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

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17 Scopus citations

Abstract

Chronic lymphocytic leukemia (CLL) is a prevalent B-cell neoplasia that is often preceded by a more benign monoclonal CD5(+) 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 CD5(+) B-cell lymphocytosis attributed to a defect in secondary V(D)J rearrangements initiated to edit autoreactive B-cell receptor (BCR) specificity. Hypothesizing that CD5(+) B cells in these animals represent potential CLL precursors, we crossed dnRAG1 mice with CLL-prone Eμ-TCL1 mice to determine whether dnRAG1 expression in Eμ-TCL1 mice accelerates CLL onset. Consistent with this hypothesis, CD5(+) B-cell expansion and CLL progression occurred more rapidly in double-transgenic mice compared with Eμ-TCL1 mice. Nevertheless, CD5(+) B cells in the 2 mouse strains exhibited close similarities in phenotype, immunoglobulin 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 CD5(+) 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

All Science Journal Classification (ASJC) codes

  • 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