Accelerated progression of chronic lymphocytic leukemia in Em-TCL1 mice expressing catalytically inactive RAG1

Abstract

Chronic lymphocytic leukemia (CLL) is a prevalent B-cell neoplasia that is often preceded by a more benign monoclonal CD51 B-cell lymphocytosis. We previously generated transgenic mice expressing catalytically inactive RAG1 (dominant-negative recombination activating gene 1 [dnRAG1] mice) that develop an early-onset indolent CD51 B-cell lymphocytosis attributed to a defect in secondary V(D)J rearrangements initiated to edit autoreactive B-cell receptor (BCR) specificity. Hypothesizing that CD51 B cells in these animals represent potential CLL precursors, we crossed dnRAG1 mice with CLL-prone Em-TCL1 mice to determine whether dnRAG1 expression in Em-TCL1 mice accelerates CLL onset. Consistent with this hypothesis, CD51 B-cell expansion and CLL progression occurred more rapidly in double-transgenic mice compared with Em-TCL1 mice. Nevertheless, CD51 B cells in the 2 mouse strains exhibited close similarities in phenotype, im-munoglobulin gene usage, and mutation status, and expression of genes associated with immune tolerance and BCR signaling. Gene expression profiling further revealed a potential role for prolactin signaling in regulating BCR editing. These results suggest a model in which benign accumulation of CD51 B cells can be initiated through a failure to successfully edit autoreactive BCR specificity and may, in turn, progress to CLL upon introduction of additional genetic mutations.