Guanine nucleotides drive ribosome biogenesis and glycolytic reprogramming in acute myeloid leukemia stem cells
Therapy resistance in acute myeloid leukemia (AML) remains a major clinical obstacle, particularly because of the persistence of leukemia stem cells (LSC) capable of metabolic adaptation. Although venetoclax (Ven) inhibits oxidative phosphorylation (OXPHOS), we found that Ven-resistant LSC undergo glycolytic reprogramming to bypass OXPHOS inhibition. This metabolic shift is supported by enhanced ribosome biogenesis, which is sustained by upregulated de novo guanine nucleotide biosynthesis. Abundant guanine nucleotides suppress the impaired ribosome biogenesis checkpoint (IRBC), leading to TP53 destabilization and persistent MYC expression. The inhibition of inosine monophosphate dehydrogenases (IMPDH1/2) depletes guanine nucleotides, activates IRBC, stabilizes TP53, represses MYC, and impairs the metabolic shift to glycolysis. This metabolic rewiring disrupts LSC stemness and suppresses the reconstitution of human AML cells in xenotransplantation experiments. Notably, the suppression of LSC stemness was observed regardless of Ven resistance or the TP53 mutational status of AML cells. These findings reveal that mutation-independent TP53 inactivation is involved in resistant AML and suggest that targeting guanine nucleotide biosynthesis may offer a clinically actionable strategy to eradicate therapy-resistant LSC.
Authors
- Yuichiro Semba (ORCID: https://orcid.org/0000-0001-8576-3530)
- Takahiro Shima (ORCID: https://orcid.org/0000-0003-0062-6161)
- Yoshikane Kikushige (ORCID: https://orcid.org/0000-0002-7721-1696)
- Koji Kato (ORCID: https://orcid.org/0000-0002-5815-4585)
- Daisuke Ishihara (ORCID: https://orcid.org/0000-0001-9070-0016)
- Takahiro Maeda (ORCID: https://orcid.org/0000-0003-4530-6460)
- Yu Kochi (ORCID: https://orcid.org/0000-0002-9411-7239)
- Tomoyoshi Soga (ORCID: https://orcid.org/0000-0001-9502-2509)
- Sanae Ashitani
- Yasuo Mori (ORCID: https://orcid.org/0000-0001-6425-1720)
- Teppei Sakoda (ORCID: https://orcid.org/0000-0002-7521-0366)
- Toshihiro Miyamoto (ORCID: https://orcid.org/0000-0002-6533-1594)
- Gentaro Kawano (ORCID: https://orcid.org/0009-0002-1732-9868)
- Shunsuke Yamamoto (ORCID: https://orcid.org/0000-0002-5313-7161)
- Ryohei Ikeda (ORCID: https://orcid.org/0009-0008-4917-0648)
- Koichi Akashi
Institutions
- Kanazawa University (JP)
- Kyushu University (JP)
- Kanazawa Medical University (JP)
- Keio University (JP)
- Kyushu University Hospital (JP)
Publication Details
- Journal
- Blood
- Published
- 2025-11-05
- DOI
- https://doi.org/10.1182/blood.2025030209
- Citations
- 1
- Primary Topic
- Biochemical and Molecular Research
- Type
- article
- Field-Weighted Citation Impact
- 0.81
Funders
- Japan Agency for Medical Research and Development
- Ministry of Education, Culture, Sports, Science and Technology
- SENSHIN Medical Research Foundation
- Princess Takamatsu Cancer Research Fund
- National Institutes of Health
- Japan Society for the Promotion of Science
- Core Research for Evolutional Science and Technology