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Mesenchymal Inflammation Drives Genotoxic Stress in Hematopoietic Stem Cells and Predicts Disease Evolution in Human Pre-leukemia. | LitMetric

AI Article Synopsis

  • The study investigates how mesenchymal niche cells contribute to tissue failure and leukemia in the blood system, revealing that changes in these cells can lead to serious cellular stress in stem and progenitor cells.
  • It finds that in a mouse model of Shwachman-Diamond syndrome, disrupting mesenchymal cells causes issues like mitochondrial dysfunction and DNA damage, which are linked to an inflammatory signaling pathway involving p53-S100A8/9-TLR.
  • The research highlights that this inflammatory signaling is a common factor in multiple pre-leukemic disorders and can predict disease progression and survival outcomes in patients with myelodysplastic syndrome, suggesting it could be a potential target for treatment.

Article Abstract

Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system, but the underlying molecular mechanisms and relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the pre-leukemic disorder Shwachman-Diamond syndrome (SDS) induces mitochondrial dysfunction, oxidative stress, and activation of DNA damage responses in hematopoietic stem and progenitor cells. Massive parallel RNA sequencing of highly purified mesenchymal cells in the SDS mouse model and a range of human pre-leukemic syndromes identified p53-S100A8/9-TLR inflammatory signaling as a common driving mechanism of genotoxic stress. Transcriptional activation of this signaling axis in the mesenchymal niche predicted leukemic evolution and progression-free survival in myelodysplastic syndrome (MDS), the principal leukemia predisposition syndrome. Collectively, our findings identify mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as a targetable determinant of disease outcome in human pre-leukemia.

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Source
http://dx.doi.org/10.1016/j.stem.2016.08.021DOI Listing

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