LACK OF EXTENSIVE MUTATIONS IN THE V(H)5 GENES USED IN COMMON B-CELL CHRONIC LYMPHOCYTIC-LEUKEMIA

B cell chronic lymphocytic leukemia (CLL) is a malignancy of the CD5+ B cells. Prior studies indicated that CLL B cells generally express immunoglobulin (Ig) V(H) and V(L) genes with little or no somatic mutations. However, a recent report indicated that V(H)251, one of three V(H) genes belonging to the V(H)5 subgroup (e.g., V(H)251, V(H)32, and V(H)15), not only is frequently rearranged in this disease, but also has extensive and selective mutations when expressed by CLL B cells. The extent and nature of these mutations contrasts markedly from the low level of mutations noted in V(H)5 genes used by normal B cells or other Ig V genes found expressed in CLL. To determine whether this difference reflects a unique property of V(H)251 or a previously unrecognized subgroup of CLL, we examined for V(H)5 Ig gene rearrangements in leukemia cells from 68 patients that satisfied clinical and diagnostic criteria for CD5+ B cell CLL. Southern blot hybridization studies with probes for V(H)251 and the J(H) locus revealed that only 7 (10%) of the 68 monoclonal CLL cell populations had undergone Ig gene rearrangement involving V(H)5 genes. Two (3%) were found to have functionally rearranged V(H)5 genes that shared greater-than-or-equal-to 98% sequence homology with 5-2R1, a V(H)251 gene isolated from a pre-B cell acute lymphocytic leukemia. The other five CLL (7%) had functionally rearranged V(H)5 genes that each shared greater-than-or-equal-to 99% nucleic acid sequence homology with a germline V(H)32 isolated from human sperm DNA. These data indicate that V(H)251 or V(H)32 also may be expressed by CD5+ CLL B cells with little or no somatic mutation. These findings contrast with a recently published study on V(H)5 gene expression in B CLL and contest the hypothesis that extensive somatic mutation is a common property of the V(H)5 genes used in this disease. Further work to define the clinical and/or phenotypic characteristics of patients with leukemia cells that express mutated versus nonmutated Ig V genes may reveal subsets of CLL that possibly differ in their cytogenesis, etiopathogenesis, and/or clinical behavior.