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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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IMMUNOBIOLOGY
A proportion of patients with lymphoma may harbor mutations of the perforin gene
Rita Clementi,
Franco Locatelli,
Loïc Dupré,
Alberto Garaventa,
Lorenzo Emmi,
Marco Bregni,
Graziella Cefalo,
Antonia Moretta,
Cesare Danesino,
Margherita Comis,
Andrea Pession,
Ugo Ramenghi,
Rita Maccario,
Maurizio Aricò, and
Maria Grazia Roncarolo
From Medical Genetics, University of Pavia and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Pavia, Italy; Pediatric Haematology-Oncology IRCCS Policlinico San Matteo, Pavia, Italy; Hospital San Raffaele (HSR)-Telethon Institute for Gene Therapy (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, Milan, 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; and Pediatric Hematology-Oncology Ospedale dei Bambini "G. Di Cristina," Palermo, Italy.
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 analyzed 29 patients and found that 4 patients, who developed either Hodgkin or non-Hodgkin lymphoma, had biallelic 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 of the 4 patients with biallelic 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 monoallelic 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 also plays a key role in the mechanisms of immune surveillance that prevent tumor growth and/or development.
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