Previous research has revealed that patients with acute myeloid leukemia who also have a particular mutation in a gene called NPM1 have a higher rate of remission with chemotherapy.
About one-third of leukemia patients possess this favorable mutation, but until now, how it helps improve outcomes has remained unknown. Scientists from the University of Illinois at Chicago report on how this mutation helps improve sensitivity to chemotherapy in patients in the journal JCI Insight.
The protein coded for by the NPM1 gene affects the location and activity of another protein called FOXM1. FOXM1 activates other cancer-promoting genes and has been found to be elevated in cancer cells.
Acute myeloid leukemia
The presence of FOXM1, especially at high levels, is a strong predictor of worse treatment outcomes and decreased survival in patients with cancer. When the NPM1 gene is mutated, FOXM1 cannot activate additional oncogenes, so patients with this mutation tend to respond better to chemotherapy.
A drug that targets and incapacitates FOXM1 in patients without the beneficial NPM1 mutation may help improve the efficacy of chemotherapy. Acute myeloid leukemia (AML) is a cancer of the bone marrow.
In AML, stem cells that would normally differentiate into blood cells instead multiply unchecked and fail to develop into mature blood cells. Patients with AML have a high risk of death from uncontrolled infection, fatigue easily and get organ damage because they lack adequate numbers of oxygen-carrying red blood cells.
They are also at high risk for dangerous bleeding because of low numbers of cells that help with blood clotting. It has been known that patients with a mutation in the NPM1 gene have a better response to standard chemotherapy, with up to 80 percent of patients being cured compared to just 40 percent for patients without the mutation.
In previous studies, researchers at UIC led by Andrei Gartel, associate professor of molecular genetics, discovered that one of the roles of the NPM protein is to stabilize FOXM1 and keep it in the nucleus where it can activate other cancer-promoting genes.
Gartel and his colleagues determined that when the NPM1 gene is mutated, FOXM1 migrates out of the nucleus and into the cell's cytoplasm, where it can't interact with DNA. This may explain why patients with this NPM1 mutation have a much better response to chemotherapy and are less likely to relapse.
The researchers analyzed bone marrow cells taken via biopsies from 77 patients with AML and found that the presence of FOXM1 in the cells' nuclei was a strong predictor of poor treatment outcome for individual patients.