V(H)3-21 gene usage in chronic lymphocytic leukemia--characterization of a new subgroup with distinct molecular features and poor survival

Abstract

During recent years it has become evident that lymphoproliferative diseases of B-cell origin display preferential immunoglobulin (Ig) variable heavy chain (V(H)) gene usage. For instance, the V(H)1-69 and V(H)4-34 genes were early found to be overexpressed in B-cell chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. The implications of biased V(H) gene usage have been speculated to be a result of stimulation of unknown antigens, which gives increased proliferation of B-cells with certain V(H) gene configuration and consequently higher probability to undergo transformation. Thus, V(H) gene usage may play a role in development of leukemias and lymphomas. Recently, we could confirm the over usage of the V(H)1-69 and V(H)4-34 genes in CLL, but a novel finding was that the V(H)3-21 gene was preferentially utilized in CLL patients with mutated V(H) genes. These V(H)3-21+ Ig rearrangements showed molecular peculiarities such as shorter lengths of the third complementarity determining region (CDR) and had similar amino acid composition of their CDR3s, implicating recognition of the same antigen in individual tumors. Most of the V(H)3-21+ patients also showed a predominance of lambda chain expression and biased usage of 1 specific V(lambda) gene, V2-14. Furthermore, overall survival appeared to correlate with V(H)3-21 usage and, regardless of V(H) gene mutation status, V(H)3-21+ patients had a poor outcome. All in all, it appears that V(H)3-21 gene usage define a new entity of CLL. The remaining question now to be clarified is if antigen(s) actually are involved in the pathogenesis of V(H)3-21+ CLL.