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.
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-gamma, tumor necrosis factor-alpha, transforming growth factor-beta (TGF-beta), 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.
authors.affiliation: Hematology Division, Department of Internal Medicine, Patras University Medical School, Patras, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Themeli
authors.forename: L
authors.initials: L
authors.lastname: Petrikkos
authors.forename: M
authors.initials: M
authors.lastname: Waterhouse
authors.forename: H
authors.initials: H
authors.lastname: Bertz
authors.forename: E
authors.initials: E
authors.lastname: Lagadinou
authors.forename: N
authors.initials: N
authors.lastname: Zoumbos
authors.forename: J
authors.initials: J
authors.lastname: Finke
authors.forename: A
authors.initials: A
authors.lastname: Spyridonidis
mesh_terms: D000328:Adult; D000368:Aged; D004848:Epithelium / Q000378:metabolism*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000209:etiology* / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014184:Transplantation, Homologous
chemical_list: D017382:Reactive Oxygen Species