High frequency of somatic mutations in the V-H genes expressed in prolymphocytic leukemia

Prolymphocytic leukemia (PLL) is a chronic lymphoproliferative disorder, characterized by prominent splenomegaly, prolymphocytes accounting for more than 55% of circulating lymphocytes, and short-term survival. To better characterize the nature of the cellular origin in this disease, we analyzed Ig heavy chain variable region (V-H) genes in eleven cases of de novo PLL. Leukemic cells expressed a skewed repertoire characterized by predominant use of the V3 family members (73%), with preferential use of the V3-23 gene (50% of the V(H)3 genes). All sequences from expressed V-H genes diverged from their putative germline counterpart, and in eight cases the divergence was greater than 5%. In seven cases, which expressed the V3-23 gene and V(H)4 family members, nucleotide substitutions could be confidently attributed to somatic mutations. The type and distribution of these mutations clearly indicated that in three cases the cells had been subjected to an antigen selection process. Taken together, these results suggest that B-PLL cells display a skewed repertoire of Ig V-H regions and probably represent, at least in some instances, expansion of postgerminal center cells that have undergone antigen driven selection. (C) 1996 by The American Society of Hematology.