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Up-regulation of DDIT4 predicts poor prognosis in acute myeloid leukaemia.

ABSTRACT: The mammalian target of rapamycin (mTOR) inhibitor, DNA damage inducible transcript 4 (DDIT4), has inducible expression in response to various cellular stresses. In multiple malignancies, studies have shown that DDIT4 participates in tumorigenesis and impacts patient survival. We aimed to study the prognostic value of DDIT4 in acute myeloid leukaemia (AML), which is currently unclear. Firstly, The Cancer Genome Atlas was screened for AML patients with complete clinical characteristics and DDIT4 expression data. A total of 155 patients were included and stratified according to the treatment modality and the median DDIT4 expression levels. High DDIT4 expressers had shorter overall survival (OS) and event-free survival (EFS) than the low expressers among the chemotherapy-only group (all P < .001); EFS and OS were similar in the high and low DDIT4 expressers of the allogeneic haematopoietic stem cell transplantation (allo-HSCT) group. Furthermore, in the DDIT4high group, patients treated with allo-HSCT had longer EFS and OS than those who received chemotherapy alone (all P < .01). In the DDIT4low group, OS and EFS were similar in different treatment groups. Secondly, we analysed two other cytogenetically normal AML (CN-AML) cohorts derived from the Gene Expression Omnibus database, which confirmed that high DDIT4 expression was associated with poorer survival. Gene Ontology (GO) enrichment analysis showed that the genes related to DDIT4 expression were mainly concentrated in the acute and chronic myeloid leukaemia signalling pathways. Collectively, our study indicates that high DDIT4 expression may serve as a poor prognostic factor for AML, but its prognostic effects could be outweighed by allo-HSCT.

SUBMITTER: Cheng Z

PROVIDER: S-EPMC6933361 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:Secreted frizzled-related proteins (SFRPs) as Wnt signaling antagonists have been found to be dysregulated by promoter hypermethylation in several cancers including acute myeloid leukemia (AML). This study aimed to investigate the methylated status of SFRPs promoter region and its clinical relevance in Chinese non-M3 AML patients.SFRPs methylation in 139 primary non-M3 AML patients was determined using methylation-specific real-time quantitative polymerase chain reaction.The frequency of aberrant methylation was as follows: 30.2% for SFRP1, 27.3% for SFRP2, 5.0% for SFRP4, and 1.4% for SFRP5. Hypermethylation of at least one SFRP gene occurred in 51.8% (72/139) of non-M3 AML patient samples, which was significantly higher compared to normal control (0/21) (P<0.001). Hypermethylation of SFRP1 was potentially associated with N/K-RAS mutations (P=0.043), and the frequency of SFRPs methylation was higher in patients ≥50 years compared to those <50 years, especially for SFRP2 (P<0.05). Furthermore, both whole cohort and cytogenetically normal (CN) patients with high SFRPs-methylated group showed a shorter overall survival (OS) compared to those with low group (P=0.036 and P=0.035, respectively). Moreover, Cox regression multivariate analysis revealed that SFRPs hypermethylation acts as an independent prognostic biomarker among both whole cohort (hazard ratio =1.804, P=0.026) and CN (hazard ratio =2.477, P=0.023) patients. In leukemic cell line HL60 treated with 5-aza-2'-deoxycytidine, the alteration of SFRP1/2 expression inversely correlated with change in SFRP1/2 methylation (r=-0.975, P=0.005 and r=-0.975, P=0.005, respectively). A tendency of negative correlation was observed between SFRP1 expression and its promoter methylation in AML patients (r=-0.334, P=0.038).These findings suggested that hypermethylation of SFRP1/2 was a frequent event and silenced SFRP1/2 expression in AML. Moreover, hypermethylation of SFRPs promoter was an adverse risk factor for OS in Chinese non-M3 AML patients.

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Up-regulation of DDIT4 predicts poor prognosis in acute myeloid leukaemia.

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