Acute myeloid leukemia is usually treated with chemotherapy, but patients often stop responding to these drugs and develop resistance to them. Now MSK investigators are learning why that is the case.
Doctors have used chemotherapy to treat people with cancer for decades, but there is still much to be learned about how it works — and why it doesn’t always work. In particular, not much is known about the molecular mechanisms that enable some tumors to develop resistance to treatment with chemotherapy drugs. A new study led by Memorial Sloan Kettering physician-scientist Ross Levine is providing clues about how acute myeloid leukemia (AML), the most common acute leukemia in adults, can become resistant to a common chemotherapy drug. The research has also allowed investigators to develop a more accurate mouse model of the disease, which will help them to gain a greater understanding of how it can be treated with new therapies.
“Despite the fact that we use chemotherapy every day, we understand very little about why it’s not always effective,” says Dr. Levine, who was co-senior author of the study, published recently in the journal Nature Medicine. “We’re finding that cancer cells use different approaches to develop resistance. These novel insights are giving us some paths forward that we can explore with new treatments.”
Focus on a Common Mutation
In the study, the researchers focused on a mutation in the gene DNMT3A, which is present in about one-third of all AML cases. Previous studies have shown that chemotherapy is not very effective against leukemia cells that have this mutation compared with other subtypes that don’t. “Chemotherapy normally damages cancer cells, but we showed that here, the mutation allows these cells to avoid its effects,” Dr. Levine explains.
The mechanism that allows the mutant cells to evade the damage lies in epigenetics — the chemical modifications of a cell’s genetic material that can modulate gene expression. In this case, the epigenetic mechanism is based on how DNA is packaged inside the cell. “Normally when chemotherapy damages DNA, cells unreel their genetic material to correct the defects. This unreeling lets the cell know that DNA has been damaged, leading cells to either repair the defect or to undergo programmed cell death,” Dr. Levine says. Cells with this mutation in DNMT3A can’t do this. “If you can’t unreel the DNA, the leukemia cells can’t recognize the damage. They continue to grow and divide, making the chemotherapy ineffective,” he adds.
