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Nudt15-mediated inflammatory signaling contributes to divergent outcomes in leukemogenesis and hematopoiesis.
- Source :
-
Leukemia [Leukemia] 2024 Sep; Vol. 38 (9), pp. 1958-1970. Date of Electronic Publication: 2024 Jul 18. - Publication Year :
- 2024
-
Abstract
- NUDT15 encodes nucleotide triphosphate diphosphatase that is responsible for metabolizing purine analog drugs, and its genetic mutation results in severe side effects from thiopurine therapy. However, the functions of Nudt15 in leukemic stem cells (LSCs) and hematopoietic stem cells (HSCs) remain unknown. Here we reveal the Nudt15-regulating self-renewal of both mouse LSCs and HSCs. Our data show that Nudt15 negatively regulates murine leukemogenesis and its deficiency prolongs the survival of murine AML recipients by impairing LSC self-renewal, while Nudt15 ablation markedly enhances mouse HSC regenerative potential and self-renewal. Mechanistically, Nudt15 modulates inflammatory signaling in mouse LSCs and HSCs, leading to divergent self-renewal outcomes. Nudt15 depletion inhibits mouse LSC self-renewal by downregulating Ifi30, resulting in elevating intracellular ROS level. Gata2, a key regulator, is required for Nudt15-mediating inflammatory signaling in mouse HSCs. Collectively, our results present new crucial roles of Nudt15 in maintaining the functions of mouse LSC and HSC through inflammatory signaling and have a new insight into clinical implications.<br /> (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Subjects :
- Animals
Humans
Mice
GATA2 Transcription Factor metabolism
GATA2 Transcription Factor genetics
Inflammation metabolism
Inflammation pathology
Leukemia, Myeloid, Acute metabolism
Leukemia, Myeloid, Acute pathology
Leukemia, Myeloid, Acute genetics
Leukemia, Myeloid, Acute etiology
Mice, Inbred C57BL
Neoplastic Stem Cells metabolism
Neoplastic Stem Cells pathology
Reactive Oxygen Species metabolism
Hematopoiesis
Hematopoietic Stem Cells metabolism
Hematopoietic Stem Cells pathology
Pyrophosphatases genetics
Pyrophosphatases metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5551
- Volume :
- 38
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Leukemia
- Publication Type :
- Academic Journal
- Accession number :
- 39025986
- Full Text :
- https://doi.org/10.1038/s41375-024-02352-1