Carolyn A. Felix,

Description of Research Expertise

Research Interests
Infant and chemotherapy-related leukemias with MLL (Mixed Lineage Leukemia; Myeloid Lymphoid Leukemia) gene translocations.

Key words: leukemia, infant, DNA topoisomerase II, epipodophyllotoxin, MLL gene, translocation.

Description of Research
The research activities of my laboratory are directed at solving the problems of leukemias in infants and leukemias caused by chemotherapeutic DNA topoisomerase II inhibitors. My research group has shown that these leukemias have similar chromosomal translocations of the MLL gene at chromosme band 11q23. While most children with leukemia can be cured; the treatment options for patients with MLL-rearranged leukemias, which include intensive chemotherapy and hematopoietic stem cell transplantation, are associated with excessive toxicity and a poor prognosis. The therapies have lagged far behind the scientific advances of the new genomics era. New risk factors and insights on the DNA damage leading to the translocations have emerged from the work of my laboratory, the mission of which is to build bridges between basic science and the bedside that will accelerate targeted prevention and more efficacious, less toxic, targeted new treatments for these high-risk patients.

The research of my laboratory has pioneered new panhandle PCR methodology for the detection of MLL translocations. The MLL gene can be fused with one of many different partner genes to form translocations. My laboratory has discovered a large proportion of the known partner genes of MLL. In studies of AML in infant twins we have shown that the translocations and, therefore the DNA damage leading to the translocations, occur in the prenatal period. In the chemotherapy-related cases we have shown that the translocations can be present early during the primary cancer treatment. Work in my laboratory using an in vitro assay has suggested that DNA topoisomerase II, an essential protein in all cells, may be involved in the chromosomal breakage that leads to translocations. These studies are important because the chemotherapy drugs associated with this form of leukemia are DNA topoisomerase II inhibitors and, in leukemia in infants, classical epidemiology has suggested associations of maternal prenatal consumption of certain dietary DNA topoisomerase II inhibitors with an increased risk. Currently we are developing an experimental model that exploits human bone marrow progenitor cells and novel DNA array technology in order to mimic the damage to the MLL gene and localize the DNA topoisomerase cleavage complexes that are formed in vivo. In other work, we have determined that genetic variations in the detoxifying pathways NQO1 and CYP3A4, respectively, confer susceptibility to infant and treatment-related leukemias with MLL translocations. In the infant leukemias, the prenatal period when the translocation must occur holds possibilities for prevention if there are relevant exposures in high-risk individuals. In the treatment-related leukemias, the identification of high-risk individuals could lead to alterations in chemotherapy dose or schedule and preventative strategies for the future. In addition to experiments that are focused on prevention, other efforts in my laboratory are directed at developing better treatments. We are using gene expression profiling and we are planning profiling experiments via large-scale proteomics to understand the influence of the partner genes of MLL on disease biology and identify new drug targets. We have also shown that leukemias in infants have increased Bcl-2 expression, and other current research involves testing an anti-sense compound directed at this central anti-apoptotic protein, which confers chemotherapy resistance. Therefore, the research of my laboratory is relevant to new gene discovery and to diagnosis, prognosis and monitoring in patients with leukemia, and may lead to strategies for treatment and prevention.