Mutations in the Fas antigen in patients with multiple myeloma

Terry H Landowski, Ning Qu, Ibrahim Buyuksal, Jeffrey S. Painter, William S. Dalton

Research output: Contribution to journalArticle

207 Citations (Scopus)

Abstract

Programmed cell death, or apoptosis, is well documented as a physiological means of eliminating activated lymphocytes and maintaining immune homeostasis. Apoptosis has also been implicated in the targeting of tumor cells by cytotoxic T lymphocytes and natural killer cells. One of the two primary mechanisms used in cell-mediated cytotoxicity is the Fas/FasLigand system. Activated or transformed cells expressing the Fas antigen on their surface are susceptible to killing by immune effector cells that express the Fas ligand. Many neoplastic cells, including those derived from patients with multiple myeloma, express Fas antigen on their surface, but do not undergo apoptosis in response to antigen crosslinking. One possibility for the lack of Fas-mediated apoptosis includes mutations in the Fas antigen. Loss of function mutations in the Fas antigen have been associated with congenital autoimmune disease in humans, and have been defined as the genetic defect the in Ipr mice. Mutations in the Fas antigen have not been previously described in cancer patients. In this study, we show that mutations occur in the Fas antigen which may cause loss of function and contribute to the pathogenesis of the neoplastic disease, multiple myeloma. Using reverse transcriptase-polymerase chain reaction (RT-PCR), single- stranded conformation polymorphism (SSCP) analysis, and DNA sequencing, we examined the cDNA structure of the Fas antigen in 54 hone marrow (BM) specimens obtained from myeloma patients. Six patient specimens (11%) did not express detectable levels of Fas antigen mRNA. Of the 48 BM specimens which did express Fas antigen, 5 (10%) displayed point mutations. All of the mutations identified were located in the cytoplasmic region of the Fas antigen known to be involved in transduction of an apoptotic signal. Two separate individuals demonstrated an identical mutation at a site previously shown to be mutated in the congenital autoimmune syndrome, ALPS. One patient exhibited a point mutation at a site only two amino acids removed from the documented lesion of the Ipr(cg) mouse. Although the functional status of these point mutations remains to be determined, we propose that Fas antigen mutations may contribute to the pathogenesis and progression of myeloma in some patients.

Original languageEnglish (US)
Pages (from-to)4266-4270
Number of pages5
JournalBlood
Volume90
Issue number11
StatePublished - Dec 1 1997
Externally publishedYes

Fingerprint

CD95 Antigens
Multiple Myeloma
Mutation
Point Mutation
Apoptosis
Cells
Fas Ligand Protein
T-cells
Lymphocytes
Polymerase chain reaction
RNA-Directed DNA Polymerase
Cytotoxic T-Lymphocytes
Cell death
Cytotoxicity
Polymorphism
Reverse Transcriptase Polymerase Chain Reaction
DNA Sequence Analysis
Natural Killer Cells
Crosslinking
Autoimmune Diseases

ASJC Scopus subject areas

  • Hematology

Cite this

Landowski, T. H., Qu, N., Buyuksal, I., Painter, J. S., & Dalton, W. S. (1997). Mutations in the Fas antigen in patients with multiple myeloma. Blood, 90(11), 4266-4270.

Mutations in the Fas antigen in patients with multiple myeloma. / Landowski, Terry H; Qu, Ning; Buyuksal, Ibrahim; Painter, Jeffrey S.; Dalton, William S.

In: Blood, Vol. 90, No. 11, 01.12.1997, p. 4266-4270.

Research output: Contribution to journalArticle

Landowski, TH, Qu, N, Buyuksal, I, Painter, JS & Dalton, WS 1997, 'Mutations in the Fas antigen in patients with multiple myeloma', Blood, vol. 90, no. 11, pp. 4266-4270.
Landowski TH, Qu N, Buyuksal I, Painter JS, Dalton WS. Mutations in the Fas antigen in patients with multiple myeloma. Blood. 1997 Dec 1;90(11):4266-4270.
Landowski, Terry H ; Qu, Ning ; Buyuksal, Ibrahim ; Painter, Jeffrey S. ; Dalton, William S. / Mutations in the Fas antigen in patients with multiple myeloma. In: Blood. 1997 ; Vol. 90, No. 11. pp. 4266-4270.
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abstract = "Programmed cell death, or apoptosis, is well documented as a physiological means of eliminating activated lymphocytes and maintaining immune homeostasis. Apoptosis has also been implicated in the targeting of tumor cells by cytotoxic T lymphocytes and natural killer cells. One of the two primary mechanisms used in cell-mediated cytotoxicity is the Fas/FasLigand system. Activated or transformed cells expressing the Fas antigen on their surface are susceptible to killing by immune effector cells that express the Fas ligand. Many neoplastic cells, including those derived from patients with multiple myeloma, express Fas antigen on their surface, but do not undergo apoptosis in response to antigen crosslinking. One possibility for the lack of Fas-mediated apoptosis includes mutations in the Fas antigen. Loss of function mutations in the Fas antigen have been associated with congenital autoimmune disease in humans, and have been defined as the genetic defect the in Ipr mice. Mutations in the Fas antigen have not been previously described in cancer patients. In this study, we show that mutations occur in the Fas antigen which may cause loss of function and contribute to the pathogenesis of the neoplastic disease, multiple myeloma. Using reverse transcriptase-polymerase chain reaction (RT-PCR), single- stranded conformation polymorphism (SSCP) analysis, and DNA sequencing, we examined the cDNA structure of the Fas antigen in 54 hone marrow (BM) specimens obtained from myeloma patients. Six patient specimens (11{\%}) did not express detectable levels of Fas antigen mRNA. Of the 48 BM specimens which did express Fas antigen, 5 (10{\%}) displayed point mutations. All of the mutations identified were located in the cytoplasmic region of the Fas antigen known to be involved in transduction of an apoptotic signal. Two separate individuals demonstrated an identical mutation at a site previously shown to be mutated in the congenital autoimmune syndrome, ALPS. One patient exhibited a point mutation at a site only two amino acids removed from the documented lesion of the Ipr(cg) mouse. Although the functional status of these point mutations remains to be determined, we propose that Fas antigen mutations may contribute to the pathogenesis and progression of myeloma in some patients.",
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AB - Programmed cell death, or apoptosis, is well documented as a physiological means of eliminating activated lymphocytes and maintaining immune homeostasis. Apoptosis has also been implicated in the targeting of tumor cells by cytotoxic T lymphocytes and natural killer cells. One of the two primary mechanisms used in cell-mediated cytotoxicity is the Fas/FasLigand system. Activated or transformed cells expressing the Fas antigen on their surface are susceptible to killing by immune effector cells that express the Fas ligand. Many neoplastic cells, including those derived from patients with multiple myeloma, express Fas antigen on their surface, but do not undergo apoptosis in response to antigen crosslinking. One possibility for the lack of Fas-mediated apoptosis includes mutations in the Fas antigen. Loss of function mutations in the Fas antigen have been associated with congenital autoimmune disease in humans, and have been defined as the genetic defect the in Ipr mice. Mutations in the Fas antigen have not been previously described in cancer patients. In this study, we show that mutations occur in the Fas antigen which may cause loss of function and contribute to the pathogenesis of the neoplastic disease, multiple myeloma. Using reverse transcriptase-polymerase chain reaction (RT-PCR), single- stranded conformation polymorphism (SSCP) analysis, and DNA sequencing, we examined the cDNA structure of the Fas antigen in 54 hone marrow (BM) specimens obtained from myeloma patients. Six patient specimens (11%) did not express detectable levels of Fas antigen mRNA. Of the 48 BM specimens which did express Fas antigen, 5 (10%) displayed point mutations. All of the mutations identified were located in the cytoplasmic region of the Fas antigen known to be involved in transduction of an apoptotic signal. Two separate individuals demonstrated an identical mutation at a site previously shown to be mutated in the congenital autoimmune syndrome, ALPS. One patient exhibited a point mutation at a site only two amino acids removed from the documented lesion of the Ipr(cg) mouse. Although the functional status of these point mutations remains to be determined, we propose that Fas antigen mutations may contribute to the pathogenesis and progression of myeloma in some patients.

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