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

• DOI: 10.1016/j.stem.2016.08.021
• Publication Date: 2016-09-22T20:21:08Z
• Authors: Noemi A. Zambetti; Zhen Ping; Si Chen; Keane J.G. Kenswil; Maria A. Mylona; Mathijs A. Sanders; Remco M. Hoogenbo...; Eric M.J. Bindels; Maria N. Adisty; Paulina M.H. Van ...; Cindy S. van der ...; Theresia M. Westers; Eline M.P. Cremers; Chiara Milanese; Pier G. Mastrober...; Johannes P.T.M. v...; Bram C.J. van der...; Ivo P. Touw; Taco W. Kuijpers; Roland Kanaar; Arjan A. van de L...; Thomas Vogl; Marc H.G.P. Raaij...
• Keywords: 0301 basic medicine; DNA Repair; Bone and Bones; Mice; 03 medical and health sciences; SDG 3 - Good Health and Well-being; Animals; Humans; Lipomatosis; Bone Marrow Diseases; Inflammation; Leukemia; Integrases; Pathogen-Associated Molecular Pattern Molecules; Mesenchymal Stem Cells; Hematopoietic Stem Cells; cancer; hematopoietic stem cell; inflammation; leukemia; mesenchymal; microenvironment; myelodysplastic syndrome (MDS); niche; S100A8; shwachman-diamond syndrome; Animals; Bone Marrow Diseases; Bone and Bones; DNA Repair; Exocrine Pancreatic Insufficiency; Gene Deletion; Hematopoietic Stem Cells; Humans; Inflammation; Integrases; Leukemia; Lipomatosis; Mesenchymal Stem Cells; Mice; Mitochondria; Oxidative Stress; Pathogen-Associated Molecular Pattern Molecules; Precancerous Conditions; Proteins; Risk Factors; S100 Proteins; Signal Transduction; Sp7 Transcription Factor; Stem Cell Niche; Toll-Like Receptors; Transcription Factors; Treatment Outcome; Tumor Suppressor Protein p53; DNA Damage; Disease Progression; Molecular Medicine; Genetics; Cell Biology; Mitochondria; 3. Good health; EMC MM-03-32-04; Oxidative Stress; EMC MM-01-39-02; EMC MM-02-41-04; Disease Progression; EMC MGC-01-12-03; Exocrine Pancreatic Insufficiency; Precancerous Conditions; Gene Deletion; DNA Damage

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.