Cancer researchers discover pre-leukemic stem cell at root of AML and relapse

TORONTO – Canadian researchers have discovered a pre-leukemic stem cell that may be at the root of acute myeloid leukemia and also be the “bad actor” that evades chemotherapy and triggers a relapse in patients who have gone into remission.

Acute myeloid leukemia, or AML, is a rapidly progressing cancer of the blood and bone marrow that affectsmyeloid cells, which normally develop into mature red and white blood cells and platelets.

Leukemia develops when blood stem cells in the bone marrow make abnormal blood cells, which over time crowd out normal blood cells, affecting their ability to function as they should.

In a paper published online Wednesday in the journal Nature, researchers led by John Dick of Princess Margaret Cancer Centre in Toronto report on the discovery of a pre-leukemic stem cell — the forerunner to leukemia stem cells that give rise to the disease.

“A leukemia stem cell … can lie dormant and they’re the ones that will sustain the growth of the leukemia,” Dick said in an interview. “The pre-leukemic guys are basically the ancestors that are on their way to becoming leukemia and becoming leukemic stem cells.”

Dick’s lab was the first to identify the existence of leukemia stem cells, in 1994, followed by the discovery of colon cancer stem cells in 2007.

Teasing out pre-leukemic stem cells from the blood of AML patients — based on samples taken at diagnosis, after chemotherapy-induced remission, and then following recurrence — advances the understanding of the genetic changes a normal cell has to go through before it turns into AML.

“What set this thing off? How long did it take? What are the ancestral steps that led us to this place? … In what cell did leukemia first arise?” These were some of the questions driving the research, Dick said.

“What we’re essentially doing is peering back into a black box.”

The findings show that about one-quarter of AML patients have a mutation in a specific gene that causes the development of pre-leukemic stem cells, which function like normal blood stem cells but grow abnormally.

Dick believes further genetic sequencing studies will likely turn up similar mutated pre-disease-causing stem cells in the other 75 per cent of AML patients.

Pre-leukemic stem cells, which he described as the “bad actors,” are unaffected by chemotherapy and can be found in the bone marrow of patients at remission.

“What that means is these stem cells survived chemotherapy, they’re not killed like leukemia cells are. And that means they can provide a reservoir which could be triggered again to cause a recurrence,” he explained.

“So if the recurrence is actually coming not from some leukemia cell that survived but from one of these pre-leukemic stem cells, it’s like setting off a new disease.”

The research suggests these primordial stem cells could be targeted by a drug that could potentially stop the disease at an elemental stage.

“For the first time we can recognize that a disease that normally is diagnosed when the person walks into the clinic, there’s the possibility of diagnosing it earlier,” he said.

“Now we have a potential tool for earlier diagnosis that may allow early intervention before the development of full AML,” he said. “We can also monitor remission and initiate therapy to target the pre-leukemic stem cell to prevent relapse.”

AML is most common in adults age 65 and older, and men are slightly more likely to develop the disease than women, the Canadian Cancer Society says on its website (www.cancer.ca).

In 2007, the latest year for which case incidence statistics are available, 1,130 Canadians were diagnosed with acute myeloid leukemia. The most recent mortality statistics for AML show 897 Canadians died from the disease in 2009.

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