In today’s program, we continue our series on disease subtyping with Dr. Jeffery Klco, a pediatric pathologist and researcher at St. Jude Children’s Research Hospital. Dr. Klco joins us to discuss groundbreaking work recently published in Nature Genetics, which redefines the genomic landscape of childhood acute myeloid leukemia (AML).

Klco and his team have identified twelve novel molecular subtypes of pediatric AML—some driven by genetic alterations that had long gone undetected by standard computational tools. Chief among these is the UBTF tandem duplication, a complex mutation previously overlooked but now shown to be a distinct disease subtype that accounts for up to 10% of pediatric AML cases and is associated with relapse and poor outcomes.

“We’ve been misclassifying childhood AML for years,” says Klco. “It’s the same disease as in adults—but it behaves very differently. And we’ve been using an adult framework to treat kids.”

* 0:00 We’ve been misclassifying childhood AML

* 7:25 Challenges with current treatment paradigm

* 11:05 Doing clinical whole genome and RNA sequencing

* 17:25 How might this new approach work for other pediatric cancers?

The conversation delves into how St. Jude’s use of whole genome and RNA sequencing, paired with advanced analytics, has enabled more precise subtyping. In response, Klco’s team is already developing targeted therapies, including the use of menin inhibitors, which have shown early promise.

But discovery is just one side of the coin. Implementation is another. Klco discusses the development of a new 357-gene panel—specifically designed for pediatric cancers and incorporating structural variants—that is now in clinical use at St. Jude. It fills key gaps in diagnosis, risk stratification, and minimal residual disease monitoring, especially in complex cases such as post-transplant patients or those whose tissue samples are incompatible with full genome sequencing.

Asked about future potential, Klco notes that while most pediatric cancers may now be genomically defined, new methods such as long-read sequencing and methylation profiling still hold promise for sharpening diagnostic tools and stratifying risk.

“Pediatric cancers are driven by different genomic forces than adult cancers,” he explains. “Even within the first 18 years of life, we see distinct subtypes emerge at different ages. If a child under three comes in with AML, I already have a good idea what subtype it might be.”

It’s a compelling example of how detailed genomic subtyping is not only advancing our understanding of pediatric disease—but directly shaping the next generation of therapies.

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