Chromosomal rearrangement is key to progress against aggressive infant leukemia
A highly aggressive form of leukemia in infants has surprisingly few mutations beyond the chromosomal rearrangement that affects the MLL gene, according to new research published in Nature Genetics (2015; doi:10.1038/ng.3230). The findings suggest that targeting the alteration is likely the key to improved survival.
The study, conducted by The St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project, is the most comprehensive analysis yet of this rare but aggressive subtype of pediatric acute lymphoblastic leukemia (ALL) that occurs during the first year of life and is sometimes diagnosed at birth.
The leukemia cells of up to 80% of infants with ALL have a chromosomal rearrangement that fuses the MLL gene to a gene on a different chromosome. The resulting MLL fusion gene encodes an abnormal protein. The fusion protein plays a key role in transforming normal blood cells into leukemia cells.
Researchers used whole genome sequencing and other techniques to identify the genetic alterations in 65 infants with ALL, including 47 with the MLL rearrangement. Scientists were surprised to find that despite being an aggressive leukemia, the MLL rearranged subtype had among the lowest mutation rates reported for any cancer.
"These results show that to improve survival for patients with this aggressive leukemia we need to develop drugs that target the abnormal proteins produced by the MLL fusion gene or that interact with the abnormal MLL fusion protein to shut down the cellular machinery that drives their tumors," said senior and co-corresponding author James R. Downing, MD, president and chief executive officer of St Jude Children's Research Hospital in Memphis, Tennessee. "That will not be easy, but this study found no obvious cooperating mutations to target."
St. Jude researchers are working to identify compounds and develop combination therapies to improve cure rates for infants with the MLL rearrangement. Nationally, 85% of pediatric ALL patients now enjoy long-term, cancer-free survival compared to 28% to 36% of infants with the high-risk subtype.
"We frequently associate a cancer's aggressiveness with its mutation rate, but this work indicates that the two don't always go hand-in-hand," said co-author Richard K. Wilson, PhD, director of The Genome Institute at Washington University School of Medicine in St. Louis, Missouri. "Still, our findings provide a new direction for developing more effective treatments for these very young patients."
Almost half of infants with MLL-rearranged ALL had activating mutations in the biochemical pathway tyrosine kinase-phosphoinositide-3-kinase (PI3K)-RAS pathway. Surprisingly, the mutations were often present in only some of the leukemic cells. Researchers analyzed leukemia cells in infants whose cancer returned after treatment and found that at the time of relapse the cells lacked the pathway mutations.
"The fact that the mutations were often lost at relapse suggests that patients are unlikely to benefit from therapeutically targeting these mutations at diagnosis," Downing said.
Researchers also found that older pediatric patients with leukemia that has the MLL-rearrangement had significantly more mutations than infants. Almost half of the older children had mutations in genes that encode epigenetic regulatory proteins. Epigenetic proteins influence activation of other genes.
The researchers explained that their observation raises the possibility of a fundamental difference in the cell targeted for transformation in infants versus older patients.