Analysis of V -J expression in plasma cells from primary (AL) amyloidosis and normal bone marrow identifies 3r ( III) as a new amyloid-associated germline gene segment

Primary (AL) amyloidosis is a plasma cell dyscrasia characterized by extracellular deposition of monoclonal light-chain variable region (V) fragments in the form of amyloid fibrils. Light-chain amyloid is rare, and it is not fully understood why it occurs in only a fraction of patients with a circulating monoclonal component and why it typically associates with isotype and VI family light-chain proteins. To provide insights into these issues, we obtained complete nucleotide sequences of monoclonal V regions from 55 consecutive unselected cases of primary amyloidosis and the results were compared with the light-chain expression profile of polyclonal marrow plasma cells from 3 healthy donors (a total of 264 sequences). We demonstrated that: (1) the III family is the most frequently used both in amyloidosis (47%) and in polyclonality (43%); (2) both conditions are characterized by gene restriction; (3) a very skewed repertoire is a feature of amyloidosis, because just 2 germline genes belonging to the III and VI families, namely 3r (22% of cases, III) and 6a (20%, VI), contributed equally to encode 42% of amyloid V regions; (4) these same 2 gene segments have a strong association with amyloidosis if their prevalences are compared with those in polyclonal conditions (3r, 8.3%, P .024; 6a, 2.3%, P .0008, 2 test); (5) the J 2/3 segment, encoding the fourth framework region, appears to be slightly overrepresented in AL (83% versus 67%, P .03), and this might be related to preferential J 2/3 rearrangement in amyloid (11 of 12 cases) versus polyclonal 3r light chains (13 of 22 cases). These findings demonstrate that V -J expression is more restricted in plasma cells from amyloidosis than from polyclonal bone marrow and identify 3r as a new disease-associated gene segment. Overusage of just 2 gene segments, 3r and 6a, can thus account for the light-chain overrepresentation typical of this disorder. (Blood. 2002;100: 948-953)