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

Stephen E. Straus, Elaine S. Jaffe, Jennifer M. Puck, Janet K. Dale, Keith B. Elkon, Angela Rösen-Wolff, Anke M J Peters, Michael C. Sneller, Claire W. Hallahan, Jin Wang, Roxanne E. Fischer, Christine M. Jackson, Albert Y. Lin, Caroline Bäumler, Elke Siegert, Alexander Marx, Akshay K. Vaishnaw, Tamara Grodzicky, Thomas A. Fleisher, Michael J. Lenardo

Research output: Contribution to journalArticle

335 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)194-200
Number of pages7
JournalBlood
Volume98
Issue number1
DOIs
StatePublished - Jul 1 2001

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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