Fas gene mutations in mycosis fungoides: analysis of laser capture-microdissected specimens from cutaneous lesions.
Fas (APO-1/CD95) is a transmembrane protein which mediates programmed cell death (apoptosis). Cells with a mutated Fas gene are resistant to apoptosis and thus accumulate in lesional tissues. This might provide a basis for the development of neoplasias. Genomic DNA selectively obtained from Pautrier's microabscesses in 16 cases of mycosis fungoides (MF) using a laser capture microdissection method was analyzed. Fas gene mutations were detected in 3 of 16 cases of MF (18.8%); 1 was silent and 2 were missense mutations located in exon 9. One of the 2 missense mutations involved the death domain of the Fas gene, which is essential for apoptotic signal transduction. The missense mutations resulted in the substitution of Ala with Asp at codon 220 and Ile with Thr at codon 314. Mouse T cell lymphoma cells transfected with mutant genes were resistant to apoptosis induced by the anti-Fas antibody, indicating that the missense mutations found in MF were loss-of-function mutations, thus causing the accumulation of cells in the cutaneous lesions. These findings suggest that the accumulation of lymphoid cells with Fas mutations provides, in part, a basis for the development or maintenance of MF.
Nagasawa
Tomohiko
T
Department of Pathology, Osaka University Medical School, Osaka, Japan.
Takakuwa
Tetsuya
T
Takayama
Hitoshi
H
Dong
Zhiming
Z
Miyagawa
Sachiko
S
Itami
Satoshi
S
Yoshikawa
Kunihiko
K
Aozasa
Katsuyuiki
K
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000409:Alanine; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001224:Aspartic Acid; D002352:Carrier Proteins / Q000235:genetics*; D056970:Co-Repressor Proteins; D003062:Codon / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007532:Isoleucine; D053685:Laser Therapy; D016399:Lymphoma, T-Cell / Q000235:genetics; D008297:Male; D051379:Mice; D042282:Microdissection / Q000379:methods; D008875:Middle Aged; D018832:Molecular Chaperones; D020125:Mutation, Missense; D009182:Mycosis Fungoides / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D013912:Threonine; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D056970:Co-Repressor Proteins; D003062:Codon; C106985:DAXX protein, human; D004273:DNA, Neoplasm; C491473:Daxx protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D007532:Isoleucine; D013912:Threonine; D001224:Aspartic Acid; D000409:Alanine