The Laboratory of Linda M. Boxer, MD, PhD
Activation of oncogenes in hematologic malignancies, gene expression patterns in malignancies
We are interested in how an oncogene becomes expressed in a deregulated manner in hematologic malignancies. This is an important and seemingly simple question that has proven to be very difficult to answer. We have chosen two model systems to study this fundamental problem:
- c-myc in Burkitt’s lymphoma
- bcl-2 in t(14;18) lymphomas
Our goal is to determine the molecular mechanisms of oncogene deregulation and then to design novel therapeutic reagents to interfere with the deregulation. These will be tested in cell lines and animal models of the malignancies.
c-myc in Burkitt’s lymphoma
The c-myc gene is translocated to the immunoglobulin locus in Burkitt’s lymphoma. As a result of this translocation, high-level expression of c-myc is observed. The expression is from the translocated allele, and the normal allele is silent. We have separated the two c-myc alleles by electrophoresis and performed in vivo footprinting on each allele to identify the transcription factors involved in the deregulation. We are also investigating the role of the immunoglobulin locus and identifying sites in the enhancers that are required for the deregulation of c-myc expression. Model systems are being used to further investigate the molecular mechanisms involved in the activation of c-myc by the immunoglobulin locus.
bcl-2 in t(14;18) lymphomas
The t(14;18) is the most common translocation in human lymphomas. The bcl-2 gene is translocated to the immunoglobulin heavy chain locus and expressed at high levels while the normal bcl-2 allele is silent. It is likely that the increased bcl-2 expression contributes to the resistance to apoptosis of the lymphoma cells. We are characterizing the differential protein binding to the two bcl-2 alleles. Regions of the immunoglobulin enhancers that are required for the deregulation of bcl-2 expression are being identified. Several model systems have been developed to study the activation of bcl-2 expression. We are also examining the regulation of bcl-2 expression during B-cell development.
Gene expression patterns in malignancies
Recurrent translocations have been identified in a number of hematologic diseases. Cytogenetic analysis provides additional prognostic information in acute lymphoblastic leukemia. We are using gene expression profiling to identify critical genes and pathways in human B-cell acute lymphoblastic leukemia, particularly in response to chemotherapeutic agents. Both adult and pediatric samples are being studied. The gene expression profiles of the different translocation subtypes are being analyzed and compared. Correlation with prognosis and relapse is being performed.
- Wu, Y.-L., Mehew, J.W., Heckman, C.A., Arcinas, M., and Boxer, L.M. “Negative Regulation of Bcl-2 Expression by p53 in Hematopoietic Cells”, Oncogene 20:240-251, 2001.
- Arcinas, M., Heckman, C.A., Mehew, J.W., and Boxer, L.M. “Molecular Mechanisms of Transcriptional Control of Bcl-2 and c-Myc in Follicular and Transformed Lymphoma”. Cancer Research 61:5202-5206, 2001.
- Hu, H.-M. and Boxer, L.M. “A MAZ-Related Factor Binding Site Is Required for the Deregulation of c-Myc Expression by the Immunoglobulin Heavy Chain Gene Enhancers in Burkitt’s Lymphoma”. J. Biol. Chem. 277:9819-9824, 2002.
- Heckman, C.A., Mehew, J.W., and Boxer, L.M. “NF- kB Activates Bcl-2 Expression in t(14;18) Lymphoma Cells”. Oncogene 21:3898-3908, 2002.
- Zhang, C., Wu, Y.-L., and Boxer, L.M. “Impaired Proliferation and Survival of Activated B Cells in Transgenic Mice Expressing a Dominant-Negative CREB Transcription Factor in B Cells”. J. Biol. Chem. 277:48359-48365, 2002.
- Heckman, C.A., Wheeler, M.A., and Boxer, L.M. “Regulation of Bcl-2 by C/EBP in t(14;18) Lymphoma Cells”. Oncogene 22:7891-7899, 2003.
- Heckman, C.A., Cao, T., Somsouk, L., Duan, H., Mehew, J.W., Zhang, C., Boxer, L.M. “Critical Elements of the Immunoglobulin Heavy Chain Gene Enhancers for Deregulated Expression of Bcl-2”. Cancer Research 63:6666-6673, 2003.
- Fine, B.M., Stanulla, M., Schrappe, M., Ho, M., Viehmann, S., Harbott, J., and Boxer, L.M. “Gene Expression Patterns Associated with Recurrent Chromosomal Translocations in Acute Lymphoblastic Leukemia”. Blood 103:1043-1049, 2004.