FREQUENT SOMATIC MUTATIONS IN D-SEGMENTS AND OR JH-SEGMENTS OF IG GENE IN WALDENSTROMS MACROGLOBULINEMIA AND CHRONIC LYMPHOCYTIC-LEUKEMIA (CLL) WITH RICHTERS-SYNDROME BUT NOT IN COMMON CLL/

V(D)J recombination and somatic hypermutations are developmentally reg ulated during B-cell differentiation; therefore, DNA analysis of the l g gene delineates the cellular origin of B-cell neoplasms. We analyzed the third complementarity-determining region and adjacent regions of the lg heavy-chain gene of tumor cells from 7 patients with Waldenstro m's macroglobulinemia (WM) and from 10 patients with B-cell chronic ly mphocytic leukemia (CLL), 2 of whom progressed to high-grade non-Hodgk in's lymphoma (NHL), ie, Richter's syndrome (RS). There were no intrac lonal variations resulting from VH replacements or ongoing somatic mut ations in both WM and CLL, We found replacement mutations in the D and /or JH segments in all patients with WM and in 4 of the 10 patients wi th CLL, including the 2 RS patients. Replacement mutations were cluste red in codon 102 of the JH segment. Preferential utilization of the JH 4 gene was found in WM (5 of 7 [71.4%]) and in CLL (7 of 10 [70.0%]), and DXP family genes in CLL (5 of 10 [50.0%]). In conclusion, WM and C LL with RS are generated under the influence of antigenic stimulation and selection. However, the majority of CLL may arise from a distinct subpopulation that has the restricted repertoire of nonmutated lg gene s. (C) 1995 by The American Society of Hematology.