etoposide treatment was accompanied by elevated acetylation of FOXO1. Furthermore, inhibition of SIRT1 led to decreased activity of DNA damage repair by NHEJ and HR, accompanied by increased Ku70 acetylation. Furthermore, SIRT1 downregulation prolonged the survival time of Jurkat-xenografted mice. These results suggested that SIRT1 promotes DNA double‑strand repair pathways in Jurkat cells by deacetylating Ku70, and increases cell proliferation by deacetylating FOXO1. The results suggest that SIRT1 is a potential target for the development of combinatorial treatment for ATL.

RAD51, is a key homologous recombination protein that repairs DNA damage and maintains gene diversity and stability. Previous studies have demonstrated that the over-expression of RAD51 is associated with chemotherapy resistance of tumor cells to chemotherapy, and enhanced activity of DNA damage repair (DDR) systems contributes to resistance of adult T-cell leukemia-lymphoma (ATL) resistance to chemotherapy. Thus, targeting RAD51 is a potential strategy for the sensitization of ATL cells to chemotherapeutic drugs by inducing DNA damage. In general, cells can repair minor DNA damage through DDR; however, serious DNA damage may cause cell toxicity in cells which cannot be restored. In the present, down regulation of RAD51 by shRNA and imatinib sensitized Jurkat cells to etoposide by decreasing the activity of homologous recombination (HR). We found that the suppression of RAD51 by shRNA inhibited tumor cells proliferation and enhanced apoptosis of Jurkat cells after etoposide treatment. Importantly, downregulation of RAD51 by imatinib obviously increased the apoptosis of Jurkat cell after etoposide treatment. These results demonstrated that RAD51 may be of great value to as a novel target for the clinical treatment of adult T-cell leukemia-lymphoma (ATL), and it may improve the survival of leukemia patients.

rearrangement of the mixed lineage leukemia (MLL; also known as lysine methyltransferase 2A) gene is a recurrent genomic aberration in acute myeloid leukemia (aMl). MLLT3, super elongation complex subunit (AF9) is one of the most common Mll fusion partners in aMl. The present study aimed to explore the aberrant expression of genes associated with the MLL-AF9 translocation and identified potential new targets for the therapy of aMl with Mll-aF9 translocation. The transcriptomic and epigenetic datasets were downloaded from national center of Biotechnology information Gene expression omnibus (Geo) database. differentially expressed genes were obtained from two independent datasets (GSe68643 and GSe73457). Gene ontology biological process and Kyoto encyclopedia of Genes and Genomes pathway enrichment analysis was performed using the database for annotation, Visualization and integrated discovery. Mll-aF9-associated chromatin immunoprecipitation sequencing (ChIP-Seq) data was analyzed and identified binding sites for Mll-aF9 and wild type Mll (Mll WT). The chiP-Seq of histone modification data was downloaded from the Geo database, including histone 3 lysine 4 trimethylation (H3K4me3), histone 3 lysine 79 dimethylation (H3K79me2) and histone 3 lysine 27 acetylation (H3K27ac), was used for comparing histone modification marks between the Mll-aF9 leukemia cells and normal hematopoietic cells at Mll-aF9 and Mll WT binding sites. The differentially expressed genes with the same trend in H3K79me2, H3K27ac and H3K4me3 alteration were identified as potential MLL-AF9 direct target genes. upon validation using rna-Seq data from the Therapeutically applicable research to Generate effective Treatments aMl project, eight potential direct target genes of MLL-AF9 were identified and further confirmed in MLL-AF9 mouse model using reverse transcription-quantitative polymerase chain reaction. These genes may have a critical role in aMl with Mll-aF9 translocation.

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