Their study, published in the May 15 issue of Cancer Research, focused on the HMG-I gene, whose protein product is overexpressed in several human cancers, but whose exact role in the formation and development of these diseases had been unknown.
Using seven genetically engineered, or transgenic, mice designed to overexpress the HMG-I gene in the lymphoid tissues and white blood cells, the Hopkins researchers found that each mouse quickly developed cases of leukemia and lymphoma similar to these diseases in humans.
"The early onset of cancerous tumors in 100 percent of these mice provides the most direct evidence for the link between overexpression of the HMG-I gene and cancer," says Linda Resar, M.D., a pediatric hematologist at the Children' Center, and the study's senior author.
The seven transgenic mice carried between one and 28 copies of the HMG-I gene. All of the mice developed lymphoid tumors and died between the ages of 1 and 8.5 months.
One of the mice was successfully bred to establish a line of genetically engineered mice, each of which also developed lymphoid malignancies. In most cases, lymphoma was found in the animals' thymus, spleen, bone marrow, lymph nodes and peripheral blood, all of which is consistent with a leukemia-like disease process. In another segment of the study, the researchers also found that the HMG-I gene was overexpressed in bone marrow samples from patients with leukemia.
Resar says it is not yet known how overexpression of HMG-I interferes with normal cell growth and leads to the development of cancer in either mice or humans. She speculates that since the gene's proteins are involved in a process known as transcriptional regulation, in which cells decide which genes to use to make proteins, increased expression of HMG-I may alter the expression of those genes involved in regulating cell growth, in turn leading to cancerous transformations.
"We believe the transgenic mouse used in this study will also provide a valuable tool for determining how overexpression of the HMG-I gene leads to cancer cell growth and for identifying new therapeutic targets for the treatment of human cancers. Much work remains to be done," she says.
The study was supported by grants from the National Cancer Institute and the American Cancer Society. Several of the study co-authors were also supported by a training grant from the National Institutes of Health.
Hopkins contributors to the study were Yi Xu, Takita Felder Sumter, Raka Bhattacharya, and Abeba Tesfaye, from the divisions of Hematology, Pediatrics and Oncology; Ephraim J. Fuchs from the Division of Oncology; David L. Huso from the Division of Comparative Medicine; and Lisa J. Wood, currently with the Oregon Health and Sciences University School of Nursing.
Johns Hopkins Children's Center