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

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.

The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications

“…26,73 For instance, in mice, damage-associated molecular pattern (DAMP) molecules S100A8/A9 DAMPs, are shown to activate TLR4 signaling in HSPCs and induce genotoxic stress, a mechanism by which niche cells may cooperate with aberrant HSPCs toward leukemogenic transformation. Notably, S100A8/A9 signaling in mesenchymal niche cells appears to be an independent predictor of disease outcome in human MDS.…”

“…Notably, S100A8/A9 signaling in mesenchymal niche cells appears to be an independent predictor of disease outcome in human MDS. 73 Moreover, S100A9 binding to CD33 is also reported to expand myeloid-derived suppressor cells, which contribute to the development of myelodysplastic phenotypes in mice. 97 Importantly, human myeloid-derived suppressor cells also express CD33 97 and their number correlates with the number of regulatory T cells and disease progression in MDS patients.…”

The bone marrow microenvironment—driver of leukemia evolution?

“…Next, Zambetti and colleagues analyzed the HSPCs and found that while their numbers were unaffected the transcriptional profile was similar to profiles associated with leukemic evolution of human CD34+ cells, specifically pathways linked to mitochondrial abnormalities were triggered (8). Further analysis of mitochondria found increased membrane potential leading to increased levels of reactive oxygen species (ROS); which activated DNA damage response and repair pathways indicated by accumulation of Ser139-phosphorylated H2AX histone (γH2AX) (8). Depletion of S-phase cells indicated cell cycle arrest at G1-S.…”

“…Recently, Zambetti and colleagues identified the mechanism by which deletion of Sbds in this SDS mouse model causes disease. They found that increased inflammatory signals in the microenvironment caused genotoxic stress in both the mouse model and SDS patient samples (8).…”

“…By detailed characterization of the skeletal system in the SDS model Zambetti and colleagues were able to define a skeletal phenotype with reduced growth, trabecular area and bone volume recapitulating the human disease (8). Interestingly, they observed an increase in the mesenchymal progenitor pool and found by transcriptional profiling that these progenitors where impaired to differentiate into matrix depositing osteoblast, leading to the observed phenotype.…”