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Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Biology

Background:

  • Malignant self-renewal is a hallmark of cancer, particularly in leukemia stem cells (LSCs).
  • The regulatory mechanisms governing LSC self-renewal and activity remain incompletely understood.
  • Ribosomal RNA (rRNA) modifications are increasingly recognized for their roles in cellular processes.

Purpose of the Study:

  • To investigate the role of rRNA 2 -O-methylation dynamics in regulating leukemia stem cell activity in acute myeloid leukemia (AML).
  • To establish the complete rRNA 2 -O-methylation landscape in human AML and its association with disease characteristics.
  • To elucidate the functional consequences of altered rRNA 2 -O-methylation on LSC phenotype and translation.

Main Methods:

  • Comprehensive analysis of the rRNA 2 -O-methylation landscape in 94 AML patients.
  • Biochemical, genetic, and functional assays to assess LSC activity.
  • In vivo studies using NSG mice to evaluate engraftment and AML development.
  • Analysis of ribosome translation programs and intracellular amino acid levels.

Main Results:

  • Dynamic rRNA 2 -O-methylation was identified specifically at exterior ribosome sites in AML patients.
  • The rRNA 2 -O-methylation pattern correlated with AML development stage and LSC gene expression.
  • Forced expression of fibrillarin (FBL) induced an LSC phenotype and enhanced engraftment.
  • Enhanced 2 -O-methylation shifted translation towards amino acid transporter mRNAs, increasing intracellular amino acids.
  • Methylation at 18S-guanosine 1447 was critical for LSC activity.

Conclusions:

  • Dynamic rRNA 2 -O-methylation is a key regulator of AML LSC self-renewal.
  • This epigenetic plasticity alters protein translation, reprogramming cell fate and function in cancer.
  • The rRNA 2 -O-methylation landscape offers a novel target for AML therapy.