title: Accelerated progression of chronic lymphocytic leukemia in Eμ-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 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.
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68178, USA.
authors.forename: Vincent K
authors.initials: VK
authors.lastname: Nganga
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Palmer
authors.forename: Hina
authors.initials: H
authors.lastname: Naushad
authors.forename: Michele D
authors.initials: MD
authors.lastname: Kassmeier
authors.forename: Dirk K
authors.initials: DK
authors.lastname: Anderson
authors.forename: Greg A
authors.initials: GA
authors.lastname: Perry
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Schabla
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Swanson
mesh_terms: D000054:Acceleration; D000818:Animals; D002384:Catalysis; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018450:Disease Progression; D004789:Enzyme Activation / Q000235:genetics; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D060152:V(D)J Recombination / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; C490393:Tcl1 protein, mouse; C064658:RAG-1 protein