The Kupfer lab works on the relationship of genomic instability and the propensity towards development of cancer. Specifically, we focus on the genetic syndrome Fanconi anemia (FA). Interestingly, children with FA are born with congenital anomalies and develop aplastic anemia and an assortment of leukemias and other cancers. FA serves as a paradigm where the disciplines of development, genetics, and molecular oncology come together. Like other cancer susceptibility syndromes, such as ataxia telangiectasia and xeroderma pigmentosum, FA patients exhibit a unique hypersensitivity to DNA crosslinking agents, which is the key to the biology of FA. Unlike the other syndromes, exceedingly little is known about FA. Thirteen complementation groups have been elucidated, with all exhibiting similar phenotypic characteristics, suggesting an interrelationship of proteins in a complex or in a linear pathway. To date, 15 genes have been cloned, but the encoded proteins bear no resemblance to each other or to any other known proteins. Recent work, including our own, has implicated a role for FA in homologous recombinatorial repair. Interestingly, the FA pathway and breast cancer biology have significant overlap, as at least 5 FA genes are bona fide familial breast cancer genes.
Our work has focused on:
- protein-protein interactions of FA proteins
- signal transduction pathway of FA proteins
- biochemistry of FA protein function
The Kupfer laboratory is part of the wider community of researchers involved in DNA repair. We formally have established a connection with the Sung/Glazer/Sweasy/Sartorelli/Rockwell labs in a program project focused on DNA repair.
Based on our interest in bone marrow failure and genomic instability, we are working on 3 related projects.
- We have started a new project on another rare blood disorder congenital dyserythropoietic anemia (CDA).
- As in FA, codanin, the protein whose gene is mutated in CDA has no known function, and additional genes accounting for additional genetic complementation groups remain to be cloned and identified. The work on CDA is performed in collaboration with a group of Yale scientists (Krause, Gallagher, Weissman) in the Yale Molecular Hematology Center. We have identified a novel role for codanin in erythroid differentiation via transcriptional control. Such work, while focused on a rare disorder, has the promise to confer insight into the normal processes of red cell production.collapse
- We are investigating ways to use our knowledge of genomic instability for improving cancer therapeutics.
- We have been working on Tax, a viral oncogene, in collaboration with the Semmes laboratory at Eastern Virginia Medical School. Interestingly, Tax chemosensitizes p53 mutant cells in culture. This observation is especially important, as p53 mutations are found in a majority of all human cancers and are the leading cause of resistance to chemotherapy. Our goal is adapt the tax1 effect on cells with p53 mutations in order to make cancer therapy more effective in resistant tumors. We have identified the activation of the cell cycle kinase CDK4 as the mechanism of Tax action. Towards this goal, we have set up screens to detect small molecule activators of CDK4 as well as uncover the crystal structure of Tax-CDK4 in an effort to identify a drug to use clinically to make chemotherapy more effective.collapse
- We have also started more clinical projects, using the same mass spectroscopy technology we have used to find FA binding proteins.
- Again in collaboration with the Semmes laboratory, we have adapted the mass spec to analyze sera from patients with pediatric malignancies, specifically Hodgkin lymphoma in order to identify unique protein markers of disease. These markers could then be used for diagnosis, prognosis, staging, and tracking of minimum residual disease in patients. In addition, our goal is to identify interesting proteins for further analysis in our laboratory.
Further, we have collected blood from 6 families in which there is a parent and child with Hodkgin lymphoma. We have teamed up with Dr Richard Lifton to apply his cutting edge genome sequencing platform to identify a candidate gene for familial Hodgkin. We have already identified several exciting candidates and are in the process of further evaluation.collapse