Abstract
Fanconi anemia (FA) is an inherited disorder of DNA repair due to mutation in one of 20+ interrelated genes that repair intrastrand DNA crosslinks and rescue collapsed or stalled replication forks. The most common hematologic abnormality in FA is anemia, but progression to bone marrow failure (BMF), clonal hematopoiesis, or acute myeloid leukemia may also occur. In prior studies, we found that Fanconi DNA repair is required for successful emergency granulopoiesis; the process for rapid neutrophil production during the innate immune response. Specifically, Fancc−/− mice did not develop neutrophilia in response to emergency granulopoiesis stimuli, but instead exhibited apoptosis of bone marrow hematopoietic stem cells and differentiating neutrophils. Repeated emergency granulopoiesis challenges induced BMF in most Fancc−/− mice, with acute myeloid leukemia in survivors. In contrast, we found equivalent neutrophilia during emergency granulopoiesis in Fancc−/−Tp53+/− mice and WT mice, without BMF. Since termination of emergency granulopoiesis is triggered by accumulation of bone marrow neutrophils, we hypothesize neutrophilia protects Fancc−/−Tp53+/− bone marrow from the stress of a sustained inflammation that is experienced by Fancc−/− mice. In the current work, we found that blocking neutrophil accumulation during emergency granulopoiesis led to BMF in Fancc−/−Tp53+/− mice, consistent with this hypothesis. Blocking neutrophilia during emergency granulopoiesis in Fancc−/−Tp53+/− mice (but not WT) impaired cell cycle checkpoint activity, also found in Fancc−/− mice. Mechanisms for loss of cell cycle checkpoints during infectious disease challenges may define molecular markers of FA progression, or suggest therapeutic targets for bone marrow protection in this disorder.
Original language | English (US) |
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Article number | 107548 |
Journal | Journal of Biological Chemistry |
Volume | 300 |
Issue number | 8 |
DOIs | |
State | Published - Aug 2024 |
Funding
L. H. W. H. B. L. and E. A. E. investigation; L. H. W. H. B. L. and E. A. E. methodology; L. H. and E. A. E. formal analysis; E. A. E. conceptualization; E. A. E. data curation; E. A. E. funding acquisition; E. A. E. project administration; E. A. E. supervision; E. A. E. writing\u2013original draft; E. A. E. writing\u2013review and editing. This work was supported by Grants NIH R01 DK121354 and VA CX001864 to E. A. E. This work was supported by R01 DK121354 and CX001864 to EAE.
Keywords
- DNA damage response
- DNA repair
- cell cycle
- hematopoiesis
- inflammasome
- innate immunity
- neutrophil
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology