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

Zhiheng Cheng1,2,3,4, Yifeng Dai2, Yifan Pang5

  • 1Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Journal of Cellular and Molecular Medicine
|November 23, 2019
PubMed

Insights

High DNA damage inducible transcript 4 (DDIT4) expression indicates a poor prognosis in acute myeloid leukaemia (AML), particularly with chemotherapy. However, allogeneic stem cell transplantation may overcome this negative impact.

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • DNA damage inducible transcript 4 (DDIT4), an inhibitor of the mammalian target of rapamycin (mTOR), is induced by cellular stress.
  • DDIT4 plays a role in tumorigenesis and affects patient survival in various cancers.
  • The prognostic significance of DDIT4 in acute myeloid leukaemia (AML) remains largely unelucidated.

Purpose of the Study:

  • To investigate the prognostic value of DDIT4 expression in patients with acute myeloid leukaemia (AML).
  • To determine the impact of DDIT4 levels on survival outcomes in AML based on treatment modality.

Main Methods:

  • Analysis of DDIT4 expression and clinical data from 155 AML patients in The Cancer Genome Atlas (TCGA).
  • Stratification of patients based on DDIT4 expression levels (high vs. low) and treatment (chemotherapy vs. allogeneic haematopoietic stem cell transplantation [allo-HSCT]).
  • Validation in two independent cytogenetically normal AML (CN-AML) cohorts from the Gene Expression Omnibus (GEO) database and Gene Ontology (GO) enrichment analysis.

Main Results:

  • In the chemotherapy-only group, high DDIT4 expression was significantly associated with shorter overall survival (OS) and event-free survival (EFS) (P < .001).
  • In the allo-HSCT group, no significant difference in OS or EFS was observed between high and low DDIT4 expressers.
  • Patients with high DDIT4 expression treated with allo-HSCT showed improved EFS and OS compared to those receiving chemotherapy (P < .01), an effect not seen in the low DDIT4 group. Validation cohorts confirmed high DDIT4 as a marker of poorer survival. GO analysis linked DDIT4 to AML signalling pathways.

Conclusions:

  • High DDIT4 expression is a potential poor prognostic factor in acute myeloid leukaemia (AML).
  • The negative prognostic impact of high DDIT4 expression may be mitigated or overcome by allogeneic haematopoietic stem cell transplantation (allo-HSCT).
  • DDIT4 warrants further investigation as a therapeutic target or biomarker in AML management.
Keywords:
DNA damage inducible transcript 4acute myeloid leukaemiaallogeneic haematopoietic stem cell transplantationchemotherapyprognosis

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