KATHRYN CALAME

Our laboratory studies gene regulation in the immune system. Our current work focuses primarily on B lymphocytes and monocyte/macrophages.

1. A major focus of our work is an unusual transcriptional repressor called Blimp-1 (B lymphocyte induced maturation protein). Blimp-1 is unusual because when ectopically expressed in activated B cells, it alone is sufficient to drive B cells to differentiate into end-stage effectors of the B cell lineage called plasma cells. Thus, Blimp-1 has been called a "master regulator" of terminal B cell differeniation.

In order to understand how Blimp-1 functions as a master regulator, we are studying its direct and indirect targets. Classical approaches and microarray analyses have allowed us to develop a detailed understanding of the transcriptional regulatory cascades initiated by Blimp-1. These studies also reveal that in addition to blocking proliferation and inducing immunoglobulin secretion, Blimp-1 represses many genes required for earlier stages of B cells, thereby ensuring that plasma cell differentiation is irreversible. In further studies, we hope to expand our understanding of plasma cell development to understand what is involved in the alternate fate choice, to become a memory B cell.

We have created and are studying mice lacking Blimp-1 in their B cells. These mice demonstrate that Blimp-1 is required for Ig secretion and will allow us to determine the precise time and way Blimp-1 acts. In conjunction with these studies we are studying the regulation of Blimp-1 in B cells.

Blimp-1 is not, however, a B-cell specific protein. We have shown that it is important for differentiation of monocyte/macrophages and is induced in myeloid dendritic cells upon activation. In addition, Blimp-1 is strongly expressed in epithelial cells, but we do not yet know its function, if any, in this lineage. We are generating mice lacking Blimp-1 in other cell lineages to further understand the role of this protein. We believe these studies provide understanding of how specific lineage cells become terminally differentiated and also may allow a better understanding of general aspects of terminal differentiation.

2. Another project in the laboratory focuses on how the unique DNA rearrangement of immunolgobulin and T cell receptor genes, called VDJ recombination, is regulated. There is increasing evidence that one important level of regulation involves chromatin structure. Recently we have shown that rearrangement of immunoglobulin heavy chain V genes during ontogeny and development correlates with the acetylation status of histones associated with them. We are studying other aspects of chromatin structure and how it may be regulated in early B cell development.

3. We are also interested in the mechanism by which the viral oncogene v-Abl, a non-receptor tyrosine kinase, causes transformation of early B cells. In previous work we have studied mitogenic signaling pathways from v-Abl that are required for transformation and have also shown that p53 inhibits v-Abl-dependent transformation. Currently we are trying to understand in more detail the delicate balance between p53 and v-Abl activity and are carrying out experiments designed to identify additional genetic changes that are important for v-Abl transformation.

Recent publications:

Zou, X., Cong, F., Cattoretti, G., Coutts, M., Goff, S.P. and Calame, K. (2000) "p53 Deficiency Increases Transformation by v-Abl and Restores the Ability of a C-Terminally Truncated v-Abl Mutant to Induce PreB Lymphoma In Vivo" Mol. Cell. Biol. 20: 628-33.

Chang, D., Angelin-Duclos, C. and Calame, K (2000) "Blimp-1: trigger for differentiation of myeloid lineage." Nature Immunol. 1:169-76.

Angelin-Duclos, C., Cattoretti, G. and Calame, K. (2000) "Commitment to a Plasma Cell Fate Is Associated with Blimp-1 Expression In Vivo" J. Immunol. 165: 5462-71 and cover 4/01-6/01.

Piskurich, J., Lin, K., Wang, Y., Lin, Y., Ting, J. and Calame, K. (2000) "Blimp-1/PRDI- BF1 Mediates Extinction of Major Histocompatibility Class II Transactivator (CIITA) in Plasmacytes" Nature Immunol. 1:526-32.

Calame, K. (2001) "Plasma Cells: New Light at the End of B Cell Development" Nature Immunol, 2:1103-8

Shaffer, A.,* Lin, K., Yu, X., Hurt, E., Rosenwald, A., Giltnane, J., Zhao, H., *Calame, K. and *Staudt, L. (*first authors contributed equally and senior authors contributed equally) (2002) "Blimp-1 orchestrates plasma cell differentiation by extingushing the mature B cell gene expression program" Immunity, 17:51-62

Angelin-Duclos, C., Johnson, K., Liao, J. and Calame, K. (2002) "An Interfering Form of Blimp-1 increases IgM secreting plasma cells and blocks maturation of peripheral B cells" Eur. J. Immunol. In Press.

Calame, K., Lin, K. and Tunyaplin, C. (2003) "Regulatory Mechanisms in Plasma Cells" Annual Reviews of Immunology. In press.