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Transforming growth factor-β signaling modifies the hematopoietic acute inflammatory response to drive bone marrow failure

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...

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Autores principales: Javier, Jose, Hinge, Ashwini, Bartram, James, Xu, Juying, Filippi, Marie-Dominique
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9152956/
https://www.ncbi.nlm.nih.gov/pubmed/34706493
http://dx.doi.org/10.3324/haematol.2020.273292
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author Javier, Jose
Hinge, Ashwini
Bartram, James
Xu, Juying
Filippi, Marie-Dominique
author_facet Javier, Jose
Hinge, Ashwini
Bartram, James
Xu, Juying
Filippi, Marie-Dominique
author_sort Javier, Jose
collection PubMed
description 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.
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spelling pubmed-91529562022-06-13 Transforming growth factor-β signaling modifies the hematopoietic acute inflammatory response to drive bone marrow failure Javier, Jose Hinge, Ashwini Bartram, James Xu, Juying Filippi, Marie-Dominique Haematologica Article - Bone Marrow Failure 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. Fondazione Ferrata Storti 2021-10-28 /pmc/articles/PMC9152956/ /pubmed/34706493 http://dx.doi.org/10.3324/haematol.2020.273292 Text en Copyright© 2022 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article - Bone Marrow Failure
Javier, Jose
Hinge, Ashwini
Bartram, James
Xu, Juying
Filippi, Marie-Dominique
Transforming growth factor-β signaling modifies the hematopoietic acute inflammatory response to drive bone marrow failure
title Transforming growth factor-β signaling modifies the hematopoietic acute inflammatory response to drive bone marrow failure
title_full Transforming growth factor-β signaling modifies the hematopoietic acute inflammatory response to drive bone marrow failure
title_fullStr Transforming growth factor-β signaling modifies the hematopoietic acute inflammatory response to drive bone marrow failure
title_full_unstemmed Transforming growth factor-β signaling modifies the hematopoietic acute inflammatory response to drive bone marrow failure
title_short Transforming growth factor-β signaling modifies the hematopoietic acute inflammatory response to drive bone marrow failure
title_sort transforming growth factor-β signaling modifies the hematopoietic acute inflammatory response to drive bone marrow failure
topic Article - Bone Marrow Failure
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9152956/
https://www.ncbi.nlm.nih.gov/pubmed/34706493
http://dx.doi.org/10.3324/haematol.2020.273292
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