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

Noemi Zambetti, Zhen Ping, Si Chen, Keane Kenswil, Athina Mylona, Mathijs Sanders, Remco Hoogenboezem, Eric Bindels, Maria Adisty, Paulette Strien, Cindy Leije, TM Westers, EMP Cremers, Chiara Milanese, Pier Mastroberardino, Hans van Leeuwen, Bram van der Eerden, Ivo Touw, TW Kuijpers, Roland KanaarAAV de Loosdrecht, T Vogl, Marc Raaijmakers

Research output: Contribution to journalArticleAcademic

257 Citations (Scopus)

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.
Original languageUndefined/Unknown
Pages (from-to)613-627
Number of pages15
JournalCell Stem Cell
Volume19
Issue number5
DOIs
Publication statusPublished - 2016

Research programs

  • EMC MGC-01-12-03
  • EMC MM-01-39-02
  • EMC MM-02-41-04
  • EMC MM-03-32-04

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