Hematology In the Department of Medicine

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:

  1. c-myc in Burkitt’s lymphoma
  2. 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.

Location and Contact Information

The Boxer Lab is located at the Palo Alto VA at 3801 Miranda Ave.

Lab Phone: (650) 493-5000, ext 63127
Fax: (650) 849-0528

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