Anatomy of a cancer. Children with acute lymphoblastic leukemia, as that little girl, may relapse after cancerous cells lose or acquire additional DNA.
The Leukemia & Lymphoma Society
What does cancer come back? Nobody really knows, but for a long time researchers have thought that some modifications of the DNA in cancer cells can protect from chemotherapy and allow them to stage a resurgence. Examine one of the most studied cancers, childhood leukemia, a team in Tennessee has now cataloged exactly what happens to these leukemia cells in children who relapse. What they found, but not necessarily true for other cancers, could be a major step toward new ways to prevent relapse and to identify children at risk.
St. Jude Children's Research Hospital in Memphis has one of the best fabrics libraries in the country for acute lymphoblastic leukemia (ALL), the most common childhood cancer. Although the cure rate for all jumped single digits to over 80% today, some children still relapse. For them, the chance of survival decreases dramatically, to about 30%, says James Downing, scientific director of St. Jude. These children remain one of the biggest challenges for all specialists.
Wondering what changes in DNA could be responsible for these relapses, Downing, hematologist and pathologist Charles Mullighan, and their colleagues at St. Jude focused on a particular type of pattern of DNA, called copy number. Increasingly, researchers are finding that additional sections of DNA, or DNA that is deleted in some people - so-called changes in copy number (CNA) - appear to play a role in the disease, in particular neuropsychiatric condition such as autism or mental retardation ( science NOW, November 14).
their tissue bank, the team eliminated the 61 samples of all patients who had relapsed and compared samples at diagnosis with those taken when the cancer returned. Tomorrow Science Downing and colleagues report that 92% of leukemia cells in relapsed patients harbored changes CNAs; most often, they found a loss of DNA that caused some genes off. A total of 15 genes had lost DNA relapse, and two genes had gained DNA. Many genes control cell division or development of immune cells, which goes awry in certain leukemias. To the surprise of Downing, CNAs does not seem to be hitting genes involved in drug resistance. Some doctors have assumed that the resistance was important because patients with ALL who relapse often respond poorly to chemotherapy.
Where did the CNAs come from? In many cases, CNAs present at diagnosis appeared in much of the relapse cells, suggesting that they managed to escape treatment and proliferate while others leukemic cells died. Another possibility is that the DNA changes appeared after chemotherapy. Several experts dismissed this theory, however, because the changes occurred in genes associated with leukemia, not at random in the genome.
In terms of treatment, hematologist-oncologist Matthew Walter, of Washington University in St. Louis, Missouri, suggests focusing on CNAs who can score an "ancestor" preleukemia cell in the bone marrow ; Downing found the group sets of CNAs in samples of relapse and diagnosis from the same child that overlapped, but not the same. Some CNAs were lost to relapse and others have won. What happened, they deduced, because all CNAs were probably ancestors of the cells that helped spawn leukemia and later relapse. "Maybe these are the changes that our therapies should be addressing," he said.
The work "is fascinating to many viewpoints" and "perhaps raises more questions than answers," says Bert Vogelstein oncologist at Johns Hopkins University in Baltimore, Maryland. Although known for years that ALL and other cancers that relapse usually acquire new genetic changes, "we were expecting not there so many" as seen here, said Vogelstein .
Puzzles remain. Not all results involved CNAs, for example. Seven children actually lost all CNAs present to relapse, and five children had no change in CNAs between diagnosis and relapse. Furthermore, much less CNAs in childhood leukemia appear more aggressive and lethal, acute myeloid leukemia. Downing is studying whether the results can all be used at diagnosis to identify patients who have a high or low risk of relapse.
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