If this is not your name, click here.
| | If this is not your name, click here. | | |
| | Contact Us | Order Now | Journals | Bookstore | Register a colleague | | |
| |  Gene Abnormality Found To Predict Childhood Leukaemia Relapse BETHESDA, Md -- January 8, 2009 -- Scientists have identified mutations in a gene that predict a high likelihood of relapse in children with acute lymphoblastic leukaemia (ALL). The findings of the Children's Oncology Group (COG) are published early online and will appear in the January 29 issue of the New England Journal of Medicine. Although the researchers caution that further research is needed to determine how changes in the genes IKZF1 or IKAROS lead to leukaemia relapse, the findings are likely to provide the basis for future diagnostic tests to assess the risk of treatment failure. By using a molecular test to identify this genetic marker in patients with ALL, physicians should be better able to assign patients to appropriate therapies. "Great progress has been made in recent years in improving the cure rate of childhood ALL," said lead COG investigator Stephen Hunger, MD, University of Florida, Gainesville, Florida. "The findings of this study help us further subdivide those patients who are unlikely to be cured, and identify patients in whom different therapies should be tested." In the study, researchers analysed genetic data on leukaemia cells obtained at diagnosis from 221 children with high-risk leukaemia who had been treated in an existing COG study. They conducted their analysis using microarrays and DNA sequencing. Using these technologies to identify genetic abnormalities in leukaemia cells, the investigators examined the DNA of the leukaemia cells at the time of diagnosis and then determined if any of the identified genetic changes predicted relapse. To confirm that specific genetic changes were associated with relapse, the scientists also examined a second group of 258 children with ALL who were treated at St. Jude, Memphis, Tennessee. "We looked across the genome in an unbiased fashion in an attempt to pull out any genes that were significantly associated with outcome," first author Charles Mullighan, MD, Department of Pathology, St. Jude. "From these findings, we identified a group of genetic abnormalities that together predicted poor outcome." The most significant association was with the deletions or changes in the IKAROS gene. Mutations of IKAROS were shown to identify a subgroup of patients who were treated in the COG study that had a very poor prognosis. The prognostic significance of these genetic alterations was validated in the independent St. Jude patient group, a finding of particular importance since different types of therapies were used in these 2 groups of patients. Previous research has shown that the IKAROS gene serves as the blueprint for production of the IKAROS protein, which regulates the activity of many other genes. The IKAROS protein plays an essential role in the development of lymphocytes, the white blood cells that, when changed, give rise to pediatric ALL. The way in which IKAROS abnormalities contribute to the development of relapse remains to be determined. The study also examined gene expression in the leukaemia cells using microarray chips, and found that leukaemia cells from patients with IKAROS alterations expressed primitive, stem cell-like genes, suggesting that the cells are less mature and possibly more resistant to the effects of drugs used to treat ALL. The researchers also tested whether the presence of IKAROS alterations was associated with levels of minimal residual disease, another measure of treatment response in ALL. "Measurement of levels of minimal residual disease is widely used to monitor treatment responsiveness and also to alter patients' therapy if they have a very poor response to treatment," said senior author James Downing, MD, of St. Jude. "An important analysis we conducted was to see whether identifying the association of IKAROS alterations with poor outcome added anything to just measuring levels of minimal residual disease. And, indeed, it did." The researchers' analysis indicated that identifying IKAROS alterations may be clinically useful and will complement existing diagnostic tests and measurement of minimal residual disease levels. While a clinical test for alterations of IKAROS could prove valuable for predicting poor outcomes in children with ALL, complexities remain. There are different types of deletions in the gene, some that involve the entire IKAROS gene and others that involve only parts of the gene. Because the genetic alterations in IKAROS in ALL are not uniform or limited to a single mutation or deletion, it may be necessary to develop a panel of different tests to detect IKAROS lesions and identify which patients are at highest risk for relapse.
SOURCE: National Institutes of Health
|
