Researchers Discover Mutations Linked to Relapse Of Childhood Leukemia
After an intensive 3-year hunt through the genome, researchers have pinpointed mutations that lead to drug resistance and relapse in acute lymphoblastic leukemia (ALL) ,the most common type of childhood cancer—the first time anyone has linked the disease’s reemergence to specific genetic anomalies.
The discovery, co-led by William L. Carroll, MD, Director of NYU Langone Medical Center’s Cancer Institute, is reported in a study published online February 3, 2013, in Nature Genetics.
Discovery Could Thwart Most Common Pediatric Cancer
“There has been no progress in curing children who relapse, in spite of giving them very high doses of chemotherapy and bone marrow transplants,” said Dr. Carroll.
The discovery suggests how scientists may be able to thwart a dangerous form of ALL, which strikes about 6,000 people in the United States every year and accounts for more than one in four pediatric cancers. Eventually, such information could help doctors detect the early emergence of chemotherapy-resistant leukemia cells in patients and switch to a different treatment strategy before the disease can fully reassert itself.
In ALL, the body’s bone marrow produces an abnormally large number of lymphocytes. Improved treatments have increased the overall cure rate to roughly 80%. But Dr. Carroll says the prognosis is especially dire for some 20% of patients who relapse.
Medical researchers have suspected that the reemergence of disease could be due to drug resistance, but previous efforts had not uncovered any definitive pathway. For the new study, led by Dr. Carroll and graduate student Julia Meyer, researchers at five U.S. institutions spent 3 years analyzing multiple bone marrow samples from pediatric ALL patients for more clues to the disease’s progression.
20 Relapse-specific Mutations
With the help of the Children’s Oncology Group, the researchers analyzed the entire transcriptome from 10 children with pediatric B-lymphoblastic leukemia, the most common subtype of ALL.
For each patient, the team pieced together a complete sequence of RNA extracted from the bone marrow at three time points: at diagnosis, during remission, and upon relapse some months or years later. All told, the project required the researchers to sequence 100 billion letters of RNA. By comparing the before and after sequences, the team found that each patient had acquired between one and six mutations that changed the genetic code over the course of the disease. In some cases researchers were able to detect these mutations in a very small subset (0.01%) of the tissue samples at diagnosis so that these cells likely expanded because their drug resistant properties provided the leukemia cells with a survival advantage.
In all, the team documented 20 relapse-specific mutations—none of which had previously been implicated in ALL recurrences. Intriguingly, two patients harbored a mutation in the same gene, NT5C2, encoding a 5′-nucleotidase, which normally regulates some building blocks used to construct DNA but also can degrade an important class of drugs called purine analogues used in ALL therapy.
When the researchers fully sequenced NT5C2 in 61 other cases in which pediatric ALL patients had relapsed, they found five more mutations that altered the gene’s coding region. Further experiments suggested that these NT5C2 mutations all increased the protein’s enzymatic activity, making the cancer cells more resistant to treatment with nucleoside analog therapies. All seven patients with NT5C2 mutations relapsed within 3 years of the initial diagnosis (P = .03)—an early, particularly hard-to-treat reemergence likely mediated by the drug resistance.
Next Steps
Armed with the new knowledge, Dr. Carroll says doctors may be better equipped to identify patients likely to relapse. “We plan to test the feasibility of screening patients during therapy using sophisticated sequencing technology to pick up low-level mutations in NT5C2 and other genes indicating that a mutant clone is growing,” he says. His team is researching whether that advance warning could allow doctors to administer separate drugs to beat back the cancer cells, and is also working on a strategy to directly inhibit the mutant enzyme.
The research was supported by the National Institutes of Health and National Cancer Institute, with additional support from the American Society of Hematology and St. Baldrick’s Foundation. The study authors reported no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
