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

M. Themeli, L. Petrikkos, M. Waterhouse, H. Bertz, E. Lagadinou, N. Zoumbos, J. Finke, A. Spyridonidis*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)536-543
Number of pages8
JournalLeukemia
Volume24
Issue number3
DOIs
Publication statusPublished - Mar 2010

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