Research reveals high-risk subtype of relapsed pediatric AML
“We started broadly because it was clear that we didn’t have a deep enough understanding about why kids with AML relapse in the first place,” said co-corresponding author Jeffery Klco, M.D., Ph.D., St. Jude Department of Pathology. “We have a number of clinical trials at St. Jude for relapsed AML, so that gave us access to a large cohort of samples, and that is where the collaboration with our colleagues in Computational Biology became really beneficial to help us analyze the genetics.
“It became clear early on that there was a group of cases who had curious alterations in this gene UBTF, which had really only been superficially considered in the past,” Klco said.
A new high-risk subtype
The researchers evaluated the genomics of 136 St. Jude patients treated for relapsed AML. A specific type of mutation called a UBTF exon 13 tandem duplication (UBTF-TD) occurs in 9% of relapsed pediatric AML. This represents a significant and previously unrecognized subtype.
UBTF-TD AML is more common in children than adults. It is also associated with poor outcomes and an increased incidence of minimal residual disease (MRD). MRD refers to cancer cells that persist in small numbers after initial treatment, often giving rise to recurrence of the cancer.
Genetic analysis
The genomics of AML have been studied for many years, but this mutation has been mostly overlooked or undetected in previous work. Researchers at St. Jude developed the computational approaches to identify this, and potentially similar mutations, in AML and other cancers.
“This is an extremely difficult mutation to detect, so a lot of work went into developing the right algorithms. We had to develop our method from scratch,” said co-corresponding author Xiaotu Ma, Ph.D., St. Jude Department of Computational Biology. “Most of the existing methodologies assume there is only one event creating these kinds of mutations but, as with UBTF-TD, that isn’t always the case.”
“Now that we know what we’re looking for and how to find it, we can readily incorporate it into clinical genomics,” Ma said.
Clinical genomics can be used to screen for UBTF-TD mutations in AML to help identify high-risk patients. This process is already underway at St. Jude. The findings also open up new areas of investigation, including findings ways to target the protein created by UBTF-TD and determining how the aberrant peptide contributes to leukemia.