Childhood Leukemia: High Risk, High Rewards

New insights into rare leukemias

Only a small number of children have the form of AML Stella has. Another subtype, known as core-binding factor acute myeloid leukemia (CBF-AML), accounts for about 20 percent of childhood AML cases. Recently an international team headed by St. Jude scientists created a detailed map of the genetic variations that drive CBF-AML.

Researchers had already identified two genes affected by chromosomal rearrangements in CBF-AML. Until recently, scientists did not know what other mutations worked with those rearrangements to cause disease.

Jeffery Klco, MD, PhD, of St. Jude Pathology, teamed up with Downing; St. Jude Computational Biology Chair Jinghui Zhang, PhD; and other scientists to identify the genetic changes that contribute to this cancer.

The findings were an outgrowth of the St. Jude – Washington University Pediatric Cancer Genome Project, an unprecedented initiative to uncover the genetic origins of childhood cancer.

“This study highlights how the Pediatric Cancer Genome Project continues to generate new insights into genetic alterations and cooperating mutations that give rise to diseases like AML,” Downing says.

Scientists are already at work to determine the precise roles of the genetic changes discovered as part of that study.

Homing in on ALL

As teams of researchers toil to solve the mysteries of AML, scientists in nearby labs and clinics study rare ALL subtypes. ALL is the most common childhood cancer, so even though its overall survival rate is 94%, it remains one of the top causes of childhood cancer deaths. The 6% of children who are not cured often have high-risk subtypes or have disease that is initially identified as standard-risk and yet fails to respond to treatment.

“Every person is important, so obviously we want to cure every child with ALL,” says St. Jude pathologist Charles Mullighan, MD, MBBS, who has spent most of his career identifying new subtypes of the disease. His work has led to many new approaches to diagnosis and therapy, with several of his discoveries incorporated into precision medicine trials.

Last fall, the American Society of Hematology honored Mullighan for his success in providing insights into the genetic basis of ALL, particularly high- risk forms of the disease.

And yet, for all his expertise even Mullighan cannot yet identify exactly how many high-risk subtypes are in existence.

“There’s still an appreciable chunk of leukemia cases—both in children and adults—that don’t fall into one of the subgroups historically defined by conventional methods,” says Mullighan, who predicts the main subtypes of ALL will soon be mapped.

“There will always be more to learn,” he says. “You’ll always find another gene or another type of mutation or another fusion partner, but the overall grouping will be largely resolved in the next year or two as some very large studies come to completion.”

The best place

Mullighan and his colleagues have experienced great success in uncovering new information about high-risk subtypes.

Last October, Mullighan led an international team that discovered the genetic origins of one subtype of B-precursor ALL. The researchers described a unique mechanism showing how one genetic change or rearrangement—in this case, a gene called DUX4—can trigger another change in regulation of a second gene, ERG, which then results in leukemia. That paper is the culmination of research Mullighan began when he was a postdoctoral fellow in 2004.

“The study highlights the importance of detailed genetic study to fully understand how the disease develops,” he says. “While we advanced our understanding over several years, it wasn’t until the advent of genome sequencing that we could crack the case.”

A month after that paper published, he and his colleagues revealed new details about a new, high-risk ALL subtype called MEF2D-rearranged ALL. The team also found a promising targeted therapy for patients with that disease.

Also in November of 2016, Mullighan’s lab announced that the prevalence of Ph-like ALL remains high among adults of all ages with ALL. The researchers found that the outcome for these patients may be improved by using medications that are already available.

Mullighan says he’s in the best place to make those kinds of discoveries.

“St. Jude offers the perfect convergence of opportunity and resources and expertise,” he explains. “There’s the hospital’s mission and its strategic direction; the infrastructure and resources; the historic biorepository of tumor samples; our leading role in frontline leukemia trials; our collaborations with investigators around the world; and our culture of very careful annotation, follow-up and uniform treatment of children with leukemia.

“Those things are often done elsewhere,” he adds, “but it’s rare that everything is under the same roof like it is here.”

Reasons for the research

All of those discoveries are occurring on the same campus where Stella Ellwood is pursuing equally important activities.

While she’s fighting for her life, she’s making jewelry and painting pictures. Reading books and playing practical jokes on her mommy. Swinging on the playground and playing dress-up. Making plans to be a pediatrician when she grows up.

If all goes according to schedule, Stella will undergo a bone marrow transplant in the summer of 2017. Then this bright and intelligent little girl will return home to Maryland with her loving family—who have always known, after all, that Stella truly is the rarest of the rare.

From Promise, Spring 2017