A smear of blood cells showing chronic myeloid leukemia cells in the stage known as ‘blast crisis’ (magenta).
Image courtesy of CDC/Stacy Howard
Once chronic myeloid leukemia (CML) has progressed to its most advanced stage, it is a tough cancer to treat. Drugs that help control earlier stages of the disease no longer work, leaving patients who develop so-called ‘blast crisis CML’ with few effective treatment options. Encouragingly, a team of scientists in Singapore has discovered a promising way to kill the cells that are responsible for this type of aggressive leukemia. They demonstrated in mice that compounds targeted at a specific enzyme prevent blast crisis cells from behaving like cancer stem cells.
“The identification of a ‘druggable’ target in the terminal stage of CML is the first concrete step toward finding a life-extending treatment for this deadly disease,” say Sharon Lim and Ong Sin Tiong, the authors of the study from the Duke–National University of Singapore (Duke–NUS) Graduate Medical School.
The finding was the result of a long-standing research collaboration between Duke–NUS and the A*STAR Experimental Therapeutics Centre. The research team started by characterizing blast crisis-stage leukemia stem cells (see image). These cells self-renew owing to elevated levels of the cancer-causing protein β-catenin. This property would make β-catenin a good drug target; however, this protein is also required for normal blood cell development. Lim, Ong and co-workers therefore searched for a protein that is involved in activating β-catenin, but in cancerous cells only.
The researchers found their target in an enzyme called MAP kinase interacting serine/threonine kinase, or MNK. In leukemia cells, they showed that MNK adds a chemical tag to another protein called eIF4E. This modification in turn prompts eIF4E to trigger β-catenin production. This ‘MNK-eIF4E axis’ proved to be the ideal drug target because the pathway is not involved in normal β-catenin expression in healthy cells.
Lim, Ong and co-workers next treated leukemia and healthy cells with a small-molecule drug that blocks MNK function. They also gave the compound to mice implanted with human blast crisis cells. They found that drug treatment reduced the cancer burden by preventing the leukemia stem cells from self-renewing. Importantly, the treatment did not affect normal stem cell function.
“This [finding] will represent a critical step toward finding the best and safest MNK inhibitors to test in patients,” say A*STAR scientists Jeffrey Hill and Kassoum Nacro. The collaborative team is currently working on inhibitors of MNK and other selected kinases to treat blast crisis CML.
Funding for the study was provided by the Duke–National University of Singapore Signature Research Program funded by A*STAR; the Ministry of Health (Singapore); and the National Research Foundation Singapore Clinician Scientist Award (CSA), awarded to Professor Ong by the National Medical Research Council (NMRC).
The A*STAR‐affiliated researchers contributing to this research are from the Experimental Therapeutics Centre (ETC).
