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Dysregulation of miR-138-5p/RPS6KA1-AP2M1 Is Associated With Poor Prognosis in AML

Dong-Hu Yu1,2, Chen Chen1, Xiao-Ping Liu3

  • 1Department of Biological Repositories, Human Genetics Resource Preservation Center of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan, China.

Frontiers in Cell and Developmental Biology
|March 18, 2021
PubMed

Insights

FLT3-ITD mutations in acute myeloid leukemia (AML) interact with the CXCL12/CXCR4 axis, activating pathways that increase chemoresistance via RPS6KA1 and AP2M1.

Area of Science:

  • Hematology
  • Molecular Biology
  • Bioinformatics

Background:

  • Acute myeloid leukemia (AML) is a severe hematopoietic stem/progenitor cell malignancy.
  • FLT3-ITD mutations occur in 20-30% of AML patients, impacting prognosis.
  • The CXCL12/CXCR4 axis is implicated in cancer progression and drug resistance.

Purpose of the Study:

  • To investigate the interplay between FLT3-ITD mutations and the CXCL12/CXCR4 axis in AML.
  • To elucidate the molecular mechanisms underlying this interaction and its impact on chemoresistance.
  • To identify novel prognostic biomarkers and therapeutic targets in AML.

Main Methods:

  • Bioinformatic analyses including Gene Set Variation Analysis (GSVA).
  • Survival analyses using TCGA-AML data.
  • Weighted Gene Co-expression Network Analysis (WGCNA).
  • KEGG and Gene Ontology (GO) pathway analysis.

Main Results:

  • The PI3K-Akt-mTOR pathway positively correlates with FLT3-ITD mutation status.
  • RPS6KA1 and AP2M1 are identified as significant prognostic candidates for overall survival in AML.
  • RPS6KA1 and AP2M1 expression is linked to chemoresistance and regulated by the CXCL12/CXCR4 axis.
  • Hsa-miR-138-5p downregulation, influenced by the CXCL12/CXCR4 axis, leads to increased RPS6KA1/AP2M1 expression.

Conclusions:

  • The interaction of FLT3-ITD and the CXCL12/CXCR4 axis activates the PI3K-Akt-mTOR pathway in AML.
  • Upregulated RPS6KA1 and AP2M1, driven by miR-138-5p downregulation, contribute to multi-drug resistance.
  • These findings highlight a novel mechanism of chemoresistance in AML and suggest potential therapeutic strategies targeting this axis.
Keywords:
AP2M1GSVAPI3K-Akt-mTOR pathwayRPS6KA1WGCNAacute myeloid leukemiachemoresistanceprognosis

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