A potential Achilles heel of pediatric acute myeloid leukemia

Acute myeloid leukemia (AML) is a type of blood cancer that makes it difficult for the body to fight infection. dr. Joanna Yi, assistant professor of pediatric oncology at Baylor College of Medicine and Texas Children’s Hospital, studies AML in children. In this study, she and her colleagues focused on finding more effective and less toxic treatments for this devastating disease.

Microscopy view of acute myeloid leukemia. National Cancer Institute.

Yi and colleagues’ approach involved identifying molecular drivers of pediatric AML that were specifically expressed in leukemia cells and absent in normal cells.

“This would increase the chances of developing a more effective treatment for AML that would specifically attack the leukemia cells, while having no or minimal effects on normal cells in the body,” Yi said.

Dr Joanna Yi

In general, Yi explained, childhood cancers are genomically silent, meaning there are typically few mutated genes associated with childhood cancer. In addition, the discovered mutations do not appear to be amenable to drug regulation.

super amps

In the current study, the team was the first to identify specific superenhancers (SE) — regions of DNA that direct the overproduction of certain gene products — in cells of children with AML.

These SE were associated with leukemia-promoting genes and were generally different from the previously published SE of adult AML. One SE of specific interest was associated with the RARA gene. Sixty-four percent of the pediatric AML samples the researchers studied had this RARA SE.

Yi and her colleagues were excited to find that tamibarotene slowed proliferation, induced apoptosis, or promoted cell maturation in laboratory cultures of AML cells from patients with the RARA SE. In contrast, cells without the RARA SE were not sensitive to the drug.

In addition, tamibarotene prolonged survival in an animal model of AML with RARA SE, but did not slow cancer growth in an animal model without RARA SE.

Our findings support taking the next step to bring this potential new treatment to the clinic by conducting a clinical trial of tamibarotene in children with AML with high levels of RARA,” said Yi, a member of the Dan L Duncan Comprehensive Baylor Cancer Center.

Curious about all the details of this research? Find it in Blood Advances magazine.

For a full list of collaborators, their affiliations, and the financial sources of this work, visit the publication.

By Ana María Rodriguez, Ph.D.

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