Immunoglobulin gene sequence-analysis of B-1 (cd5+b) cell clones in a murine model of chronic lymphocytic-leukemia and richters syndrome

Abstract

The NZB mouse has recently been proposed as an animal model for the human malignancy chronic lymphocytic leukemia (CLL) because of the age-dependent onset of clonally expanded hyperdiploid B-1 cells these mice develop by one year of age. We have examined the immunoglobulin sequence of several NZB B-1 malignant clones and found these clones to have several common characteristics. The B-1 malignant clones all use unmuated VH genes and DFL16.1, a D region gene which pre-dominates during fetal B cell development. In addition, no N base insertions were observed in the clones. A continually passaged line of murine CLL-like cells was examined in more detail. This line used a germline S107 VH gene that showed no evidence of accumulated somatic mutation over the course of five years of in vivo passage. The D gene (DFL16.1) was also unmutated with no evidence of non-germline diversity at the junction sites. The non-mutated state was maintained despite a continued transformation of the CLL-like cells into a more aggressive large cell lymphoma known as Richter's syndrome. Several years after the development of Richter's syndrome, the usage of a completely new VH gene family was detected. This second B-1 clone employing a new VH gene was expressed with similar characteristics as the initial B-1 clone, both employing DFL16.1 with no N base insertions at the junction sites. This demonstrates that B-1 cells which are destined to clonally expand have unique characteristics in the expression of surface immunoglobulin. Therefore, B-1 (CD5+ B) cells which undergo transformation in CLL are not randomly derived from the normal B-1 cell population but instead come from a subpopulation of B-1 cells which display these specific features of immunoglobulin expression.