Leukemia: Do genes influence how people respond to therapy?

Acute myeloid leukemia, or cancer that affects the bone marrow, progresses at a fast rate. Its causes are not yet well understood. A common treatment for this type of leukemia is chemotherapy, but some people respond to it better than others. A new study explains why that is.

According to a recent study — the findings of which now appear in the journal JCI Insight — the chemotherapy approach fo acute myeloid leukemia (AML) has a response rate of 40–70 percent.

However, "over half of patients relapse within 3 years."

What makes some individuals respond better to treatment, and who is less likely to experience a relapse following therapy?

First study author Dr. Irum Khan and his colleagues from the University of Illinois at Chicago (UIC) report that about a third of people diagnosed with AML have a specific variant of a gene called NPM1, and it is these people who have a better response to treatment.

In their study, the researchers show how the NPM1 mutation benefits people with AML, and they discuss how their findings may lead to better, more efficient therapy for this condition.

A key genetic mutation

As the researchers explain, the association between the NPM1 gene mutation and the improved response rates was first spotted by UIC researcher Andrei Gartel and colleagues in previous studies.

NPM1 encodes the protein of the same name, which, in turn, regulates the activity, and influences the position, of another protein known as FOXM1. Usually, the NPM1 protein keeps FOXM1 in the cells' nuclei.

In cancer cells, this allows FOXM1 to activate certain oncogenes, or genes that play a role in cancer growth when active. People with highly elevated levels of FOXM1 often see poorer outcomes following treatment.

However, in individuals with the specific mutation in the NPM1 gene, FOXM1 is "pushed" out of the cell nucleus — where it can influence gene activity — and into the citoplasm, thus ensuring that this protein is "isolated" and unable to interact with oncogenes.

This means that people with the NPM1 gene mutation respond better to chemotherapy, as well as experience better long-term outcomes.

Due to these results, the UIC researchers hypothesized that if they could target and block FOXM1 in people with AML who do not have the beneficial NPM1 gene variant, they might be able to improve those individuals' responses to chemotherapy.

How one protein impacts prognosis

In the new study, Khan, Gartel, and colleagues decided to have a closer look at the mechanisms of the NPM1 and FOXM1 protein in cases of AML. First, they collected and analyzed samples of bone marrow cells from 77 people diagnosed with this condition.

The researchers' analysis confirmed that the presence of FOXM1 in cell nuclei was associated with a poorer response to chemotherapy.

"When we then looked in the patients' medical records, we saw that those with FOXM1 present in the nucleus of their cancer cells had worse treatment outcomes, higher rates of chemotherapy resistance, and lower survival rates compared to patients without FOXM1 present in the nucleus."

Dr. Irum Khan

They also tested these outcomes in a mouse model of leukemia, with rodents engineered to produce more FOXM1, which would stimulate the development of this disease.

When these mice were treated with cytarabine, a chemotherapy drug that is frequently used in AML therapy, the researchers noticed that these animals responded less well to the treatment, compared with a control group of rodents with leukemia but with normal FOXM1 levels.

"Our finding suggests that overexpression of FOXM1 directly induces chemoresistance [resistance to chemotherapy], which matches what we saw in our analysis of patients' FOXM1 levels and their treatment outcomes," says Khan.

The search for better therapy

Finally, the research team used in vitro experiments on AML cells to test the effectiveness of a new drug — ixazomib, which is currently used to treat multiple myeloma, a type of blood cancer — in treating myeloid leukemia.

The researchers saw that ixazomib showed promise, particularly as it blocked FOXM1 activity within cells.

Also, when Khan and colleagues treated the AML cells both with ixazomib and chemotherapy drugs typically used to address myeloid leukemia — such as cytarabine and anthracyclines — the cancer cells died at a much higher rate, compared with when they applied only standard chemotherapy.

"Ixazomib," explains Gartel, "produced a synergized chemotherapeutic response when added to standard chemotherapy," adding, "We believe this is caused by ixazomib inhibiting the activity of FOXM1."

In turn, Khan stresses that "[t]here is a real unmet need for new ways to get around the resistance to chemotherapy that patients who don't have this beneficial mutation often face."

This is why the researchers are aiming to test their new combination drug strategy further, in the hope that, in the future, they will be able apply it to individuals with AML and a poor response to regular treatments.

"Drugs that suppress FOXM1 in combination with the standard treatment, such as ixazomib, should result in better outcomes," says Khan, "but clinical trials will ultimately be needed to prove this theory."