Given the high mortality rate of acute myeloid leukemia, an aggressive cancer that forms in the developing blood cells of bone marrow, researchers at the University of Colorado Anschutz Medical Campus are looking at how to improve treatment methods.
A potential answer, they have found, may be inhibiting a gene called the signal transducer and activator of transcription-3 (STAT3), explained Maria Amaya, MD, PhD, an assistant professor in the Division of Hematology and a University of Colorado Cancer Center member.
As part of the CU Department of Medicine’s recent Research Achievement Highlights (REACH) forum, Amaya presented her research into the role STAT3 plays in acute myeloid leukemia and ways to target it.
“Acute myeloid leukemia is one of the most aggressive leukemia types,” Amaya said. “We definitely need better therapies for this cancer.”
Targeting leukemia stem cells
An estimated 20,800 new cases of acute myeloid leukemia will occur in 2024, according to the National Cancer Institute. It is most commonly diagnosed among older adults, and the median age at diagnosis is 69.
The relative five-year survival rate — which is an estimate of the percentage of patients expected to survive five years or more after being diagnosed — is 31.9%.
“We think the reason why this leukemia is so aggressive, and why we have a difficult time healing these patients, is because they have these leukemia populations called leukemia stem cells,” Amaya said. “When patients develop leukemia, they have a leukemia stem cell that can give rise to the whole disease, which is what we call the myeloblast.”
Typically, when patients are treated with intensive induction chemotherapy or targeted therapies, the myeloblasts are eliminated.
“But some of these leukemia stem cells can be left behind, and they give rise to relapse disease. This is what we typically see a few years later, in the absence of curative therapies,” Amaya said.
“Our whole goal in our field has been to target leukemia stem cells that give rise to the disease,” she continued. “If we target those, we can probably have more durable remissions for these patients.”
The role of STAT3
Research studies have shown that leukemia stem cell populations behave differently than many other cancer cells, as these cells rely mostly on mitochondrial activity and oxidative phosphorylation (OXPHOS) as a source of fuel and survival.
OXPHOS is a cellular process that contributes to the formation of the energy-carrying molecule adenosine triphosphate (ATP).
“We’ve been focusing, in the last several years, on trying to find a pathway where we can target mitochondrial function and OXPHOS in these leukemia stem cells,” Amaya said.
Research has shown that one way to obstruct OXPHOS is by targeting the STAT3 gene, which is involved in many important pathways of leukemia survival.
Amaya was the first author of a paper published in 2022 that found STAT3 is highly expressed in primary acute myeloid leukemia cells, and it plays a role in OXPHOS. Data also showed STAT3 localized to the mitochondria of many of the acute myeloid leukemia cells.
“Next, we wanted to target mitochondrial STAT3,” she said.
How a small molecule can lead to cell death
Research has shown that a small molecule called “stattic” can inhibit STAT3, launching a domino effect that can ultimately lead to the death of the leukemia stem cell.
Through experiments, Amaya and her colleagues found that using stattic to inhibit STAT3 resulted in mitochondrial dysfunction.
They also found that STAT3 appears to interact with the protein known as “voltage-dependent anion channel” (VDAC1). Located in the outer membrane of the mitochondria, VDAC1 is important for many functions of the mitochondria. Research showed that when STAT3 was inhibited, VDAC1 decreased.
“We think that STAT3 localizes to the mitochondria and interacts with VDAC1, and then if we inhibit STAT3, this increases reactive oxygen species in the mitochondria, decreases calcium, causes mitochondrial dysfunction, and ultimately, cell death,” Amaya said.
“What we care about is: Can we actually target the leukemia stem cells if we target STAT3? And the answer is yes,” she continued.
She noted that further research is needed on STAT3 inhibition — something that she and her colleagues continue to work on.
“All of this research, we do it for our patients,” Amaya said, expressing gratitude to researchers at the CU Anschutz Medical Campus who continue to work at advancing knowledge and improving therapeutic interventions.
Photo at top: Maria Amaya, MD, PhD, pictured center, smiles alongside fellow researchers in her lab, the Amaya Lab.
June 25, 2024