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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4424-4428.
Prepublished online as a Blood First Edition Paper on February 22, 2005; DOI 10.1182/blood-2004-04-1477.
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Submitted April 23, 2004
Accepted January 31, 2005
A proportion of patients with lymphoma may harbor mutations of the perforin gene
Rita Clementi*, Franco Locatelli, Loic Dupre, Alberto Garaventa, Lorenzo Emmi, Marco Bregni, Graziella Cefalo, Antonia Moretta, Cesare Danesino, Margherita Comis, Andrea Pession, Ugo Ramenghi, Rita Maccario, Maurizio Arico, and Maria G Roncarolo
Medical Genetics, University of Pavia and IRCCS Policlinico San Matteo, Pavia, Italy
Pediatric Haematology-Oncology, IRCCS Policlinico San Matteo, Pavia, Italy
HSR-TIGET, San Raffaele Telethon Institute for Gene Therapy, Milan, Italy
Unit of Haematology and Oncology, G. Gaslini Institute, Genova, Italy
Department of Internal Medicine, University of Florence, Florence, Italy
Division of Haematology and Bone Marrow Transplantation Unit, San Raffaele Institute, Milano, Italy
Department of Pediatrics, National Institute for Cancer Study and Care, Milano, Italy
Department of Hematology, Azienda Ospedaliera 'Bianchi-Malacrino-Morelli', Reggio Calabria, Italy
Department of Pediatrics, Ospedale Sant'Orsola, University of Bologna, Bologna, Italy
Department of Pediatrics, Ospedale Regina Margherita, University of Turin, Turin, Italy
Pediatric Hematology-Oncology, Ospedale dei Bambini 'G. Di Cristina', Palermo, Italy
* Corresponding author; email: rita.clementi{at}hsr.it.
Perforin mutations have been demonstrated in a proportion of patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH). In the present study, we evaluated whether some patients with lymphoma sharing clinical characteristics with HLH might harbor mutations of the perforin gene. We analysed 29 patients and we found that 4 patients, who developed either Hodgkin or non-Hodgkin lymphoma, had bi-allelic mutations of the perforin gene. One of these 4 patients, a 19-year-old female with T-cell lymphoma, had a brother, carrying the same mutations, who developed HLH. In 2 out of the 4 patients with bi-allelic mutations of the perforin gene, we evaluated perforin expression by flow-cytometry and natural killer (NK) activity, and both were found to be absent. Moreover, we documented the presence of mono-allelic mutations of the perforin gene in 4 more patients. One of these 4 latter patients also carried a mutation of the Fas gene. These data indicate that perforin deficiency, either alone or in combination with other mutations of genes involved in lymphocyte survival or functional activity, may be present in patients with lymphoma. These findings suggest that perforin plays a key role also in the mechanisms of immune-surveillance that prevent tumor growth and/or development.
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