期刊
BLOOD
卷 121, 期 19, 页码 3855-3866出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-08-446732
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资金
- Health Future Foundation
- Nebraska LB506 and LB595 Cancer and Smoking Disease Research Programs
- Nebraska LB692 Biomedical Research Program
- National Center for Research Resources of the National Institutes of Health (NIH) [C06 RR17417-01]
- Creighton University Animal Resource Facility [G20RR024001]
- NCRR [5P20RR016469, RR018788-08]
- National Institute of General Medical Sciences of the NIH [8P20GM103427, GM103471-09]
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 E mu-TCL1 mice to determine whether dnRAG1 expression in E mu-TCL1mice accelerates CLL onset. Consistent with this hypothesis, CD5(+) B-cell expansion and CLL progression occurred more rapidly in double-transgenic mice compared with Em-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.
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