Strikingly Homologous Immunoglobulin Gene Rearrangements and Poor Outcome in V_H3-21-Utilizing Chronic Lymphocytic Leukemia Independent of Geographical Origin and Mutational Status.

We recently reported that Swedish V_H3-21-utilizing chronic lymphocytic leukemia (CLL) patients showed restricted immunoglobulin gene features and poor prognosis despite V_H mutation status. To investigate whether V_H3-21⁺ CLLs have similar characteristics in different parts of the world, we analyzed the V_H and V_L gene rearrangements in 90 patients from Sweden, Germany, Italy, USA, Finland and Australia and correlated these data with survival. Sixty-three percent of cases exhibited mutated V_H genes and 37% had unmutated V_H genes. Fifty patients (56%) displayed a short and homologous heavy-chain CDR3, many of these with the amino acid motif, DANGMDV. Also, a highly biased V_λ2-14 usage was evident in 73% 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_H3-21⁺ CLLs have a remarkably predominant λ-expression, analyses of kappa deleting element showed a conserved rearrangement order of the light-chain loci. The overall survival was poor in the V_H3-21⁺ cohort (median survival 88 months) with no significant difference in relation to mutation status or homologous/non-homologous CDR3. In summary, highly restricted B-cell receptors and worse outcome characterize V_H3-21⁺ CLLs independent of geographical origin and mutation status. V_H3-21 usage should now be included in prognostic stratification of CLL when assessing mutation status.