Gene Abnormalities Help Predict Likelihood of Childhood Leukemia Relapse
The Bottom Line
Abnormalities in a gene called IKZF1, which produces a protein that plays an important role in the development of white blood cells, are associated with an increased risk of relapse in patients with childhood acute lymphoblastic leukemia.
The Whole Story
Acute lymphoblastic leukemia (ALL) is an aggressive cancer of the blood in which too many lymphoblasts (immature white blood cells) accumulate in the blood and bone marrow. It can occur in both children and adults, but most cases are diagnosed in individuals under the age of 20, with a sharp peak in incidence among children 2 to 3 years of age. It is the most common cancer of childhood, representing approximately 20 percent of all cancers diagnosed before the age of 20 and affecting one in 29,000 children annually in the United States.
With currently available treatments, more than 80 percent of children diagnosed with ALL can be cured of their cancer; however, these treatments cause substantial toxic side effects and about 20 percent of patients will eventually experience a relapse. An improved ability to determine the risk of relapse for individual patients would help doctors tailor treatment better, identifying those who are unlikely to be cured with existing therapies and in whom different treatments should be tested.
To identify genetic abnormalities that might prove useful in better defining the prognosis of patients with childhood ALL, researchers analyzed the DNA in leukemia cells from 221 children with B-cell progenitor ALL (also called precursor B-cell ALL) who were judged to be at high risk of relapse. B-cell progenitor ALL is the most common form of childhood ALL. The children were classified as high-risk patients on the basis of age, gender, white blood cell count at diagnosis, the presence of cancer cells in the central nervous system or testes (males), and the presence of abnormalities in a gene called MLL. Abnormalities in the MLL gene are found in five to ten percent of children with ALL, 80 percent of the time in patients younger than 1 year of age, and indicate a poor prognosis.
Many of the 221 children were found to have abnormalities in multiple regions of their cancer cell DNA. These abnormalities included DNA deletions, duplications, and nucleotide changes. The same DNA regions were often affected in more than one patient, that is, there were recurrent abnormalities.
Further analysis of the data from these patients and analysis of the leukemia cell DNA from an additional 258 patients revealed that abnormalities involving a single gene, called IKZF1, had the strongest association with disease relapse. Sixty-seven (30 percent) of the original 221 patients had a DNA abnormality involving IKZF1. When patients who had only one of the recurrent DNA abnormalities were considered, 39 percent in the original group and 23 percent in the second group had an abnormality involving IKZF1.
The IKZF1 gene produces a protein called IKAROS, which regulates the activity of many other genes. IKAROS protein plays an important role in the development of white blood cells, and other research indicates that it can also play a role in the development of leukemias and lymphomas.
Additional work by the research team offers clues about how abnormalities affecting IKAROS might contribute to relapse in patients with ALL. The researchers examined gene expression in leukemia cells that had IKZF1 abnormalities and determined whether the presence of such abnormalities was associated with higher levels of residual disease following treatment. Measuring the level of residual disease after treatment is a widely used method for monitoring a disease's responsiveness to therapy. The research team found that leukemia cells with IKZF1 abnormalities had increased expression of genes that are normally turned on in blood stem cells and immature blood cells. Considerable evidence suggests that stem cells are more resistant to chemotherapy drugs than other types of cells. In addition, the researchers showed that IKZF1 abnormalities were associated with significantly higher levels of residual disease following treatment.
The researchers say their results provide support for eventually incorporating IKZF1 gene status in the evaluation of patients with childhood ALL.
This study was conducted under NCI's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative, which seeks to use the results of genomics research to develop more effective treatments for childhood cancers
More summaries of selected scientific advances from NCI-supported research are available at http://www.cancer.gov/aboutnci/servingpeople/advances.
