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Cell Stem Cell. 2016 Nov 3;19(5):613-627. doi: 10.1016/j.stem.2016.08.021. Epub 2016 Sep 22.

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

Author information

1
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
2
Department of Internal Medicine, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
3
Department of Hematology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam 1081HV, the Netherlands.
4
Department of Molecular Genetics, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
5
Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Centre (AMC), University of Amsterdam (UvA), Amsterdam 1105AZ, the Netherlands.
6
Departments of Genetics and Radiation Oncology, Cancer Genomics Center, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands.
7
Institute of Immunology, University of Münster, Münster 48149, Germany.
8
Department of Hematology, Erasmus MC Cancer Institute, Rotterdam 3015CN, the Netherlands. Electronic address: m.h.g.raaijmakers@erasmusmc.nl.

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.

KEYWORDS:

S100A8; cancer; hematopoietic stem cell; inflammation; leukemia; mesenchymal; microenvironment; myelodysplastic syndrome (MDS); niche; shwachman-diamond syndrome

PMID:
27666011
DOI:
10.1016/j.stem.2016.08.021
[Indexed for MEDLINE]
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