Pediatrics, Pathology (Division of Hem-Onc)
Keck School of Medicine
The Saban Research Institute
Childrens Hospital Los Angeles
- Cancer genetics
- Signal transduction
- Leukemia-stromal adhesion mechanisms
- role of the BAFF-R in survival of ALL cells
- molecular mechanisms of environmentally-mediated drug resistance
- glycomics as a tool for diagnosis and treatment of acute lymphoblastic leukemia
Research OverviewMechanisms of leukemogenesis and drug resistance
The innate immune system
Accomplishments in the area of cancer research and our main previous focus include the unraveling of major aspects of the molecular basis of chronic myeloid leukemia (CML) and Ph-chromosome positive acute lymphoblastic leukemia (ALL): during the period of 1981-1984, we identified two genes, BCR and ABL, which become fused as a result of a chromosomal translocation in CML and Ph-positive ALL. Research projects in our laboratory continue to concentrate on the signalling processes perturbed by BCR/ABL which lead to chronic myeloid and acute lymphoblastic leukemia, using in vitro and in vivo techniques. We also are studying gene products related to Bcr and Abl (Abr and Fer) to gain further understanding of the cellular function of those families of proteins.
One approach to investigate the in vivo involvement of specific proteins in leukemia and development is through the generation of transgenic and/or knockout mice. We have used this technology to demonstrate that BCR/ABL directly causes leukemia in transgenic mice. This finding provided unambiguous proof that the fusion of BCR and ABL in CML and Ph-positive ALL is the initiating event necessary for the development of leukemia. In addition, the BCR/ABL transgenic mice are valuable for investigating the aberrant signaling associated with leukemogenesis, and they provide a model for testing new treatment protocols. We also culture the leukemic cells on a fibroblast feeder layer and test the activity of anti-leukemia drugs in vitro. Current lines of investigation include the development of drug resistence in the presence of stromal support and the role of the microenvironment in helping leukemic cells become drug resistant.
To explore the normal cellular function of the Bcr protein, which is a negative regulator of the small GTPase Rac, we have generated bcr null mutant mice. We discovered that lack of Bcr protein function leads to enhanced ROS production and development of sepsis following experimental exposure to bacterial lipopolysaccharide in these animals. We have also generated Abr null mutants and, through breeding, Abr x Bcr double null mutant mice were obtained. These mice have cerebellar and inner ear abnormalities and develop endotoxemia with pulmonary involvement upon injection with bacterial endotoxin. Currently, we are investigating the mechanisms by which Abr and Bcr negatively regulate functions of the innate immune system, including the molecular interactons that are needed for this, with an emphasis on pulmonary diseases such as chronic lung disease.