Currently we test and support the following browsers:
St. Jude scientists identify a completely new and deadly subtype of leukemia that arises from early T-cell precursors. The discovery allows early detection and therapeutic intervention to improve the outcome for children with this form of drug-resistant leukemia.
Upon discovering their child has leukemia, parents tumble into a dizzying vortex of emotions. For one agonizing heartbeat, the sun ceases to shine; the atmosphere loses its oxygen; the world tilts on its axis. The universe narrows down to one overwhelming question: “Will our child survive?”
If the child has acute lymphoblastic leukemia, the most common form of cancer in children, the answer is most likely “yes.” But if the patient has T-cell acute lymphoblastic leukemia (T-ALL), that question is more difficult to answer.
T-ALL is a type of leukemia in which immature white blood cells called T cells proliferate in the child’s blood and bone marrow. Normally, T cells are an important component of the human immune system. Their job is to seek out and destroy invaders. But when these cells run awry, they crowd out normal blood cells, wreaking havoc and—if unchecked—causing death. In fact, about one in five children with T-ALL die of the disease.
In 1973, researchers at St. Jude Children’s Research Hospital were the first scientists to identify T-ALL as a distinct subtype of acute lymphoblastic leukemia. Since that time, research on this disease has continued at the hospital, as investigators work to unlock its mysteries and to determine how to save the lives of more children.
“The survival rate for ALL now exceeds 90 percent,” explains Dario Campana, MD, PhD, of St. Jude Oncology. “It is extremely important that we identify the small subset of patients who cannot be cured with traditional therapy.”
Campana and his colleagues recently identified an aggressive subtype of T-ALL that is resistant to standard chemotherapy. They dubbed the new subtype ETP-ALL, since it arises from early T-cell precursors (ETPs). Children with this new subtype account for many of the deaths attributed to T-ALL. Because of this discovery, clinicians worldwide will now be better able to identify and treat children with this disease.
“One of the principles of modern leukemia treatment is to avoid over-treatment or under-treatment,” Campana explains. “It is extremely important to identify immediately which patients have a higher risk of relapse and need to be treated with aggressive chemotherapy or transplant. It is equally important to determine who can be successfully cured with much less-intensive and less-toxic treatment. Until now, we didn’t have solid classifications that would allow us to make these kinds of decisions for patients with T-ALL, so they were all treated in the same way.”
Like blood stem cells, ETPs are immature cells that have the ability to differentiate into several kinds of cells. Elaine Coustan-Smith of St. Jude Oncology suggested that leukemia originating from ETP cells might be more resistant to therapy than other kinds of leukemia. She and her colleagues then used genetic and immune screening to examine 139 cases of T-ALL that occurred at St. Jude within a 15-year period. The team discovered that 17 of those children had the ETP signature.
“For many years, we have stored samples from our patients,” Coustan-Smith explains. “Fifteen years ago, the technology was not sophisticated enough to allow this kind of analysis. Fortunately, we had samples that were in such good shape that we could thaw them out and analyze them.”
The scientists found that less than one-fifth of St. Jude patients with the ETP signature had survived the disease. The children who did survive had undergone bone marrow transplantation. To validate these findings, the researchers also analyzed records and samples from 100 children treated in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica. Thirteen patients had the cell marker profile that indicated ETP-ALL. Of those children, the two-year survival rate was zero.
Because of this discovery, St. Jude will recommend bone marrow transplantation to any patient who is found to have ETP-ALL, according to Ching-Hon Pui, MD, St. Jude Oncology chair.
“The vast majority of ETP-ALL patients treated with the best-available chemotherapy would still relapse,” Pui explains. Children exhibiting ETP-ALL will receive irradiation and drugs to eradicate their residual leukemic cells and bone marrow cells. The patients will then receive new blood-forming stem cells.
Armed with information from this study, other institutions will also be able to screen their patients for the new subtype. A report on the research was published earlier this year in The Lancet Oncology.
“The markers that we use to identify ETP-ALL are used routinely by everyone who does immunophenotyping of leukemia,” Campana says. “People never noticed this subset of leukemia before because they never came across the right combination of markers.”
First, the scientists want to find ways to make the cancerous cells sensitive to treatment or to identify new drugs that would target those cells. “Maybe there are ways to manipulate these cells in such a way that they become more responsive to conventional chemotherapy,” Campana says.
The investigators are also interested in more closely analyzing the molecular features of ETP-ALL. Charles Mullighan, MD, PhD, of St. Jude Pathology played an important role in characterizing the ETP-ALL subtype for the project.
“We examined gains and losses of DNA across the genome and found that there was a lot of genomic instability in this subgroup,” Mullighan says. “However, at present we have not identified a genetic change common to all patients with this type of leukemia. We plan to apply new methodologies and sequencing techniques to identify the genetic basis of this disease.”
“We also want to see whether transplantation is really an effective curative option and whether cell therapy strategies can be applied to ETP-ALL,” Campana adds.
“There is still a lot for us to do.”
Reprinted from Promise Summer 2009
To comment on this article, click here.