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-tomale transplantation and a low number of CD34 þ 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 þ and only in one (3%) MSI À 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-c, tumor necrosis factor-a, transforming growth factor-b (TGF-b), 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.

Genomic instability after allogeneic hematopoietic cell transplantation is frequent in oral mucosa, particularly in patients with a history of chronic graft-versus-host disease, and rare in nasal mucosa

“…A recent report showed that alloreactive microenvironment after HCT induces GI in epithelium through a reactive oxygen species (ROS)-mediated mechanism supports our results. 15 Finally, we have not studied any patients with secondary oral squamous cell malignancy. Faber et al 12 documented GI in 3 of 3 patients with secondary squamous cell malignancy and Themeli et al 15 reported GI in 5 of 6 patients with secondary epithelial cell malignancy.…”

Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study

“…40 In addition, evidence suggests that chronic GVHD induces a chronic inflammatory state, leading to microsatellite instability and frequent genomic alterations in epithelial tissues, predisposing to development of cancers. 41,42 Several reports have shown increased risk of subsequent malignancy associated with chronic GVHD in FA.…”

The impact of inflammatory licensing on heme oxygenase-1–mediated induction of regulatory T cells by human mesenchymal stem cells

“…Furthermore, as MSCs, despite their known hypo-immunogenicity, respond to signals of local and systemic inflammation, we evaluated the effects of the milieu generated by alloactivated lymphocytes on HO-1 expression. 2,7,24 These "prelicensed" MSCs were subsequently assessed with regards to their ability to induce Tregs and to suppress T cells.…”