THE GIX SYSTEM A CELL SURFACE ALLO-ANTIGEN ASSOCIATED WITH MURINE LEUKEMIA VIRUS; IMPLICATIONS REGARDING CHROMOSOMAL INTEGRATION OF THE VIRAL GENOME

This report concerns a cell surface antigen (GIX; G = Gross) which exhibits mendelian inheritance but which also appears de novo in cells that become productively infected with MuLV (Gross), the wild-type leukemia virus of the mouse. In normal mice, GIX is a cell surface allo-antigen confined to lymphoid cells and found in highest amount on thymocytes. Four categories of inbred mouse strains can be distinguished according to how much GIX antigen is expressed on their thymocytes. GIX- strains have none; in the three GIX+ categories, GIX3, GIX2, and GIX1, the amounts of GIX antigen present (per thymocyte) are approximately in the ratios 3:2:1. A study of segregating populations derived mainly from strain 129 (the prototype GIX3 strain) and C57BL/6 (the prototype GIX- strain) revealed that two unlinked chromosomal genes are required for expression of GIX on normal lymphoid cells. The phenotype GIX+ is expressed only when both genes are present, as in 129 mice. C57BL/6 carries neither of them. At one locus, expression of GIX is fully dominant over nonexpression (GIX fully expressed in heterozygotes). At the second locus, which is linked with H-2 (at a distance of 36.4 ± 2.7 units) in group IX (locus symbol GIX), expression is semidominant (50% expression of GIX in heterozygotes); gene order T:H-2:Tla:GIX. As a rule, when cells of GIX- mice or rats become overtly infected with MuLV (Gross), an event which occurs spontaneously in older mice of certain strains and which also commonly accompanies malignant transformation, their phenotype is converted to GIX+. This invites comparison with the emergence of TL+ leukemia cells in TL- mouse strains which has been observed in previous studies and which implies that TL- → TL+ conversion has accompanied leukemic transformation of such cells. So far the only example of GIX- → GIX+ conversion taking place without overt MuLV infection is represented by the occurrence of GCSA-:GIX+ myelomas in BALB/c (GCSA:GIX-) mice. Unlike the other Gross cell surface antigen described earlier, GCSA, which is invariably associated with MuLV (Gross) infection and never occurs in its absence, GIX antigen sometimes occurs independently of productive MuLV infection; for example, thymocytes and some leukemias of 129 mice are GCSA-:GIX+, and MuLV-producing sarcomas may be GCSA+:GIX-. The frequent emergence of cells of GIX+ phenotype in all mouse strains implies that the structural gene coding for GIX antigen is common to all mice. There is precedent for this in the TL system, in which two of the Tla genes in linkage group IX appear to be ubiquitous among mice, but are normally expressed only in strains of mice carrying a second (expression) gene. It is not yet certain whether either of the two segregating genes belongs to the MuLV genome rather than to the cellular genome. This leaves the question whether MuLV may have a chromosomal integration site still debatable. But there is a good prospect that further genetic analysis will provide the answer and so elucidate the special relationship of leukemia viruses to the cells of their natural hosts.