Tumor-suppressor proteins work to inhibit tumor growth in our bodies and when they win, they spare us a battle with cancer. But one such protein, menin, appears to have a split personality. Though menin is well-known for its ability to suppress endocrine tumors,
Researchers at Stanford University School of Medicine have discovered that menin is also a key player in the development of some forms of acute leukemia.

The researchers, who made the discovery in working with mouse cells, say this is the first time a tumor-suppressor protein has been found to have such a dramatic dual role. But there may be a silver lining in menin's dark side - understanding the mechanism could open up new avenues of treatment for the very leukemias that menin promotes.

Normally menin binds with another protein, known as MLL, in the nucleus of a cell, where the two are part of a complex of proteins that promote proper cell growth. But when MLL is mutated, it becomes a cancer-promoting oncoprotein. Usually this would put the tumor suppressor and the oncoprotein in direct conflict, as each sought to overwhelm the other, but not so in cases of acute leukemia.

When the blood system is functioning properly, the menin and the normal MLL proteins work together constructively, helping guide cells through all the stages of development from their beginnings as blood-forming stem cells to final maturation, or differentiation, into blood cells. But when MLL is mutated, the differentiation process stalls at an intermediate stage and the immature cells begin proliferating uncontrollably.

Given that menin is highly effective in suppressing endocrine tumors, Michael Cleary and first author Akihiko Yokoyama suspected that MLL was somehow deactivating menin's suppressive powers. They tested the theory with mouse cells in vitro by introducing the mutated MLL oncoprotein and letting leukemia begin to thrive. Yokoyama then genetically removed menin from the cancer cells.

If menin and MLL were struggling against each other, the researchers reasoned that removing menin would either have no effect on the rate of proliferation, or the leukemia would run even wilder, flourishing without restraint. But the leukemia ground to a halt.

Even more unexpected was what happened next - the former cancer cells matured. The immature blood cells not only ceased their bad behavior once the menin was gone, they resumed productive lives. They completed the differentiation process and became mature blood cells. The leukemia disappeared without a single cancer cell being killed.

Further work by Yokoyama established that menin was actively involved in promoting the acute leukemia, rather than simply being passive raw material for MLL to use. " This is the first example that we know of where an oncoprotein and a tumor-suppressor protein are physically working together to promote cancer," said Cleary.

Exactly what causes menin to behave as it does in acute leukemia isn't clear.

Not knowing just how menin does what it does, the researchers said it's difficult to speculate whether similar processes could be happening elsewhere in the human body. But the findings offer tantalizing possibilities for pursuing new treatments for MLL-associated acute leukemias, which make up between 5 and 10 percent of all leukemias in both adults and children.
Acute leukemias associated with MLL oncoproteins are extremely aggressive and patients generally don't respond well to conventional treatments.
But the stunning reversal of leukemia in the mouse cells when menin was removed offers clues for developing treatments. If the team's findings can be applied to humans, "we would probably stop a leukemia dead in its tracks," said Cleary. There's a lot more that needs to be learned before that could be attempted, but Yokomama and Cleary are cautiously optimistic.

Source: Stanford University Medical Center, 2005


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