The role of OCT4 in self-renewal signaling and drug-resistance of childhood acute lymphoblastic leukemia
ALSF-funded team uncovers how childhood leukemia cells become drug-resistant
Acute lymphoblastic leukemia (ALL) represents the most frequent type of cancer in children. In many cases, the leukemia is driven by an abnormally active signaling molecule. About ten years ago, Gleevec was developed as the first effective drug to block over-active signaling molecules in leukemia and became the standard of care for ALL patients. While many leukemia cells are killed by Gleevec, often residual cells persist in dormancy mode, until either treatment ceases or the leukemia cells mutate making them resistant against the drug.
In 2008, a team of researchers around Dr. Markus Müschen (UCSF) was awarded an Innovation Grant from Alex’s Lemonade Stand Foundation to investigate how leukemia cells can enter “dormancy” and remain in that state. This research has led to the discovery that the BCL6 molecule is protecting leukemia cells in dormancy mode from drug-treatment. Once the activity of anti-leukemia drug-treatment sets in, the leukemia cells activate the BCL6 molecule, which allows them to evade drug-treatment by entering dormancy mode. In addition to uncovering the mechanism of leukemia cell dormancy, Müschen and his colleagues also found a way to overcome BCL6 function and to keep the leukemia cells in a state where they remain vulnerable to drug-treatment. Markus Müschen and his team demonstrated that inhibitors of BCL6 prevent leukemia cell dormancy and make leukemia cells extremely sensitive to drug-treatment.
“This is a discovery of immediate relevance to children with leukemia,” Müschen says. Combinations of BCL6-inhibitors and conventional drug-treatment have cured leukemia in multiple mice carrying patient-derived leukemia cells that no longer responded to conventional treatment alone.” These results appeared in the May 2011 issue of the science journal “Nature” (http://www.nature.com/nature/journal/v473/n7347/full/nature09883.html).
“We are extremely grateful for the support from Alex’s Lemonade Stand Foundation and glad that we were able to come up with a new concept to develop new treatment options for children with leukemia” says Markus Müschen, a Professor of Laboratory Medicine at the University of California in San Francisco and the lead author of the study.