A Key to Fight Drug-Resistant Leukemia

Doctors who treat children with the most common form of childhood cancer – acute lymphoblastic leukemia – are often baffled at how sometimes the cancer cells survive their best efforts and the most powerful modern cancer drugs.

Now an international team led by researchers at the University of California, San Francisco and joined by scientists of the Freiburg excellence cluster BIOSS – Centre for Biological Signalling Studies, has identified a protein called BCL6 which plays a key role in the development of drug-resistance in leukemia. “It is something like an emergency mechanism whereby tumor cells try to evade drug-treatment,” said Markus Müschen, MD, PhD, a professor of laboratory medicine at UCSF and the senior author on the study.

This discovery may make cancer drugs more powerful and help doctors formulate better drug cocktails to cure more children of leukemia. As now described in the journal Nature, Müschen and his colleagues showed that mice with drug-resistant leukemia can be cured of the disease when given conventional cancer drugs in combination with a compound that disables the BCL6 protein.

In acute lymphoblastic leukemia, cells in the bloodstream and bone marrow continuously multiply, crowding out other, healthy cells. The disease progresses rapidly, and the leukemia cells begin to infiltrate tissues in other parts of the body. Treatment is neither cheap nor easy and usually involves a long course of drugs that can be physically and emotionally taxing for the children and their parents. Once finished, many enjoy complete remission and are able to live cancer-free, cured of the leukemia. Still a large number of children are not cured and ultimately succumb to the disease. In those cases, some of the cancer cells resist the therapy and survive quietly in the body. When the cancer reemerges, it is no longer sensitive to the drugs.

The work started four years ago when the scientists exposed leukemia cells in the petri dish to drugs and then looked at how the expression of 22,000 different genes changed when different cancer cells were given different drugs. “We think that this discovery will directly influence the treatment of drug-resistance in leukemia” said Hassan Jumaa, PhD, a BIOSS-scientist and a co-author on the study.

Publication in Nature: „BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR–ABL1 kinase inhibition”

Cihangir Duy, Christian Hurtz, Seyedmehdi Shojaee, Leandro Cerchietti, Huimin Geng, Srividya Swaminathan, Lars Klemm, Soo-mi Kweon, Rahul Nahar, Melanie Braig, Eugene Park, Yong-mi Kim, Wolf-Karsten Hofmann, Sebastian Herzog, Hassan Jumaa, H. Phillip Koeffler, J. Jessica Yu, Nora Heisterkamp, Thomas G. Graeber, Hong Wu, B. Hilda Ye, Ari Melnick and Markus Müschen.

Nature 473, 384–388, (19 May 2011)

Doi: 10.1038/nature09883