Expression of Receptor Tyrosine Kinases RON and c-Met in Post-Transplant Lymphoproliferative Disorders
Elizabeth Wey, Farah Keyoumarsi, Lauren Smith, Dafydd Thomas, Kojo Elenitoba-Johnson, Megan Lim. University of Michigan, Ann Arbor, MI
Background: RON and c-Met are receptor tyrosine kinases that participate in the development of epithelium. Overexpression of RON is observed in human carcinomas and in Hodgkin and non-Hodgkin lymphoma. This has led to the development of dual RON/c-Met inhibitors for clinical studies.
Post-transplant lymphoproliferative disorders (PTLD) are a heterogeneous group of lymphoid proliferations with varying pathogenetic mechanisms. Epstein-Barr virus (EBV) is central to the development of the majority of PTLD. EBV encoded proteins interact with host factors involved in cellular proliferation, differentiation and survival. The latent membrane protein 1 (LMP1) regulates RON expression, leading to enhanced B cell proliferation.
To identify therapeutic targets in PTLD, we evaluated the prevalence of RON and c-Met expression in adult and pediatric PTLD and correlated the results with Epstein Barr encoded RNA1 (EBER-1).
Design: Tissue microarrays were constructed using material from the University of Michigan. Among pediatric and adult PTLD (n=36), 24 were monomorphic, 7 were polymorphic, and 5 were early lesions. Immunohistochemistry was performed with specific antibodies to RON and c-Met. Cases with moderate to strong cytoplasmic expression of either RON or c-Met were considered positive. EBV status was interrogated by EBV in situ hybridization (EBER-1). Reactive tonsils were used as control tissues. Fisher's exact test was used to determine statistical significance.
Results: Overall, 6/36 cases expressed RON while 8/36 cases expressed c-Met. The expression of RON and c-Met were observed more frequently in pediatric PTLD compared to adult. Among monomorphic PTLD, 3/24 cases expressed both RON and c-Met, and 4/24 cases expressed only c-Met. All of the monomorphic PTLD cases that were positive for RON were also positive for c-Met. A statistically significant correlation was observed between RON and c-Met in monomorphic PTLD (p<0.02). EBER-1 was more frequently expressed in pediatric PTLD. There were no statistically significant associations between EBER-1 and RON/c-Met.
|Pediatric PTLD||21% (5/24)||29% (7/24)||75% (18/24)|
|Adult PTLD||8% (1/12)||8% (1/12)||33% (4/12)|
|Total||17% (6/36)||22% (8/36)||61% (22/36)|