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METTL3 affects FLT3-ITD+ acute myeloid leukemia by mediating autophagy by regulating PSMA3-AS1 stability

Shenghao Wu1, Shanshan Weng1, Wenjin Zhou1

  • 1Department of Hematology, The Dingli Clinical Institute of Wenzhou Medical University (The Second Affiliated Hospital of Shanghai University , Wenzhou Central Hospital), Wenzhou, Zhejiang Province, China.

Cell Cycle (Georgetown, Tex.)
|April 24, 2023
PubMed

Insights

The long non-coding RNA PSMA3-AS1 promotes acute myeloid leukemia (AML) progression by regulating autophagy via the miR-20a-5p/ATG16L1 pathway. METTL3 enhances PSMA3-AS1 stability, offering potential therapeutic targets for FLT3-ITD+ AML.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cancer Genetics

Background:

  • Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy with complex molecular underpinnings.
  • FLT3-ITD mutations are common in AML and associated with poor prognosis.
  • Long non-coding RNAs (lncRNAs) are increasingly recognized for their roles in cancer development and progression.

Purpose of the Study:

  • To investigate the role of the lncRNA PSMA3-AS1 in the initiation and progression of acute myeloid leukemia (AML).
  • To elucidate the underlying molecular mechanism of PSMA3-AS1 action in AML, particularly in FLT3-ITD+ subtypes.
  • To explore the potential of PSMA3-AS1 as a therapeutic target for AML.

Main Methods:

  • Quantitative real-time PCR (qRT-PCR) to measure RNA and gene expression.
  • Western blot assay for protein expression analysis.
  • EdU staining and flow cytometry for cell proliferation and apoptosis assessment.
  • Bioinformatics prediction, dual-luciferase reporter assays, and RNA pull-down assays to identify and verify molecular interactions.
  • Autophagy-related gene quantification (LC3, Beclin1, P62).
  • m6A modification assays to assess the role of METTL3.
  • In vivo tumor models and immunohistochemistry (Ki67, TUNEL) to evaluate tumor growth and apoptosis.

Main Results:

  • PSMA3-AS1 expression was significantly upregulated in FLT3-ITD+ AML patients.
  • Silencing PSMA3-AS1 inhibited proliferation and autophagy while promoting apoptosis in AML cell lines (MV4-11, Molm13).
  • METTL3 was found to enhance PSMA3-AS1 RNA stability.
  • PSMA3-AS1 was shown to target miR-20a-5p, which in turn modulated ATG16L1 expression, affecting AML progression.
  • PSMA3-AS1 promotes FLT3-ITD+ AML progression by regulating autophagy through the miR-20a-5p/ATG16L1 pathway.

Conclusions:

  • PSMA3-AS1 plays a crucial role in promoting FLT3-ITD+ AML progression by modulating autophagy via the miR-20a-5p/ATG16L1 axis.
  • METTL3 contributes to the increased stability of PSMA3-AS1, suggesting a mechanism for its upregulation.
  • PSMA3-AS1 represents a potential biomarker for early screening and a novel therapeutic target for FLT3-ITD+ AML.
Keywords:
Acute myeloid leukemia (AML)FLT3-ITDN6-methyladenosinePSMA3-AS1autophagy

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