Researchers discover potential Achilles heel of pediatric acute myeloid leukemia

Researchers at Baylor College of Medicine and Texas Children’s Hospital have uncovered a possible Achilles heel of childhood acute myeloid leukemia (AML) that could lead to new treatments for this devastating disease.

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.

AML cells with a RARA SE were sensitive to treatment with the drug tamibarotene in laboratory cultures and in animal models, prolonging survival and reducing the leukemia burden. In contrast, AML cells lacking RARA SE were not sensitive to tamibarotene treatment. The findings, published in Blood Advances, support the development of a clinical trial to evaluate tamibarotene in children with AML with high RARA levels.

Our team is interested in finding new drugs that are more effective and less toxic to treat children with AML.”

dr. Joanna Yi, corresponding author of the study and assistant professor of pediatric oncology at Baylor and Texas Children’s

dr. Yi and her team are trying to identify molecular causes of childhood AML that are 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,” explains Yi.

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

As with other disorders, malfunctioning gene regulators can alter the production of normal gene products. For example, super-enhancer gene regulators can cause an overabundance of a certain normal protein, which can disrupt cellular functions in ways that can lead to cancer.

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 and 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,” Yi said.


Baylor College of Medicine

Reference magazine:

Perez, MW, et al. (2021) Defining the transcriptional control of pediatric AML highlights RARA as a superenhancer-regulated drug addiction. Blood Progress.

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