BCL-6 GENE-MUTATIONS IN POSTTRANSPLANTATION LYMPHOPROLIFERATIVE DISORDERS PREDICT RESPONSE TO THERAPY AND CLINICAL OUTCOME

Posttransplantation lymphoproliferative disorders (PT-LPDs) represent a heterogeneous group of Epstein-Barr virus-associated lymphoid prolif erations that arise in immunosuppressed transplant recipients. Some of these lesions regress after a reduction in immunosuppressive therapy, whereas some progress despite aggressive therapy. Morphological, immu nophenotypic, and immunogenotypic criteria have not been useful in pre dicting clinical outcome. Although structural alterations in oncogenes and/or tumor suppressor genes identified in some PT-LPDs correlate wi th a poor clinical outcome, the presence of these alterations has not been a consistently useful predictor of lesion regression after reduct ion of immunosuppression. We examined 57 PT-LPD lesions obtained from 36 solid organ transplant recipients for the presence of mutations in the BCL-6 proto-oncogene using single-strand conformation polymorphism and sequence analysis, followed by correlation with histopathologic c lassification and clinical outcome, which was known in 33 patients. BC L-6 gene mutations were identified in 44% of the specimens and in 44% of the patients; none were identified in the cases classified as plasm acytic hyperplasia. However, mutations were present in 43% of the poly morphic lesions and 90% of the PT-LPDs diagnosed as non-Hodgkin's lymp homa or multiple myeloma. BCL-6 gene mutations predicted shorter survi val and refractoriness to reduced immunosuppression and/or surgical ex cision, Our results suggest that the BCL-6 gene structure is a reliabl e indicator for the division of PT-LPDs into the biological categories of hyperplasia and malignant lymphoma, of which only the former can r egress on immune reconstitution. The presence of BCL-6 gene mutations may be a useful clinical marker to determine whether reduction in immu nosuppression should be attempted or more aggressive therapy should be instituted. (C) 1998 by The American Society of Hematology.