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

被引:327
作者
Straus, SE
Jaffe, ES
Puck, JM
Dale, JK
Elkon, KB
Rösen-Wolff, A
Peters, AMJ
Sneller, MC
Hallahan, CW
Wang, J
Fischer, RE
Jackson, CM
Lin, AY
Bäumler, C
Siegert, E
Marx, A
Vaishnaw, AK
Grodzicky, T
Fleisher, TA
Lenardo, MJ
机构
[1] NIAID, LCI, NIH, Bethesda, MD 20892 USA
[2] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA
[3] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA
[4] NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA
[5] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA
[6] Natl Human Genome Res Inst, Ctr Clin, Dept Clin Pathol, Serv Immunol,NIH, Bethesda, MD USA
[7] Natl Human Genome Res Inst, Genet & Mol Biol Branch, NIH, Bethesda, MD USA
[8] Cornell Univ, Weill Med Coll, Dept Med, New York, NY USA
[9] Tech Univ Dresden, Kinderklin, D-8027 Dresden, Germany
[10] Lab Klin Forsch, Dresden, Germany
[11] Univ Freiburg, Childrens Hosp, Freiburg, Germany
[12] Univ Wurzburg, Inst Pathol, D-8700 Wurzburg, Germany
关键词
D O I
10.1182/blood.V98.1.194
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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) isa ceil 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 alpha/beta 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 represents newly appreciated risk factor for lymphomas, (C) 2001 by The American Society of Hematology.
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收藏
页码:194 / 200
页数:7
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