Navigation Links
Researchers discover mutations linked to relapse of childhood leukemia
Date:2/3/2013

After an intensive three-year hunt through the genome, medical researchers have pinpointed mutations that leads to drug resistance and relapse in the most common type of childhood cancerthe first time anyone has linked the disease's reemergence to specific genetic anomalies.

The discovery, co-lead 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.

"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 acute lymphoblastic leukemia, a rapidly progressing blood-borne cancer that 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 acute lymphoblastic leukemia, abbreviated ALL, the body's bone marrow produces an abnormally large number of lymphocytes, or white blood cells. Improved treatments have increased the overall cure rate to roughly 80 percent. But Dr. Carroll says the prognosis is especially dire for some 20 percent 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 three years analyzing multiple bone marrow samples from pediatric ALL patients for more clues to the disease's progression.

With the help of the Children's Oncology Group, a multi-institutional clinical trials consortium supported by the National Cancer Institute, the researchers analyzed the entire transcriptomeor the full sequence of RNA from 10 children with pediatric B lymphoblastic leukemia, the most common subtype of ALL. RNA is an essential intermediary in the cellular process that uses DNA blueprints to assemble specific proteins, thus a leukemia transcriptome gives researchers a view of all active genes within the cancerous cells.

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, or spell out, 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 percent) 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 mutationsnone of which had previously been implicated in ALL recurrences. Intriguingly, two patients harbored a mutation in the same gene, NT5C2, which encodes a protein that 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 the NT5C2 gene 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 a chemotherapy treatment designed to force the cells to kill themselves. All seven patients with NT5C2 mutations relapsed within three years of the initial diagnosisan early, particularly hard-to-treat re-emergence likely mediated by the drug resistance.

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.


'/>"/>
Contact: Christopher Rucas
Christopher.Rucas@nyumc.org
212-404-3525
NYU Langone Medical Center / New York University School of Medicine
Source:Eurekalert

Related biology news :

1. Caught in the act: Researchers capture key moments in cell death
2. Researchers harness nature to produce the fuel of the future
3. U. of Minn. researchers unveil first artificial enzyme created by evolution in a test tube
4. Prehistoric humans not wiped out by comet, says researchers
5. Clemson University researchers to study oil and gas operations impact on Gulf Coast pelicans
6. Researchers find a better way to culture central nervous cells
7. Researchers generate a mutant mouse model useful in the treatment of neuromuscular diseases
8. In breast cancer metastasis, researchers identify possible drug target
9. Clemson University researchers: What happens to peaches when the chill is gone?
10. Socially isolated rats are more vulnerable to addiction, report researchers
11. UT Dallas researchers awarded $4.3 million to create next-generation technologies
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:2/6/2017)... , Feb. 6, 2017 According ... security are driving border authorities to continue to ... reports there are 2143 Automated Border Control (ABC) ... currently deployed at more than 163 ports of ... 2013 to 2016 achieving a combined CAGR of ...
(Date:2/2/2017)...  Central to its deep commitment to honor ... Japan Prize Foundation today announced the laureates of ... envelope in their respective fields of Life Sciences ... being recognized with the 2017 Japan Prize for ... to the advancement of science and technology, but ...
(Date:1/26/2017)... , Jan. 26, 2017  Acuity Market Intelligence ... Biometrics and Digital Identity".  Acuity characterizes 2017 as ... when increased adoption reflects a new understanding of ... "Biometrics and digital identity are often perceived ... Maxine Most , Principal of Acuity Market intelligence. ...
Breaking Biology News(10 mins):
(Date:2/22/2017)... -- Aratana Therapeutics, Inc. (NASDAQ: PETX), a pet therapeutics company focused ... for companion animals, will host a live conference call on ... financial results from the fourth quarter and full year ended ... may access the audio webcast or use the ... ...
(Date:2/22/2017)... , Feb. 22, 2017 Scientists propose in ... and organ damage in Gaucher and maybe other lysosomal ... and lower costs than current therapies. An ... Medical Center , which also included investigators from the ... report their data Feb. 22. The study was conducted ...
(Date:2/22/2017)... Ca (PRWEB) , ... February 22, 2017 , ... ... engineers, and scientists from around the world, is pleased to announce the launch of ... technology, engineering and mathematics (STEM) fields. , This merit-based scholarship is open to all ...
(Date:2/22/2017)... ... February 22, 2017 , ... NDA Partners Chairman ... Acting Deputy Director in the FDA CDRH Division of Cardiovascular, Respiratory, and Neurological ... company as an Expert Consultant. , In Dr. Spyker’s accomplished career, he held ...
Breaking Biology Technology: