@article{Javier_Hinge_Bartram_Xu_Filippi_2022, place={Pavia, Italy}, title={Transforming growth factor-β signaling modifies the hematopoietic acute inflammatory response to drive bone marrow failure}, volume={107}, url={https://haematologica.org/article/view/haematol.2020.273292}, DOI={10.3324/haematol.2020.273292}, abstractNote={<p>Bone marrow failure syndromes are characterized by ineffective hematopoiesis due to impaired fitness of hematopoietic stem cells. They can be acquired during bone marrow stress or innate and are associated with driver genetic mutations. Patients with a bone marrow failure syndrome are at higher risk 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 factor, but remains to be understood in detail. In this study, we examined the effect of increased transforming growth factor-b (TGFb) signaling, in combination or not with an acute innate immune challenge using polyinosinc:polycytidilic acid (pIC), on the hematopoietic system without genetic mutations. We show that acute rounds of pIC alone drive a benign age-related myeloid cell expansion and increased TGFb signaling alone causes a modest anemia in old mice. In sharp contrast, increased TGFb signaling plus acute pIC challenge result in chronic pancytopenia, expanded hematopoietic stem and progenitor cell pools, and increased bone marrow dysplasia 3-4 months after stress, which are phenotypes similar to human bone marrow failure syndromes. Mechanistically, this disease phenotype is uniquely associated with increased mitochondrial content, increased reactive oxygen species and enhanced caspase-1 activity. Our results suggest that chronic increased TGFb signaling modifies the memory of an acute immune response to drive bone marrow failure without the need for a preexisting genetic insult. Hence, non-genetic factors in combination are sufficient to drive bone marrow failure.</p&gt;}, number={6}, journal={Haematologica}, author={Javier, Jose and Hinge, Ashwini and Bartram, James and Xu, Juying and Filippi, Marie-Dominique}, year={2022}, month={Jun.}, pages={1323-1334} }