RAPID COMMUNICATION Mutations in the Fas Antigen in Patients With Multiple Myeloma

Programmed cell death, or apoptosis, is well documented as eloma. Using reverse transcriptase-polymerase chain reaca physiological means of eliminating activated lymphocytes tion (RT-PCR), single-stranded conformation polymorphism and maintaining immune homeostasis. Apoptosis has also (SSCP) analysis, and DNA sequencing, we examined the been implicated in the targeting of tumor cells by cytotoxic T cDNA structure of the Fas antigen in 54 bone marrow (BM) lymphocytes and natural killer cells. One of the two primary specimens obtained from myeloma patients. Six patient mechanisms used in cell-mediated cytotoxicity is the Fas/ specimens (11%) did not express detectable levels of Fas FasLigand system. Activated or transformed cells expressing antigen mRNA. Of the 48 BM specimens which did express the Fas antigen on their surface are susceptible to killing Fas antigen, 5 (10%) displayed point mutations. All of the by immune effector cells that express the Fas ligand. Many mutations identified were located in the cytoplasmic region neoplastic cells, including those derived from patients with of the Fas antigen known to be involved in transduction of multiple myeloma, express Fas antigen on their surface, but an apoptotic signal. Two separate individuals demonstrated do not undergo apoptosis in response to antigen crosslinkan identical mutation at a site previously shown to be muing. One possibility for the lack of Fas-mediated apoptosis tated in the congenital autoimmune syndrome, ALPS. One includes mutations in the Fas antigen. Loss of function mutapatient exhibited a point mutation at a site only two amino tions in the Fas antigen have been associated with congeniacids removed from the documented lesion of the lpr tal autoimmune disease in humans, and have been defined mouse. Although the functional status of these point mutaas the genetic defect the in lpr mice. Mutations in the Fas tions remains to be determined, we propose that Fas antigen antigen have not been previously described in cancer pamutations may contribute to the pathogenesis and progrestients. In this study, we show that mutations occur in the sion of myeloma in some patients. Fas antigen which may cause loss of function and contribute q 1997 by The American Society of Hematology. to the pathogenesis of the neoplastic disease, multiple my-