In this interview, we speak to Dr. Jeffery Klco about acute myeloid leukemia (AML) and his recent research that is helping us to understand a new mutation found in pediatric AML.
Please can you introduce yourself, and tell us about what inspired your latest research into acute myeloid leukemia (AML)?
I’m Jeffery Klco, MD, PhD, an associate member of the faculty of St. Jude Children’s Research Hospital. I’m Director of the Division of Hematopathology and Molecular Pathology and Medical Director of Hematopathology and Immunopathology.
I've been interested in AML for about 15 years now. Before I came to St. Jude, I was very focused on AML in adults. One of the main reasons I wanted to come here was to study pediatric AML. I thought that was an area that we knew was different than AML in adults. We knew that there were certain gaps in terms of the known mutations that cause pediatric AML. I had a lot of unanswered questions that I was really interested in trying to understand. I'd always hoped that there would be something like UBTF tandem duplications that we could potentially identify.
St. Jude has several clinical trials underway for AML patients who have lapsed. Through these trials, we have collected a large cohort of samples that have not been adequately studied. Our initial goal was to characterize pediatric relapsed AML, generally. We wanted to understand mutations that can predict relapse. The study started by casting a broad net.
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Despite AML being a disease generally observed in older people, AML can also occur in children. Why is it observed more frequently in adults compared to children?
The types of mutations that cause AML are different in adults and children. Adult AML comes from a lifetime of acquiring mutations that eventually lead to AML. Pediatric AML is caused by fewer more catastrophic events.
While it’s not exclusively found in kids, UBTF-TD mutations are enriched in children. You can find them in adults, but very rarely. There must be something about acquiring this mutation, probably at the right developmental stage that allows leukemia to form.
When AML relapses, it is often more difficult to treat. How does AML relapse and why does this make treatment more challenging?
AML relapses in about 20% of cases. We don’t know the exact reasons why some children relapse, but we do know that there are some molecular features associated with relapse. Those include minimal residual disease (MRD). MRD refers to cancer cells that persist in small numbers after initial treatment, often giving rise to relapse.
Relapsed AML is often more difficult to treat because leukemic cells are typically more resistant to therapies. Usually, relapsed AML is treated with a lot of investigational drugs, because currently there aren't a lot of good options. It is important to look for the UBTF tandem duplication in kids at diagnosis to predict whether they have an increased risk of experiencing a relapse.
Can you describe how you carried out your latest research into pediatric AML? What did you discover?
We used genome sequencing technologies on AML samples gathered from clinical trials conducted at St. Jude. In this cohort, we found UBTF-TD mutations in 9% of relapsed pediatric AML. This makes the UBTF-TD the fifth or sixth most common subtype of pediatric AML, which is a significant number of cases. I had always hoped that there would be something like this out there, but I didn't think we’d find something so common. Many people, including us, have been sequencing these cases. But UBTF-TD turns out to be one of the top molecular categories of pediatric AML.
Using this data, we also looked at outcomes for pediatric AML patients with a UBTF-TD mutation and we found that the children do really poorly. Their rates of minimal residual disease are exceedingly high, probably some of the highest that we've seen. UBTF-TD mutations predict poor outcomes.
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Despite the genomics of AML being studied for years, the UBTF-TD mutation had been overlooked previously. Why is this and how important was it to develop a method to detect this mutation?
To put it simply, UBTF-TD mutations had been overlooked because they were difficult to detect. We didn’t have the necessary tools until our collaborator Xiaotu Ma, Ph.D., from St. Jude Computational Biology, built them.
With Dr. Ma, we looked at the data carefully and, using algorithms his team designed, we were able to detect these mutations. This was so important because now that we know how to look for them, we easily see that UBTF-TD mutations are found in more cases where the children do poorly. We also notice that they lack the other genomic alterations that we were typically looking for.
How will your research help to identify high-risk patients? What benefits will this have not only for research but for the patients themselves and their families?
St. Jude has a robust clinical genomics program, where children being treated can have their genetics analyzed. Now that we know to look, UBTF-TD mutations can be included in our clinical genomics program to help identify kids who are at high risk of poor outcomes. This is important information for physicians to consider when they are making decisions about how to clinically manage a patient’s cancer. The work also tells us that there is still a lot to learn about relapsed disease.
Using tools like those created by Dr. Ma we can learn more about UBTF-TD mutations in AML and other cancers, as well as similar hard-to-find mutations.
Do you believe that your research will also help to guide better treatments for these patients?
Yes, for now, the findings will help with risk stratification, and identifying patients in need of additional or different therapies to treat their disease. But having a new mutation to focus on in these cases is really exciting because in the future it might be possible to target UBTF-TD mutations therapeutically.
In your latest research, you also collaborated with your colleagues in computational biology. How important was this collaboration for your research?
I hope you can stress in your story that this work was really born out of a collaboration between a computational person and a basic and translational scientist. We have different skill sets, but both skill sets are needed to make these types of discoveries.
Dr. Ma had to develop a method from scratch to detect these mutations, and his enthusiasm for the finding caused us to dig deeper into UBTF and pursue these cases. My lab’s expertise with relapsed AML helped bring it all together and understand the finding. You had to have both labs working together to make this discovery.
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What are the next steps for you and your research?
Our next steps are to understand why or how these tandem duplications in UBTF lead to leukemia. We know that the mutations are recurrent in pediatric AML, but we don't really know how they alter the normal function of a cell to turn a hematopoietic progenitor into a leukemia.
Once we get a better understanding of what pathways are altered when they’re in the presence of a UBTF tandem duplication, we will be able to understand, or at least start thinking, about potential therapeutic options. But first, we need to understand how it is working.
Where can readers find more information?
About Dr. Jeffery Klco
Dr. Jeffery Klco is a physician-scientist that received both his MD and Ph.D. at Washington University School of Medicine. He completed his residency in Anatomic Pathology, fellowship in Hematopathology, and trained as a post-doctoral fellow under Tim Ley in acute myeloid leukemia (AML) genomics and mouse models, also at Washington University School of Medicine.
Dr. Klco is a leader in the St. Jude Pathology Department being both the Director of the Division of Hematopathology and Molecular Pathology as well as the Medical Director of Hematopathology and Immunopathology. He has an independent research program focused on defining the molecular and biological causes of pediatric myeloid tumors. As both a physician and a scientist, Dr. Klco is uniquely positioned to tailor his research in the lab to study what he observes in patients to maximize the impact of his results.
Myeloid tumors in children are commonly caused by a different set of mutations than those seen in adults, but the genetics of pediatric myeloid tumors are not well understood. Our laboratory is focused on defining the molecular and biological causes of this class of tumors. We build collaborative partnerships and use genomics to identify new classes of mutations that lead to these cancers.
Our work aims to transform the diagnosis and management of these diseases in children. Uniquely positioned at the interface of basic research and clinical care, our laboratory deciphers the underlying mechanisms of pediatric myeloid tumors.
We use genomic sequencing and -omics analyses to identify novel and recurrent mutations coupled with in vitro and in vivo strategies to model and decipher the molecular mechanisms associated with these genetic alterations. The goal of our research program is to ultimately improve the diagnosis and risk stratification of myeloid tumors and to identify molecular pathways that may be amenable to therapeutic targeting.
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