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

Journal article


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. https://doi.org/10.1016/j.stem.2016.08.021
AuthorsZambetti, 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.
Abstract

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.

Year2016
JournalCell Stem Cell
Journal citation19 (5), pp. 613-627
PublisherElsevier
ISSN1934-5909
Digital Object Identifier (DOI)https://doi.org/10.1016/j.stem.2016.08.021
Publication dates
Print22 Sep 2016
Publication process dates
Deposited21 Dec 2016
Accepted22 Aug 2016
Accepted author manuscript
Output statusPublished
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https://repository.canterbury.ac.uk/item/87zw3/mesenchymal-inflammation-drives-genotoxic-stress-in-hematopoietic-stem-cells-and-predicts-disease-evolution-in-human-pre-leukemia

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