Defective apoptosis due to a point mutation in the death domain of CD95 associated with autoimmune lymphoproliferative syndrome, T-cell lymphoma, and Hodgkin’s disease

Peters, Anke; Kohfink, Barbara; Martin, Heike; Griesinger, Frank; Wörmann, Bernhard; Gahr, Manfred; Roesler, Joachim

doi:10.1016/s0301-472x(99)00033-8

Cited by 44 publications

(23 citation statements)

References 30 publications

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“…In a limited series of patients with lymphoproliferative disorders associated with Sjö gren's syndrome or type II mixed cryoglobulinemia, no CD95 germline mutations were apparently detected, but only four of the nine exons coding for the gene were analysed. 24 Autoimmune disorders with variable patterns of clinical features can be associated with germline CD95 mutations, 25,26 hence, it might be suggested that lymphomas arising in these patients might be more frequently associated with CD95 mutations. Our results do not confirm the association of CD95 mutations with extranodal lymphomas, and a pathogenic role of CD95 mutations might be limited to the human lymphoproliferative syndrome associated with autoimmune manifestations.…”

Section: Resultsmentioning

confidence: 99%

“…Our results do not confirm the association of CD95 mutations with extranodal lymphomas, and a pathogenic role of CD95 mutations might be limited to the human lymphoproliferative syndrome associated with autoimmune manifestations. [25][26][27] In fact, in marginal zone lymphomas, especially in the extranodal MALT type subset, other anti-apoptosis mechanisms seem to be present and are likely to be more relevant, such as the recently reported fusion protein AP12/MLT determined by the recurrent t(11;18)(q21;q21) chromosomal translocation, which can be detected in approximately one third of the cases of extranodal marginal zone lymphoma. 28 Indeed, the rearrangement of the apoptosis inhibitor gene API-2 may result in a survival advantage for the lymphoma B cell clones.…”

Section: Resultsmentioning

confidence: 99%

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Lack of CD95/FAS gene somatic mutations in extranodal, nodal and splenic marginal zone B cell lymphomas

et al. 2000

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Germline CD95 (also known as FAS, APT1 and APO1) gene mutations have been associated with benign lymphoproliferative diseases and autoimmune processes. Somatic mutations have been reported in human tumours, including lymphomas. Since marginal zone B cell lymphomas usually arise in a background of chronic inflammation, often of autoimmune origin, we searched for CD95 gene mutations in an unselected series of marginal zone B cell lymphomas. The CD95/FAS full coding region, comprising exon-intron junctions, was amplified from genomic DNA by polymerase chain reaction (PCR) in 10 separate reactions. PCR products were analysed by single-strand conformation polymorphism (SSCP) and visualised by silver staining. Bands exhibiting an altered electrophoretic mobility were sequenced. Twenty-seven cases of marginal zone B cell lymphomas of whom fresh or frozen tumour material was available (18 extranodal, five splenic and four nodal) were studied. Previously described silent polymorphisms in exons 7 (C836T) and 3 (T416C) were detected in 42% and in 19% of the cases, respectively. One silent T-to-A substitution at bp 431, within exon 3, was found in one case. Our results did not reveal the presence of CD95 somatic mutations in unselected cases of marginal zone B cell lymphomas. On the basis of our data, we cannot rule out that other genes coding for proteins involved in the CD95-induced apoptotic pathway might be altered. However, this pathway does not seem to play an important role in the pathogenesis of these lymphoma subtypes. Leukemia (2000) 14, 446-448.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Lack of CD95/FAS gene somatic mutations in extranodal, nodal and splenic marginal zone B cell lymphomas

et al. 2000

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“…As for the intracellular region, the five amino acidic changes found (two of them located inside the a3 subdomain of death domain) could alter the interaction of Fas with FADD to form the DISC and trigger the death signal (43). Such assumption is reinforced by an association that has been found between a point mutation in Fas death domain and an autoimmune lymphoproliferative syndrome reported in humans, for both T-cell lymphoma and Hodgkin's disease (44).…”

Section: Discussionmentioning

confidence: 97%

A Role for the Fas/FasL System in Modulating Genetic Susceptibility to T-Cell Lymphoblastic Lymphomas

et al. 2007

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The Fas/FasL system mediates induced apoptosis of immature thymocytes and peripheral T lymphocytes, but little is known about its implication in genetic susceptibility to T-cell malignancies. In this article, we report that the expression of FasL increases early in all mice after ;-radiation treatments, maintaining such high levels for a long time in mice that resisted tumor induction. However, its expression is practically absent in T-cell lymphoblastic lymphomas. Interestingly, there exist significant differences in the level of expression between two mice strains exhibiting extremely distinct susceptibilities that can be attributed to promoter functional polymorphisms. In addition, several functional nucleotide changes in the coding sequences of both Fas and FasL genes significantly affect their biological activity. These results lead us to propose that germ-line functional polymorphisms affecting either the levels of expression or the biological activity of both Fas and FasL genes could be contributing to the genetic risk to develop T-cell lymphoblastic lymphomas and support the use of radiotherapy as an adequate procedure to choose in the treatment of T-cell malignancies.

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“…One FAS gene mutation carrier developed a NLP HL, 4,5 whereas a HL of unknown histologic subtype developed in a mutation carrier of another family. 6 It is of interest that so-called progressively transformed germinal centers (PTGCs) are frequently present in the enlarged lymph nodes of patients with ALPS. 10 PTGCs indeed are considered precursor lesions of NLP HL.…”

Section: Org Frommentioning

confidence: 99%

“…The histologic subtype of this case was not reported. 6 Based on this, the question has arisen whether there is a relationship between FAS gene mutation and the occurrence of NLP HL. We report data on a 15-year-old boy with symptoms consistent with ALPS, a mutation in exon 9 of the FAS gene, and an axillary lymph node involved by NLP HL.…”

Section: Introductionmentioning

confidence: 99%

Germline FAS gene mutation in a case of ALPS and NLP Hodgkin lymphoma

Berg

Maggio

Diepstra

et al. 2002

Blood

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FAS germline mutations have been associated with the development of autoimmune lymphoproliferative syndrome (ALPS). Occurrence of Hodgkin lymphoma (HL) has been reported in 2 families with ALPS. In both families an uncle of the index patient developed HL. A 15-year-old boy with autoimmune thrombopenia, lymphadenopathy, and splenomegaly for 6 years was studied. In an axillary lymph node biopsy nodular lymphocyte predominant (NLP) HL was diagnosed; in the areas between the nodules a proliferation of double-negative blastic T cells were present, suggestive of ALPS. Analysis for the presence of a FAS gene mutation using the denaturing gradient gel electrophoresis technique indicated a mutation in exon 9. Direct sequence analysis revealed a mutation causing a substitution of arginine with glutamine at codon 234. Because ALPS and NLP HL are both highly infrequent conditions, the occurrence in at least 3 families suggests a causative relationship between germline FAS gene mutations and NLP HL. (Blood.

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Defective apoptosis due to a point mutation in the death domain of CD95 associated with autoimmune lymphoproliferative syndrome, T-cell lymphoma, and Hodgkin’s disease

Cited by 44 publications

References 30 publications

Lack of CD95/FAS gene somatic mutations in extranodal, nodal and splenic marginal zone B cell lymphomas

Lack of CD95/FAS gene somatic mutations in extranodal, nodal and splenic marginal zone B cell lymphomas

A Role for the Fas/FasL System in Modulating Genetic Susceptibility to T-Cell Lymphoblastic Lymphomas

Germline FAS gene mutation in a case of ALPS and NLP Hodgkin lymphoma

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