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Gene Mutations Linked to Relapse of Childhood Leukemia
After a 3-year hunt through the genome, medical researchers have pinpointed mutations that lead to drug resistance and relapse in the most common type of childhood cancer — the first time anyone has linked reemergence of the disease to specific genetic abnormalities.
The new findings were reported online in Nature Genetics.
The discovery suggests how scientists may be able to thwart a dangerous form of acute lymphoblastic leukemia (ALL) — a rapidly progressing blood-borne cancer that affects approximately 6,000 people in the U.S. every year and accounts for more than one in four pediatric cancers. Eventually, such information could help physicians to detect the early emergence of chemotherapy-resistant leukemia cells in patients and could allow physicians to switch their patients to a different treatment strategy before the disease fully reasserts itself, the researchers say.
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 the prognosis is dire for about 20% of patients who relapse.
Medical researchers have suspected that the reemergence of ALL could be due to drug resistance, but previous efforts had not uncovered a definitive pathway. For the new study, researchers at five U.S. institutions spent 3 years analyzing multiple bone marrow samples from pediatric patients with ALL for more clues to disease progression.
The researchers analyzed the entire transcriptome — 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 investigators 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 all, the researchers documented 20 relapse-specific mutations — none of which had previously been implicated in ALL recurrences.
Source: NYU Langone Medical Center; February 4, 2013.