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

Vincent K. Nganga, Victoria L. Palmer, Hina Naushad, Michele D. Kassmeier, Dirk K. Anderson, Greg A. Perry, Nathan M. Schabla, Patrick C. Swanson

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3855-3866
Number of pages12
JournalBlood
Volume121
Issue number19
DOIs
StatePublished - May 9 2013

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Nganga, V. K., Palmer, V. L., Naushad, H., Kassmeier, M. D., Anderson, D. K., Perry, G. A., Schabla, N. M., & Swanson, P. C. (2013). Accelerated progression of chronic lymphocytic leukemia in Em-TCL1 mice expressing catalytically inactive RAG1. Blood, 121(19), 3855-3866. https://doi.org/10.1182/blood-2012-08-446732