Mutations in the Fas antigen in patients with multiple myeloma

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 Pas antigen on their surface are susceptible to killing by immune effector cells that express the Pas ligand. Many neoplastic cells, including those derived from patients with multiple myeloma, express Pas antigen on their surface, but do not undergo apoptosis in response to antigen crosslinking. One possibility for the lack of Pas-mediated apoptosis includes mutations in the Pas antigen, Loss of function mutations in the Pas antigen have been associated with congenital autoimmune disease in humans, and have been defined as the genetic defect the in lpr mice. Mutations in the Pas antigen have not been previously described in cancer patients. In this study, we show that mutations occur in the Pas 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 Pas antigen in 54 bone marrow (BM) specimens obtained from myeloma patients. Six patient specimens (11%) did not express detectable levels of Pas antigen mRNA. Of the 48 BM specimens which did express Pas antigen, 5 (10%) displayed point mutations. All of the mutations identified were located in the cytoplasmic region of the Pas 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 lpr(cg) mouse. Although the functional status of these point mutations remains to be determined, we propose that Pas antigen mutations may contribute to the pathogenesis and progression of myeloma in some patients. (C) 1997 by The American Society of Hematology.