ACS Research Highlights

Seeking Out the Cause of a Rare, Aggressive ChildhoodLeukemia

Researchers’ evaluation of data from 5,000+ children with cancer may open new avenues for diagnosis, prognosis, and treatment of AML.

The Challenge

Acute myeloid leukemia (AML) in children and young adults is a challenging disease to treat. Currently, the chemotherapies used to kill leukemia cells can affect several body systems. The side effects can be widespread and long-lasting, including infertility, heart failure, and the development of second cancers.

Children with AML need a more focused and personalized treatment approach using precision oncology, which involves treatment with targeted therapy drugs that recognize and kill only the unique attributes of childhood AML. So far, though, there are few targeted drugs available to treat childhood cancers. 

Many childhood cancers are caused by a rearrangement of the chromosomes. One obstacle to finding more precise treatments for AML is that children who have it can have different gene and chromosome changes, and some are more common than others. Cancer researchers are trying to figure out why these changes occur and how each type of change might lead to leukemia.

With AML, that rearrangement of chromosomes brings together two genes that are normally not found near each other. This rearrangement can result in cancer-causing genes called oncogenic fusion genes.

Oncogenic fusions have been recognized as important causes of cancer for decades, but they have been difficult to detect, especially in childhood cancers. 

That’s because chromosomal rearrangements can result in many different fusion genes, and some of them define the subtypes of AML. Thanks to advances in next-generation gene sequencing, bioinformatics, and computational biology, the ability to identify and understand these fusions has greatly increased in recent years.

Oncogenic fusions may lead to the production of defective proteins that cause cancer to grow and spread. They persist through treatment and may predict outcome. 

By learning more about them, scientists may be able to develop new drugs that target the oncogenic gene fusions, the defective proteins they produce, or both, to stop cancer in its tracks. 

Glossary for Nonscientists

Featured Term:
Oncogenic Fusion Gene

A hybrid gene formed from 2 or more previously independent genes that plays a leading role in the development and progression of cancer. These fused genes are read (transcribed) and translated as a single unit, which may lead to the production of defective proteins that cause cancer to grow and spread.

The prevalence of fusion genes varies widely across different cancers, and many fusion genes are specific to certain cancer sub-types. 

Also see the glossary to learn about computational biology,CRISPR, and next-generation sequencing (NGS).

The Research

Soheil Meshinchi, MD, PhD, is a world-renowned pediatric AML expert who runs one of the only labs in the country developing cures for children with high-risk AML. He tailors his research to childhood cancers aimed specifically at patients under 5 years old.

Meschinchi is a recognized expert in:

  • Large-scale studies of the many genes (the genome)
  • RNA molecules that are made from genes (the transcriptome)
  • Small chemical changes that can substantially change the activities of genes, RNA, and proteins (the epigenome) so that they promote the start of leukemia and its progression

In a recent paper published in Nature Communications, Meshinchi and his research team analyzed data from more than 5,000 childhood cancer patients to explore how the oncogenic fusions contributed to their disease. The research was partly funded by a research grant from The American Cancer Society and St. Baldrick’s Foundation.

In this study, we extracted information from a large database to better understand the etiology—the specific factors that shape the formation of—oncogenic fusions. We found that some specific causes lead to a higher risk of developing cancer than other causes do. In the future, researchers and doctors may be able to use this genetic information to determine a diagnosis and prognosis.”

Soheil Meshinchi, MD, PhD 
Fred Hutch Cancer Center, Seattle WA
ACS and St. Baldrick's Foundation Grantee 

The researchers reported the identification of 272 different oncogenic fusions (by using tumor transcriptome sequencing data) that appear to have a role in childhood AML. Then, they used tools to identify the factors that led to the formation of these fusions — information that provided a comprehensive picture of how these oncogenic fusions may contribute to the formation of cancer. 

“We found new separation points along DNA that seem to be good areas for using genome editing as part of treatment,” Meshinchi says. He and his team examined cell lines that contained oncogenic fusions to study a potential therapeutic approach that used CRISPR-Cas9, a gene editing tool. They demonstrated how CRISPR-Cas9 could be used to target cells containing a particular oncogenic fusion and stop their growth.

Why Does It Matter? 

By identifying oncogenic fusions linked to specific cancers, Meshinchi and his collaborators hope they can eventually develop testing methods to look for oncogenic fusions or other genetic causes driving cancer in every child with AML, as well as other types of cancer.

Having knowledge about which oncogenic fusion genes are present in a child’s cancer may help guide the development of targeted drugs that are tailored to each patient. This study’s demonstration of methods and tools may point the way to further the development of CRISPR-Cas9-based gene editing techniques for treating cancer — an approach that is considered promising.

Learning more about the genetic subtypes in AML could also lead to better prognostic tools, which would help to predict how quickly leukemia might spread from the bloodstream and into other parts of the body (like into the lymph nodes or spinal cord) how likely it is to come back, and how well it will respond to treatment.