Strikingly homologous immunoglobulin gene rearrangements and poor outcome inVH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status

We recently reported that Swedish V(H)3-21-using chronic lymphocytic leukemia (CLL) patients showed restricted immunoglobulin gene features and poor prognosis despite V-H mutation status. To investigate this further, we analyzed the V-H and V-L gene rearrangements in 90 V(H)3-21(+) patients from Sweden, Germany, Italy, United States, Finland, and Australia and correlated these data with survival and other prognostic markers. Sixty-three percent exhibited mutated V-H genes and 37% unmutated V-H genes. Fifty (56%) patients displayed a short and homologous heavy-chain CDR3, many of these with the amino acid motif DANGMDV. Also, a highly biased V(lambda)2-14 use was evident in 72% of patients with a restricted light-chain CDR3, QVWDS(S/G)SDHPWV. Combined restricted heavy- and light-chain CDR3s were found in patients from all included countries. Although V(H)3-21(+) CLILs have a remarkably predominant X expression, analyses of kappa deleting element indicated a conserved light-chain rearrangement order. The overall survival was poor in the V(H)3-21(+) cohort (median survival, 88 months), with no significant difference in relation to mutation status or CDR3 homology. High ZAP-70 and CD38 expression was found in both mutated and unmutated VH3-21(+) cases as well as a slight increase of 11q- aberrations. In summary, highly restricted B-cell receptors and worse outcome characterize VH3-21(+) CLLs independent of geographic origin and mutation status.