Newswise — When acute myeloid leukemia (AML) relapses, it is more difficult to treat and outcomes are dismal. Scientists at St. Jude Children’s Research Hospital have discovered a mutation in pediatric AML that physicians can use to identify high-risk patients and better guide treatment. A paper on the work appeared today in Blood Cancer Discovery, a journal of the American Association for Cancer Research.

“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.

Authors and Funding

The study’s other corresponding author is Soheil Meshinchi, Fred Hutchinson Cancer Research Center. The paper’s co-first authors are Masayuki Umeda and Jing Ma, both of St. Jude.

Additional authors are Benjamin Huang, University of California Benioff Children’s Hospital; Andrew Kleist, Medical College of Wiscosin; Amanda Leonti, Rhonda Ries and Jenny Smith, Fred Hutchinson Cancer Research Center; Yi-Cheng Wang, Children’s Oncology Group; Todd Alonzo, Keck School of Medicine University of Southern California; and Kohei Hagiwara, Liqing Tian, Yanling Liu, Xiaolong Chen, Pandurang Kolekar, Quang Tran, Scott Foy, Bengsheng Ju, John Easton, Delaram Rahbarinia, Michael Rusch, Jinghui Zhang, Tamara Westover, Sherif Abdelhamed, Juan Barajas, Melvin Thomas III, Michael Walsh, Guangchun Song, Jamie Maciaszek, Yen-Chun Liu, Evan Parganas, Illaria Iacobucci, Ryan Hiltenbrand, Huiyun Wu, Virginia Valentine, Marcus Valentine, Jonathan Miller, Jason Myers, Evadnie Rampersaud, Gang Wu, Hiroto Inaba, Stanley Pounds, Madan Babu, Jeffrey Rubnitz, Charles Mullighan and James R. Downing, all of St. Jude. 

The study was supported by grants from the National Institutes of Health (P30CA021765, R01-CA114563-10, U10-CA098543, U10-CA180899, U10CA180886), the Fund for Innovation in Cancer Informatics, St. Baldrick’s Foundation, Target Pediatric AML, Leukemia and Lymphoma Society, Andrew McDonough B+ Foundation, Hyundai Hope on Wheels, Project Stella, Burroughs Wellcome Fund, V Foundation Scholar Award and ALSAC, the fundraising and awareness organization of St. Jude.

 

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is leading the way the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. Treatments developed at St. Jude have helped push the overall childhood cancer survival rate from 20% to 80% since the hospital opened more than 60 years ago. St. Jude freely shares the breakthroughs it makes, and every child saved at St. Jude means doctors and scientists worldwide can use that knowledge to save thousands more children. To learn more, visit stjude.org or follow St. Jude on social media at @stjuderesearch.

Journal Link: Blood Cancer Discovery,