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- Title
Alloreactive microenvironment after human hematopoietic cell transplantation induces genomic alterations in epithelium through an ROS-mediated mechanism: in vivo and in vitro study and implications to secondary neoplasia.
- Authors
Themeli, M; Petrikkos, L; Waterhouse, M; Bertz, H; Lagadinou, E; Zoumbos, N; Finke, J; Spyridonidis, A
- Abstract
We hypothesized that chronic tissue stress due to interaction of alloreactive donor cells with host epithelium after allogeneic hematopoietic cell transplantation (allo-HCT) may cause genomic alterations. We therefore analyzed 176 buccal samples obtained from 71 unselected allotransplanted patients for microsatellite instability (MSI). MSI was observed in 52% of allotransplanted patients but never in 31 healthy or autotransplanted controls. The patient age, the donor age, a female-to-male transplantation and a low number of CD34+ cells in the graft were significantly correlated with genomic instability. There was a trend for increasing risk of MSI for patients who experienced severe graft-vs-host disease. Secondary malignancy was diagnosed in five (14%) of the MSI+ and only in one (3%) MSI− patient. In an in vitro model of mutation analysis we found significant induction of frameshift mutations and DNA strand breaks in HaCaT keratinocytes co-cultured with mixed lymphocyte cultures (MLCs) but not after their exposure to interferon-γ, tumor necrosis factor-α, transforming growth factor-β (TGF-β), MLC supernatant, peripheral blood mononuclear cells (PBMCs) or phytohemagglutinin-stimulated PBMC. A reactive oxygen species-mediated mechanism is implicated. The in vivo and in vitro data of our study show that alloreactions after allo-HCT may induce genomic alterations in epithelium. Progress in understanding DNA damage and repair after allo-HCT can potentially provide molecular biomarkers and therapeutic targets.
- Subjects
TRANSPLANTATION of organs, tissues, etc.; EPITHELIUM; TISSUES; CELL transplantation; TUMOR necrosis factors; TRANSFORMING growth factors; ORGAN donation; GENETIC mutation
- Publication
Leukemia (08876924), 2010, Vol 24, Issue 3, p536
- ISSN
0887-6924
- Publication type
Article
- DOI
10.1038/leu.2009.284