In Fanconi Anemia, impaired accumulation of bone marrow neutrophils during emergency granulopoiesis induces hematopoietic stem cell stress

Fanconi Anemia (FA) is an inherited disorder of DNA-repair caused by mutation in one of 20+ interrelated genes that repair intra-strand 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 (AML) 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 (HSCs) and differentiating neutrophils. Repeated emergency granulopoiesis challenges induced BMF in most Fancc-/- mice, with AML in survivors. In contrast, we found equivalent emergency granulopoiesis-induced neutrophilia in Fancc-/-Tp53+/- mice and wild type (WT) mice, without BMF in either. Since bone marrow neutrophil accumulation triggers termination of emergency granulopoiesis, we hypothesize neutrophilia protects Fancc-/-Tp53+/- bone marrow from the stress of sustained inflammatory physiology, as experienced by Fancc-/- mice.