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

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

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