Accelerated progression of chronic lymphocytic leukemia in Eμ-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 Swanson

Research output: Contribution to journalArticle

15 Citations (Scopus)

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
JournalBlood
Volume121
Issue number19
DOIs
StatePublished - May 9 2013

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B-Cell Chronic Lymphocytic Leukemia
B-Lymphocytes
Cells
RAG-1 Genes
Genes
Lymphocytosis
Transgenic Mice
Gene Expression
Immune Tolerance
Immunoglobulin Genes
Mutation
Gene expression
Prolactin
Immunoglobulins
Gene Expression Profiling
Animals
Defects
Phenotype

All Science Journal Classification (ASJC) codes

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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Accelerated progression of chronic lymphocytic leukemia in Eμ-TCL1 mice expressing catalytically inactive RAG1. / Nganga, Vincent K.; Palmer, Victoria L.; Naushad, Hina; Kassmeier, Michele D.; Anderson, Dirk K.; Perry, Greg A.; Schabla, Nathan M.; Swanson, Patrick.

In: Blood, Vol. 121, No. 19, 09.05.2013.

Research output: Contribution to journalArticle

Nganga, VK, Palmer, VL, Naushad, H, Kassmeier, MD, Anderson, DK, Perry, GA, Schabla, NM & Swanson, P 2013, 'Accelerated progression of chronic lymphocytic leukemia in Eμ-TCL1 mice expressing catalytically inactive RAG1.', Blood, vol. 121, no. 19. https://doi.org/10.1182/blood-2012-08-446732
Nganga, Vincent K. ; Palmer, Victoria L. ; Naushad, Hina ; Kassmeier, Michele D. ; Anderson, Dirk K. ; Perry, Greg A. ; Schabla, Nathan M. ; Swanson, Patrick. / Accelerated progression of chronic lymphocytic leukemia in Eμ-TCL1 mice expressing catalytically inactive RAG1. In: Blood. 2013 ; Vol. 121, No. 19.
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