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 it 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. “We’ve discovered a situation where they’re not antagonizing each other’s actions, they’re actually working together,” said Michael Cleary, MD, professor of pathology and of pediatrics and senior author of the paper published in the Oct. 21 issue of Cell. 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, Cleary and first author Akihiko Yokoyama, a postdoctoral scholar in pathology, 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.
