The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis

Lymphomas were studied in kindreds with autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome), a disorder of lymphocyte homeostasis usually associated with germline Fas mutations. Fas (CD95/APO-1) is a cell surface receptor that initiates programmed cell death, or apoptosis, of activ...

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Published in:	Blood 2001-07, Vol.98 (1), p.194-200
Main Authors:	Straus, Stephen E., Jaffe, Elaine S., Puck, Jennifer M., Dale, Janet K., Elkon, Keith B., Rösen-Wolff, Angela, Peters, Anke M.J., Sneller, Michael C., Hallahan, Claire W., Wang, Jin, Fischer, Roxanne E., Jackson, Christine M., Lin, Albert Y., Bäumler, Caroline, Siegert, Elke, Marx, Alexander, Vaishnaw, Akshay K., Grodzicky, Tamara, Fleisher, Thomas A., Lenardo, Michael J.
Format:	Article
Language:	eng
Subjects:	Adult Apoptosis - drug effects Apoptosis - genetics Autoimmune Diseases - complications Autoimmune Diseases - genetics Biological and medical sciences Child Family Health fas Receptor - genetics fas Receptor - pharmacology Female Germ-Line Mutation Hematologic and hematopoietic diseases Humans Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphocytes - pathology Lymphoma - etiology Lymphoma - genetics Lymphoproliferative Disorders - complications Lymphoproliferative Disorders - genetics Male Medical sciences Middle Aged Syndrome
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Summary:	Lymphomas were studied in kindreds with autoimmune lymphoproliferative syndrome (ALPS; Canale-Smith syndrome), a disorder of lymphocyte homeostasis usually associated with germline Fas mutations. Fas (CD95/APO-1) is a cell surface receptor that initiates programmed cell death, or apoptosis, of activated lymphocytes. Lymphoma phenotype was determined by immunohistochemistry, frequency of CD3+CD4−CD8− T-cell–receptor α/β cells by flow cytometry, nucleotide sequences of the gene encoding Fas (APT1, TNFRSF6), and the percentage of lymphocytes undergoing apoptosis in vitro. Of 223 members of 39 families, 130 individuals possessed heterozygous germline Fas mutations. Eleven B-cell and T-cell lymphomas of diverse types developed in 10 individuals with mutations in 8 families, up to 48 years after lymphoproliferation was first documented. Their risk of non-Hodgkin and Hodgkin lymphomas, respectively, was 14 and 51 times greater than expected (each P < .001). Investigation of these 10 patients and their relatives with Fas mutations revealed that all had defective lymphocyte apoptosis and most had other features of ALPS. The tumor cells retained the heterozygous Fas mutations found in the peripheral blood and manifested defective Fas-mediated killing. These data implicate a role for Fas-mediated apoptosis in preventing B-cell and T-cell lymphomas. Inherited defects in receptor-mediated lymphocyte apoptosis represent a newly appreciated risk factor for lymphomas.
ISSN:	0006-4971 1528-0020