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The Journal of Immunology, 2002, 169: 6594-6603.
Copyright © 2002 by The American Association of Immunologists

Ongoing In Vivo Immunoglobulin Class Switch DNA Recombination in Chronic Lymphocytic Leukemia B Cells1

Andrea Cerutti2,*, Hong Zan*, Edmund C. Kim*,{dagger}, Shefali Shah*, Elaine J. Schattner{dagger},{ddagger}, András Schaffer*,{dagger} and Paolo Casali*,{dagger}

* Division of Molecular Immunology, Department of Pathology; {dagger} Immunology Program of the Graduate School of Medical Sciences; and {ddagger} Division of Hematology, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021

Chronic lymphocytic leukemia (CLL) results from the expansion of malignant CD5+ B cells that usually express IgD and IgM. These leukemic cells can give rise in vivo to clonally related IgG+ or IgA+ elements. The requirements and modalities of this process remain elusive. Here we show that leukemic B cells from 14 of 20 CLLs contain the hallmarks of ongoing Ig class switch DNA recombination (CSR), including extrachromosomal switch circular DNAs and circle transcripts generated by direct Sµ->S{gamma}, Sµ->S{alpha}, and Sµ->S{epsilon} as well as sequential S{gamma}->S{alpha} and S{gamma}->S{epsilon} CSR. Similar CLL B cells express transcripts for activation-induced cytidine deaminase, a critical component of the CSR machinery, and contain germline IH-CH and mature VHDJH-CH transcripts encoded by multiple C{gamma}, C{alpha}, and C{epsilon} genes. Ongoing CSR occurs in only a fraction of the CLL clone, as only small proportions of CD5+CD19+ cells express surface IgG or IgA and lack IgM and IgD. In vivo class-switching CLL B cells down-regulate switch circles and circle transcripts in vitro unless exposed to exogenous CD40 ligand and IL-4. In addition, CLL B cells that do not class switch in vivo activate the CSR machinery and secrete IgG, IgA, or IgE upon in vitro exposure to CD40 ligand and IL-4. These findings indicate that in CLL at least some members of the malignant clone actively differentiate in vivo along a pathway that induces CSR. They also suggest that this process is elicited by external stimuli, including CD40 ligand and IL-4, provided by bystander immune cells.




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