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Transgenic Expression of Helios in B Lineage Cells Alters B Cell Properties and Promotes Lymphomagenesis¹

Sinisa Dovat^*, Encarnacion Montecino-Rodriguez, Valerie Schuman, Michael A. Teitell, Kenneth Dorshkind and Stephen T. Smale^2,

^* Mattel Children’s Hospital and Department of Pediatrics, Department of Pathology and Laboratory Medicine, and Howard Hughes Medical Institute and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA 90095

Helios, a member of the Ikaros family of DNA-binding proteins, is expressed in multipotential lymphoid progenitors and throughout the T lineage. However, in most B lineage cells, Helios is not expressed, suggesting that its absence may be critical for B cell development and function. To test this possibility, transgenic mice were generated that express Helios under the control of an Ig µ enhancer. Commitment to the B cell lineage was unaltered in Helios transgenic mice, and numbers of surface IgM⁺ B cells were normal in the bone marrow and spleen. However, both bone marrow and splenic B cells exhibited prolonged survival and enhanced proliferation. B cells in Helios transgenic mice were also hyperresponsive to Ag stimulation. These alterations were observed even though the concentration of ectopic Helios in B lineage cells, like that of endogenous Helios in thymocytes, was well below the concentration of Ikaros. Further evidence that ectopic Helios expression contributes to B cell abnormalities was provided by the observation that Helios transgenic mice developed metastatic lymphoma as they aged. Taken together, these results demonstrate that silencing of Helios is critical for normal B cell function.

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