St. Jude scientists’ discoveries offer hope for some of the tiniest and most vulnerable patients—babies with a rare and aggressive form of leukemia.

When a newborn is placed in mom’s arms for the first time, the introduction begins: “Hello, world.” An assessment commences—hair, nose, pretty eyes, 10 fingers, 10 toes. That’s followed by more detailed numbers: length, weight, respiration rate, heart rate. The tiny, one-of-a-kind individual has captured hearts. Doctors, nurses and family agree: this baby is perfect.

Researchers at St. Jude Children’s Research Hospital are working to make sure precious infants like these have the best chance at life even when the genetic underpinnings are not perfect.

Nipping leukemia in the bud

Alterations in a gene named MLL cause a rare but highly aggressive subtype of acute lymphoblastic leukemia (ALL) in infants. About eight out of 10 infants with ALL have a chromosomal rearrangement that fuses the MLL gene to a gene on another chromosome. The fusion process leads to production of an abnormal protein. And that protein holds the key to converting normal blood cells to leukemia cells.

The resulting disease causes ominous changes to the central nervous system, resulting in bumps on the scalp, lesions extending deeply into the brain, and leukemic cells in the spinal fluid. The long-term survival rate for babies with this subtype of leukemia, which is known as MLL-R, is a dismal 28 to 36 percent.

For doctors and researchers at St. Jude, that survival rate is simply unacceptable.

The St. Jude – Washington University Pediatric Cancer Genome Project has yielded the most comprehensive DNA analysis yet of childhood ALL, with some surprising results. St. Jude scientists discovered that infants with MLL-R had few other genetic changes besides the chromosomal rearrangement. In fact, the subtype had one of the lowest mutation rates of any cancer.

“This is one of the rare subtypes of pediatric ALL where there has been little progress in the last 15 years,” says James R. Downing, MD, St. Jude president and chief executive officer. “These results show we need to develop drugs that target the abnormal proteins produced by the MLL fusion gene or that interact with MLL fusion proteins to shut down the cellular machinery.”

Foiling the fusion

St. Jude researchers are working to identify current drugs and design therapies that will boost cure rates for children with the MLL-R subtype.

Tanja Gruber, MD, PhD, of St. Jude Oncology, is one of those scientists. She is studying the effects of two drugs in combination with standard chemotherapy. The two drugs block the action of proteasomes, which are cellular complexes that break down proteins. By inhibiting the proteasomes, Gruber and her colleagues hope to halt the MLL fusion process altogether.

“To improve survival in these patients, we need to shut down the MLL fusion protein,” Gruber explains.

The drug combo is the backbone of a clinical trial Gruber recently opened for patients whose MLL subtype leukemia returned after treatment. That clinical trial is called REL-MLL. A second study for newly diagnosed infants is scheduled to open this summer. Other sites throughout the United States plan to offer that St. Jude study, which is titled Total Therapy for Infants I or TINI.

Gruber and her colleagues are also working with scientists in St. Jude Chemical Biology and Therapeutics to identify other compounds that are effective against the MLL-R subtype.

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James R. Downing, MD, St. Jude president and chief executive officer, and Tanja Gruber, MD, PhD, of St. Jude Oncology, discuss recent progress in treating babies with a high-risk leukemia subtype, called MLL-R. Gruber recently opened a clinical trial for patients whose disease has returned after treatment.

Significant stats

St. Jude research suggests that in infants the MLL rearrangement requires very few cooperating mutations to cause ALL. By contrast, in older children, MLL-rearranged leukemia requires many more cooperating mutations. St. Jude scientists suspect that in infants the MLL fusion occurs in a unique blood stem cell that no longer exists in older children. This early blood stem cell is easily transformed to leukemia by the MLL rearrangement.

“This may also be why it is so much harder to cure the infants,” Gruber says. “The cancer cell originates from a prenatal blood stem cell that has the ability for robust growth and longevity and is resistant to standard chemotherapy. There is still a lot of work that needs to be done to determine if that is, indeed, the case.”

St. Jude is dedicated to raising the 28 to 36 percent survival rate for MLL-R so that parents of a new baby only have to concern themselves with simpler numbers: “10 fingers, 10 toes.”

Reprinted from Promise, Summer 2015

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