‘Missing silencer’ can trigger leukaemia

A completely new mechanism that leads to the development of a certain type of leukaemia could eventually be targeted by new treatments, according to research published in Nature Immunology today (Sunday)¹.

Researchers, funded by Cancer Research UK, the BBSRC and the Medical Research Council, discovered that when two genes are missing from mice they develop an aggressive form of leukaemia, similar to acute lymphoblastic leukaemia² in humans.

The two genes produce ‘silencer’ proteins that normally neutralise a group of cell messengers once they have successfully delivered their message to the cell’s machinery responsible for growth.

Without the ‘silencer’ proteins the messenger continues to deliver its message without any control. In this research the target messenger controls the production of a protein called Notch1, which plays a key role in the development of a type of white blood cell. Without the silencers, higher levels of Notch1 are produced than is needed for normal growth, causing the cells to grow out of control, leading to leukaemia.

Scientists know that these messengers have to be produced at the right speed – too fast or slow and it can lead to diseases such as cancer. But this research has shown for the first time that switching them off is also a critical control against cancer.

Dr Daniel Hodson, who was a Cancer Research UK Clinical Research Fellow and lead author on the paper, said: “We have known for some time that switching on Notch1 is an important step in the development of leukaemia, but this ‘missing silencer’ is a completely new step through which Notch1 is controlled. We need to now identify whether this aspect of Notch1 control is faulty in human leukaemia and in other types of human cancer.”

The researchers identified this new pathway by looking at two relatively unknown genes, Zfp26l1and Zfp26l2, which produce silencer proteins that ensure the timely destruction of specific messengers.

It is known that the expression of such ‘silencer’ proteins is suppressed in a number of human cancers, including breast cancer, so this may be a mechanism contributing to other cancers. Manipulating the control and destruction of these messengers may therefore be a useful strategy for developing anti-cancer agents and the treatment of human leukaemia.

Dr Lesley Walker, director of cancer information at Cancer Research UK, said: “Acute lymphoblastic leukaemia is the most common form of leukaemia in children but it also occurs in adults. It can be difficult to treat because cancer cells spread throughout the body so surgery is not an option. This exciting work, finding how the control of Notch 1 levels could lead to leukaemia in mice, could provide scientists with important new leads for treatments.”