The human immune system is in a perpetual state of self-experimentation. It expertly mutates and shuffles the DNA of its own cells to evolve new defenses against the vast array of microbes that try to invade our bodies. But when the genetic experiment goes awry, the result can be a deadly cancer.
Now, Rockefeller University scientists have discovered that the same enzyme that enables the immune system's defensive creativity is also responsible for a particular genetic malfunction - a translocation of one
piece of DNA to the wrong chromosome - that causes Burkitt's lymphoma. The findings, to be published in the December 12 edition of Cell, suggest the enzyme, called activation-induced deaminase (AID), is probably involved in a broader range of cancers as well.
"We strongly suspect that many or all of the translocations of human lymphomas in mature B cells are the product of this enzyme," says Michel C. Nussenzweig, Sherman Fairchild Professor and head of the Laboratory of Molecular Immunology. "And there's more and more data to show that it may be involved in other cancers as well. It's been identified in stomach cancers, for instance."
A very specific translocation causes Burkitt's lymphoma, a cancer that plagues children in equatorial Africa. It involves a DNA break in an immune system antibody gene and the much more rare break in a cancer-promoting gene called c-myc. Previous work had shown that AID was responsible for breaking antibody genes but not c-myc. In fact, scientists thought a host of other factors might be involved in the c-myc break, but AID had been all but ruled out.
Despite the prior studies, Davide Robbiani, a research associate in Nussenzweig's lab and a Leukemia and Lymphoma Society Fellow, believed AID was the culprit. To prove it, he and his colleagues started by deleting the promoter region of the c-myc oncogene, rendering the gene inactive, in a mutant line of mice. By looking for - and not finding - the specific translocation in these mice, he showed that c-myc had to be active in order for its DNA break to take place.