MEMPHIS, Tenn., November 7, 1997 -- Research over the past 10 years has shown that acute leukemia is in fact a genetic disorder. It arises when genes essential to correct blood cell function are not expressed at the appropriate times. In many cases, the failure of gene expression can be traced to an altered protein known as a transcription factor.
A. Thomas Look, M.D., in an article published in today's issue of Science, estimates that as many as one-half of all childhood leukemia cases result from abnormal transcription factors. Dr. Look, chairman of Experimental Oncology at St. Jude Children's Research Hospital in Memphis, TN, noted that fused transcription factors appear to represent the most common source of new leukemias. These hybrid proteins are formed when normal genes are disrupted by chromosomal breaks and recombine with parts of entirely different genes. Although the fusion products continue to function as transcription factors, their effects on cell growth and development are overriding and can trigger a series of biochemical changes that drive the cell toward leukemic transformation.
Researchers in Dr. Look's laboratory have discovered a novel leukemia-producing transcription factor called E2A-HLF. This fusion protein transforms immature lymphocytes by preventing programs that normally would trigger their destruction. The immortalized cells then accumulate to excessive numbers until they begin to produce the signs and symptoms of leukemia. An important aspect of this discovery, according to Dr. Look, is that it offers a model for studying cell death and cell survival programs in developing lymphocytes. "We know very little about leukemias that result from altered survival signals," explains Dr. Look, "and E2A-HLF may provide a window through which these changes can be understood and related to findings in other childhood tumors."
The close link between fused transcription factors and acute leukemia has enabled treatment specialists to improve their clinical protocols. "Since we know that these genetic alterations produce specific types of leukemia with specific responses to therapy," says Dr. Look, "we are able to modify therapy according to the patient's unique risk of relapse. In the not-too-distant future, we hope to exploit this genetic information to pinpoint new molecular targets for antileukemic drugs and other agents."
St. Jude Children's Research Hospital, in Memphis, Tenn., was founded by the late entertainer Danny Thomas. The hospital is an internationally recognized biomedical research center dedicated to finding cures for catastrophic diseases of childhood. The hospital's work is primarily supported through funds raised by the American Lebanese Syrian Associated Charities (ALSAC). All St. Jude patients are treated regardless of their ability to pay. ALSAC covers all costs of treatment beyond those reimbursed by third party insurers, and total costs for families who have no insurance.
Journal
Science