Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia

Zambetti, N., Ping, Z., Chen, S., Kenswill, K., Mylona, A., Sanders, M., Hoogenboezem, R., Bindels, E., Adisty, N., Van Strien, P., van der Leije, C., Westers, T., Cremers, E., Milanese, C., Mastroberardino, P., van Leeuwen, J., van der Eerden, B., Touw, I., Kuijpers, T., Kanaar, R., van der Loosdrecht, A., Vogl, T. and Raaijmakers, M. (2016) Mesenchymal inflammation drives genotoxic stress in hematopoietic stem cells and predicts disease evolution in human pre-leukemia. Cell Stem Cell, 19 (5). pp. 613-627. ISSN 1934-5909.

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Mesenchymal niche cells may drive tissue failure and malignant transformation in the hematopoietic system but the molecular mechanisms and their relevance to human disease remain poorly defined. Here, we show that perturbation of mesenchymal cells in a mouse model of the preleukemic disorder Shwachman-Diamond syndrome 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 mouse model and a range of human preleukemic 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, the principal leukemia predisposition syndrome. Collectively, our findings reveal a concept of mesenchymal niche-induced genotoxic stress in heterotypic stem and progenitor cells through inflammatory signaling as an actionable determinant of disease outcome in human preleukemia.

Item Type: Article
Subjects: R Medicine > RC Internal medicine > RC0581 Specialties of internal medicine > RC0633 Diseases of the blood and blood-forming organs
Divisions: Faculty of Social and Applied Sciences > School of Human and Life Sciences
Depositing User: Athina Mylona
Date Deposited: 21 Dec 2016 15:31
Last Modified: 03 Oct 2018 15:15

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Last edited: 29/06/2016 12:23:00