New view of leukemia cells identifies best treatment options more quickly

Decades-old technology catches cancer molecules in action

Researchers at the medical school have developed a technique that can enable doctors to more quickly determine the best treatment options for people who are diagnosed with acute myelogenous leukemia.

Although all people with AML have a cancer of the same type of white blood cells, those cells behave very differently from person to person, said Garry Nolan, PhD, associate professor of microbiology and immunology. By watching those behaviors, Nolan said doctors could quickly identify patients who need stronger treatment or less common chemotherapy drugs. He reported a new technique for getting AML patients on the right drug the first time in the July 23 issue of Cell.

AML is the most common form of leukemia, with about 10,500 new cases diagnosed each year. The cancerous white blood cells divide out of control and drown out the other types of cells normally present in the blood.

Nolan equates his technique to figuring out which people in a room are more aggressive, noting that you can’t always tell at first glance. “But if I go around and kick everybody in the shin, I can see their response and learn something about that person,” he said. Exposing cancer cells to different molecules is like kicking them in the shin, and Nolan’s technique is the snapshot that reveals how the cell behaved. Those cells that simply look surprised are fairly normal and will probably respond well to drugs; those that glower need special treatment.

Nolan watches message-carrying pathways that translate a signal in the environment into action in the cell’s nucleus. In all cells, a carefully orchestrated network of molecules passes messages between the cell’s surface and the nucleus. Molecules that relay those messages follow a strict order in healthy cells, always handing the note – in this case, a phosphate atom – to the next molecule in line.

In cancerous cells, those note-passing brigades grow independent. Molecules hand notes to the wrong counterpart, and sometimes write a note of their own and pass it along. A signal at the cell’s surface saying “stop dividing” may get handed to a neighboring pathway where it becomes a signal to divide rapidly – a hallmark of cancer cells – or may get destroyed altogether.

These disturbances aren’t visible just by looking at a tumor sample. Nolan got his first glimpse inside the cell’s machinery using a technique developed by postdoctoral scholar Omar Perez, PhD. He harnessed a decades-old device called flow cytometry to act as a hidden security camera monitoring the note-passing molecules.

Postdoctoral scholar Jonathan Irish, PhD, applied Perez’ technique to samples from healthy people, people with AML who responded to chemotherapy and people whose AML did not respond to the initial chemotherapy attempt. He monitored six of the molecular handoffs to see which differed when the cells were exposed to five different signals they would normally encounter in the body.

What he found was striking. Doctors usually treat a cancer as a single, uniform entity. When they take a sample to determine how far the cancer has progressed, the entire cancer gets graded on a scale of 1 to 4, with 4 being the most severe. But Nolan and Irish found that many different populations can exist within a cancer at any point in time. Some of these populations are farther along in their cancerous path than others and were passing a greater number of notes to the wrong counterpart.

Learning to recognize the pathways most commonly disrupted in aggressive cancers could help researchers predict which patients won’t respond to standard chemotherapy. Doctors could immediately propose that the person consider less common therapies.

“This is the first time we’ve been able to look at cancer signaling messages in a population of individual cells to distinguish treatment options,” Nolan said.