CIRM funded research could lead to treatment to prevent recurrence of deadly blood cancer

Chronic myelogenous leukemia

Chronic myelogenous leukemia (CML) is a cancer of the white blood cells. It causes them to increase in number, crowd out other blood cells, leading to anemia, infection or heavy bleeding. Up until the early 2000’s the main weapon against CML was chemotherapy, but the introduction of drugs called tyrosine kinase inhibitors changed that, dramatically improving long term survival rates.

However, these medications are not a cure and do not completely eradicate the leukemia stem cells that can fuel the growth of the cancer, so if people stop taking the medication the cancer can return.

Dr. John Chute: Photo courtesy UCLA

But now Dr. John Chute and a team of researchers at UCLA, in a CIRM-supported study, have found a way to target those leukemia stem cells and possibly eliminate them altogether.

The team knew that mice that had the genetic mutation responsible for around 95 percent of CML cases normally developed the disease and died with a few months. However, mice that had the CML gene but lacked another gene, one that produced a protein called pleiotrophin, had normal white blood cells and lived almost twice as long. Clearly there was something about pleiotrophin that played a key role in the growth of CML.

They tested this by transplanting blood stem cells from mice with the CML gene into healthy mice. The previously healthy mice developed leukemia and died. But when they did the same thing from mice that had the CML gene but lacked the pleiotrophin gene, the mice remained healthy.

So, Chute and his team wanted to know if the same thing happens in human cells. Studying human CML stem cells they found these had not just 100 times more pleiotrophin than ordinary cells, they were also producing their own pleiotrophin.

In a news release Chute, said this was unexpected:

“This provides an example of cancer stem cells that are perpetuating their own disease growth by hijacking a protein that normally supports the growth of the healthy blood system.”

Next Chute and the team developed an antibody that blocked the action of pleiotrophin and when they tested it in human cells the CML stem cells died.

Then they combined this antibody with a drug called imatinib (better known by its brand name, Gleevec) which targets the genetic abnormality that causes most forms of CML. They tested this in mice who had been transplanted with human CML stem cells and the cells died.

“Our results suggest that it may be possible to eradicate CML stem cells by combining this new targeted therapy with a tyrosine kinase inhibitor,” said Chute. “This could lead to a day down the road when people with CML may not need to take a tyrosine kinase inhibitor for the rest of their lives.”

The next step is for the researchers to modify the antibody so that it is better suited for humans and not mice and to see if it is effective not just in cells in the laboratory, but in people.

The study is published in the Journal of Clinical Investigation