The Role of Mitochondria in Bone Marrow Failure
Abstract
Bone marrow failure syndromes (BMF) are characterized by ineffective hematopoiesis due to impaired fitness of hematopoietic stem cells (HSC). BMFs can be acquired during bone marrow stress or innate are associated with driver genetic mutations.BMFs are at higher risks of developing secondary neoplasms, including myelodysplastic syndromes and leukemia. Despite the identification of genetic driver mutations, the hematopoietic presentation of the disease is quite heterogeneous raising the possibility that non-genetic factors contribute to the pathogenesis of the disease. The role of inflammation has emerged as an important contributing factors, but remain to be understood in detail. The goals of this project are to determine the role of inflammation and stress signaling as non-genetic factors initiating and contributing BMF/MDS. We show that increased TGF signaling plus acute pIC challenge result in chronic pancytopenia, and increased bone marrow dysplasia 3-4 months after stress, phenotypes similar to human bone marrow failure syndromes. Mechanistically, this disease phenotype is uniquely associated with enhanced caspase-1 activity. Further, we show that the phenotype is MAVS-dependent. Together, these findings uncover chronic increased TGF signaling modifies an acute immune response to drive bone marrow failure without the need for pre-existing genetic insult. Hence, non-genetic factors in combination are sufficient to drive bone marrow failure.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2022
- Accession Number
- AD1230145
Entities
People
- Filippi Marie-dominique