A Genetic Balance of Terror

Cancer, we are told, is a disease of the genes. It originates in mutations in the DNA. But a paper published by a Weizmann Institute group in Cell Reports flips that idea sideways by about 90 degrees: For at least some types of the disease, the healthy, non-mutated version of a gene is no less of a driving force behind the development of cancer than its mutated form.

Prof. Yoram Groner, who led the research, describes the situation as a “balance of terror.” Until now, researchers have assumed that, when a mutation causes cancer it becomes dominant in the cell, overriding the second copy of that gene. But a search through genetic databases for a particular type of mutation suggested that in a number of cases, that second copy is not only functional, it is quite active. The study was mainly conducted by postdoctoral fellow Dr. Oren Ben-Ami in Groner’s lab, together with the group of Dr. Amos Tanay of the Computer Science and Applied Mathematics Department and Dena Leshkowitz of the Israeli National Center for Personalized Medicine.

Groner and his team are interested in the gene RUNX1, which regulates the expression of many other genes, especially those involved in the differentiation of stem cells in the bone marrow into blood cells. Specific mutations in this gene are responsible for several types of leukemia.

Sure enough, when the research team created cells in which just the mutated version of RUNX1 was active, the cells died. Only when both copies – mutated and non-mutated – were present did the cells act like cancer cells: aggressive and long-lived. Further research revealed exactly at which point in the cell cycle the healthy version steps in to keep the cancer cell alive.

Pre-leukemic stem cells (top) with both mutated and healthy copies of the RUNX1 gene already display some of the characteristics of acute myeloid leukemia (AML). When the non-mutated copy of the gene is inactivated, disruptions in the spindle-assembly-checkpoint phase of cell division trigger cell death

As Groner describes the process, mutated RUNX1, because it controls other genes, actively promotes the progression of further mutations that turn the cell into an all-out cancer cell. It does this so well that the end result, if it is allowed to continue, is all-consuming burnout. The standoff between the two versions of the gene is what saves it in the end. As Groner puts it: “The leukemia cells are addicted to the normal RUNX1 gene.”

That implies, over and above the obvious relevance of these findings to diagnostics, that the path to a cure might lie in addressing the addiction.