October 03, 2019
3 min read

Researchers gain insight into link between Down syndrome, acute lymphoblastic leukemia

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Karen Rabin, MD, PhD
Karen Rabin

Children with Down syndrome face a 10 to 20 times higher risk for developing acute lymphoblastic leukemia than children without Down syndrome.

Moreover, ALL among children with Down syndrome has been associated with worse outcomes and more treatment complications.

Despite this knowledge, researchers have yet to understand the mechanisms behind these correlations.

“It’s been a long-standing mystery why these kids have a 20-fold increased risk for developing leukemia,” Karen R. Rabin, MD, PhD, director of the leukemia program at Texas Children’s Hospital, said in an interview with HemOnc Today. “It has been of interest to scientists and doctors, and there have been some theories, but nothing definitive about what causes this.”

To investigate this relationship, Rabin and colleagues conducted a genome-wide association study (GWAS) examining the genetic differences between approximately 500 children with Down syndrome who developed ALL and 1,000 children with Down syndrome but without ALL.

“Our interest for this study was to investigate which other genetic variants cooperate with having an extra copy of chromosome 21, leading to leukemia,” Rabin said. “We wanted to understand which of the children with Down syndrome are more likely to develop leukemia.”

Rabin spoke with HemOnc Today about her study, the need for further research into ALL and Down syndrome, and the potential implications of this research for clinical practice.

Question: What has been the understanding of the Down syndrome/ALL correlation until now, and what did you hope to learn from your study?

Answer: Over the past 10 years or so, GWAS studies evaluating ALL among the general pediatric population have identified gene variants associated with a risk for developing ALL. Nobody has looked specifically at whether children with Down syndrome have those variants or different ones. That’s what we set out to do. We collaborated with investigators at Emory University who have studied congenital heart disease among children with Down syndrome. They had single nucleotide polymorphism array data on a large number of children with Down syndrome with no history of leukemia, and we worked with a number of other investigators to gather SNP array data for children with Down syndrome who do have leukemia. It took a large collaboration, with a lot of different investigators, to put together all the samples for the project. It was about 5 years in the making.


Q: What did you find ?

A: We found some genetic variants that were associated with an increased risk for leukemia, and these variants have been reported among children without Down syndrome, as well. However, we observed a different pattern in terms of which variants showed up in our GWAS; several showed a stronger association with risk for leukemia among children with Down syndrome than there had been among the general population. We don’t know definitively why these variants cause a higher risk, but we tried to look at how they might mediate the risk for leukemia.

To do this, we explored a variant in the Ikaros gene in greater depth. We identified some new features of how the variant alters transcription in cells, and how having a variant in the genetic code at that site may promote leukemia. When we looked at cells that were growing in culture, we saw that when you reduce expression of Ikaros, Down syndrome cells grow faster than non-Down syndrome cells. We still don’t understand why, but we did see, functionally, a different effect in the Down syndrome cells.

Q: What will be the next step in terms of future research on this?

A: We’re doing some other, much more detailed sequencing. Rather than just using an SNP array, which looks at a few genes scattered throughout the genome, we are doing whole-genome sequencing, funded by an NIH grant. This will allow us to look at other variants that we may not have detected with the SNP arrays, and give us some additional information about variants that we could have missed in this study. We are also doing other functional experiments to understand the mechanisms of how leukemia develops in children with Down syndrome.

Q: How do you think these findings might affect clinical practice in the future?

A: This could affect genetic counseling and anticipation of risk among these patients. Also, insights into how leukemia develops can sometimes lead to new treatments. If we understand a gene that’s important in driving the leukemia, then targeting that gene or pathway can be a way to treat the leukemia more effectively.

Q: Is there anything else you would like to mention?

A: This study was a work of team science, using samples from lots of very dedicated and inspired families. These families really want to help in moving research forward, and so do the scientific investigators who have collaborated to make this research possible. – by Jennifer Byrne

For more information:

Karen Rabin, MD, PhD, can be reached at krrabin@texaschildrens.org.

Disclosure: Rabin reports no relevant financial disclosures.