Related Experiment Video

Updated: Jan 12, 2026

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

615

Guanine nucleotides drive ribosome biogenesis and glycolytic reprogramming in acute myeloid leukemia stem cells

Gentaro Kawano1,2, Riichiro Ikeda1,2, Daisuke Ishihara1,2

  • 1Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.

Blood
|November 5, 2025
PubMed

Insights

Therapy-resistant acute myeloid leukemia (AML) stem cells adapt metabolism via glycolysis. Inhibiting guanine nucleotide synthesis disrupts this adaptation, eradicating resistant AML stem cells.

Area of Science:

  • Hematology
  • Cancer Biology
  • Metabolic Pathways

Background:

  • Therapy resistance in acute myeloid leukemia (AML) is a significant clinical challenge.
  • Leukemia stem cells (LSCs) possess metabolic adaptability, contributing to treatment failure.
  • Venetoclax (Ven) targets oxidative phosphorylation (OXPHOS), but resistance emerges.

Purpose of the Study:

  • To investigate the metabolic adaptations of Ven-resistant LSCs.
  • To identify therapeutic strategies targeting LSC metabolic reprogramming.
  • To elucidate the role of guanine nucleotide biosynthesis in AML therapy resistance.

Main Methods:

  • Analysis of metabolic reprogramming in Ven-resistant LSCs.
  • Investigation of ribosome biogenesis and its link to nucleotide synthesis.
  • Assessment of inosine monophosphate dehydrogenases (IMPDH1/2) inhibition.
  • Xenotransplantation experiments to evaluate LSC stemness and AML reconstitution.

Main Results:

  • Ven-resistant LSCs switch to glycolysis to bypass OXPHOS inhibition.
  • Enhanced ribosome biogenesis, fueled by guanine nucleotide synthesis, supports this metabolic shift.
  • Guanine nucleotide accumulation suppresses checkpoints, leading to TP53 destabilization and MYC persistence.
  • IMPDH1/2 inhibition depletes guanine nucleotides, reactivates checkpoints, stabilizes TP53, and represses MYC.
  • Targeting guanine nucleotide synthesis disrupts LSC stemness and AML cell reconstitution, irrespective of Ven resistance or TP53 status.

Conclusions:

  • Mutation-independent TP53 inactivation is implicated in resistant AML.
  • Targeting de novo guanine nucleotide biosynthesis is a promising strategy against therapy-resistant LSCs.
  • Inhibition of IMPDH1/2 offers a potential therapeutic avenue for overcoming AML treatment resistance.

More Related Videos

Author Spotlight: Analyzing Bone Marrow Microenvironment in Murine Hematological Malignancies06:33

Author Spotlight: Analyzing Bone Marrow Microenvironment in Murine Hematological Malignancies

Published on: November 10, 2023

1.8K
Preparation of Primary Acute Lymphoblastic Leukemia Cells in Different Cell Cycle Phases by Centrifugal Elutriation09:09

Preparation of Primary Acute Lymphoblastic Leukemia Cells in Different Cell Cycle Phases by Centrifugal Elutriation

Published on: November 10, 2017

8.8K

Related Concept Videos

The Nucleolus02:55

The Nucleolus

The nucleolus is the most prominent substructure of the nucleus. When it was first discovered, it was considered to be an isolated organelle that forms fibrils and granules. In 1931, the relationship between the nucleolus and chromosomes was first described by Heitz. He observed that the appearance and size of nucleolus varies depending on the stage of the cell cycle. He also noticed constricted regions on different chromosomes clustered together at definite cell cycle stages. These regions,...
10.2K
Stringent Response in E. coli01:23

Stringent Response in E. coli

Bacterial growth is closely tied to nutrient availability, with cells proliferating exponentially under favorable conditions and entering a stationary phase when resources become scarce. This transition is mediated by a regulatory mechanism known as the stringent response, which allows bacteria to adapt to nutrient deprivation by modulating gene expression and metabolic activity.During nutrient scarcity, intracellular amino acid levels decline. It results in the accumulation of uncharged tRNAs...
285
Biosynthesis of Nucleic Acids01:28

Biosynthesis of Nucleic Acids

Nucleic acid biosynthesis is a fundamental biochemical process that produces the purine and pyrimidine nucleotides essential for DNA and RNA synthesis. This pathway maintains a balanced nucleotide pool, preventing imbalances that could jeopardize genetic integrity and cellular function. Given the crucial role of nucleotides, their synthesis is tightly regulated to ensure proper cellular homeostasis.Purine BiosynthesisThe biosynthesis of purine nucleotides begins with ribose-5-phosphate, a...
946
Leaky Scanning02:28

Leaky Scanning

During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA.  Marilyn Kozak discovered that the sequence RCCAUGG (where R...
5.6K
Ribosomal RNA Synthesis02:53

Ribosomal RNA Synthesis

4.1K
Ribosomal RNA Synthesis02:53

Ribosomal RNA Synthesis

Ribosome synthesis is a highly complex and coordinated process involving more than 200 assembly factors. The synthesis and processing of ribosomal components occurs not only in the nucleolus but also in the nucleoplasm and the cytoplasm of eukaryotic cells.
Ribosome biogenesis begins with the synthesis of 5S and 45S pre-rRNAs by distinct RNA polymerases. The primary transcripts are extensively processed and modified before they are bound and folded by ribosomal proteins and assembly factors,...
14.6K