Repression of c-myc Is Necessary but Not Sufficient for Terminal Differentiation of B Lymphocytes In Vitro

Abstract

The importance of c-myc as a target of the Blimp-1 repressor has been studied in BCL-1 cells, in which Blimp-1 is sufficient to trigger terminal B-cell differentiation. Our data show that Blimp-1-dependent repression of c-myc is required for BCL-1 differentiation, since constitutive expression of c-Myc blocked differentiation. Furthermore, ectopic expression of cyclin E mimicked the effects of c-Myc on both proliferation and differentiation, indicating that the ability of c-Myc to drive proliferation is responsible for blocking BCL-1 differentiation. However, inhibition of c-Myc by a dominant negative form was not sufficient to drive BCL-1 differentiation. Thus, during Blimp-1-dependent plasma cell differentiation, repression of c-myc is necessary but not sufficient, demonstrating the existence of additional Blimp-1 target genes.

ACKNOWLEDGMENTS

We are grateful to R. Dalla-Favera, I. Greenwald, C. Angelin-Duclos, and D. H. Chang for critically reading the manuscript and to the members of the Calame laboratory for helpful discussions. We especially thank D. H. Chang for allowing use of the pGC-Blimp-YFP construct and C. Tunyaplin for technical help on the RNase protection assay. We thank D. Cobrinik for providing the pSKmcyclinE construct, G. Littlewood for providing the pBabeMycNDERpuro construct, G. Fathman for the pGC-IRES-YFP plasmid, and S. Goff for cyclin E antibody. We thank J. Liao for excellent technical assistance.

This work was supported by grants GM29361 and AI 43576 to K. Calame. Kuo-I Lin is a fellow of the Leukemia and Lymphoma Society (5332-00).