City of Hope researchers have shown how leukemia stem cells hijack the bone marrow where they live, helping them to proliferate, potentially outlast powerful therapy and return to cause cancer. The findings were published online April 16 in the journal Cancer Cell.
Ravi Bhatia, left, and Bin Zhang look for ways to eliminate leukemia’s roots. (Photo by Thomas Brown)Thanks to modern medications like Gleevec, most patients with chronic myelogenous leukemia (CML) now can enjoy a long life — but as soon as they stop taking these drugs, cancer usually comes back. City of Hope researchers like Ravi Bhatia, M.D., and colleagues at Dana-Farber Cancer Institute and the University of Glasgow are pursuing ways to finish off CML more completely, knowing that current drugs are expensive and cause major side effects that hurt quality of life.
Scientists believe CML returns after therapy because drugs fail to kill leukemia stem cells, the primitive cells that produce mature leukemia cells. Work by Bhatia and his team in laboratory and mouse models shows that leukemia stem cells are even more cunning and powerful villains in the CML story than once believed. They actually transform their surrounding neighborhood — what scientists call the bone marrow microenvironment — to give themselves a protected place to hide and grow.
Normally, healthy blood stem cells live in the bone marrow and produce the many kinds of different blood and immune cells the body needs. But in CML, leukemia stem cells hide in the bone marrow and start to take the place of healthy cells. The researchers found that the leukemia stem cells do more than call the bone marrow their home, though.
“We found that in CML, leukemia stem cells actually change their microenvironment, altering the bone marrow so it selectively supports them over normal cells,” explained Bhatia, director of the Division of Hematopoietic Stem Cell and Leukemia Research at City of Hope and senior author on the study.
Researchers once believed that leukemia stem cells took over the bone marrow because they naturally grew more out of control than normal stem cells. The new study suggests that the leukemia cells change the tissue around them to block healthy “niche” cells. These niche cells tell stem cells when to grow normally and regulate the number of healthy cells needed. Leukemia cells shut down this communication and alter the bone marrow to enhance their own growth.
When they looked at the bone marrow itself, they found abnormal levels of two proteins that cells use to communicate. These proteins are called interleukin 1 and CXCL12. Higher levels of interleukin 1 and lower levels of CXCL12 appear to help leukemia stem cells grow. Researchers believe that the leukemia stem cells somehow manipulate the tissue around them into producing these protective, abnormal protein levels, even as mature leukemia cells are dying from treatment with drugs like Gleevec.
The study showed that new therapies must not only target leukemia stem cells but the microenvironment, as well.
“These results improve our understanding of leukemia stem cell regulation in CML and could guide strategies for targeting this resistant population,” said Bin Zhang, M.D., Ph.D., staff scientist in the Division of Hematopoietic Stem Cell and Leukemia Research at City of Hope and first author on the paper.
Grants from the National Cancer Institute, National Heart, Lung, and Blood Institute and Cancer Research UK funded the work.
