A new understanding of a gene that is commonly mutated in people with myeloid leukemia could help lead to new treatments.
A little more than two years ago, cancer genetics researchers sent a tremor of excitement through the field when they discovered that a significant number of people with myeloid leukemia and related diseases share a common genetic defect: a non-functioning version of a gene called Tet2. Now, in a study whose findings could lead to new treatments, Howard Hughes Medical Institute scientists believe they have characterized Tet2’s role in the disease.
When Tet2 was discovered, researchers jumped on the problem, determined to understand what the gene was doing in both healthy and cancerous cells. “At the time, everyone knew it was a new gene that was going to be important, but we didn’t have a sense of what it did,” says Ross Levine, an HHMI Physician-Scientist Early Career awardee at Memorial Sloan Kettering Cancer Center in New York. “So we began to develop cell culture and mouse systems that would allow us to determine how alterations in Tet2 function would contribute to leukemia and affect the function of blood stem cells.
For the first time, we provide conclusive evidence that Tet2 loss leads to enhancement in blood stem cell function that ultimately progresses to leukemia. And the phenotype closely resembles what we see in human patients.
Myeloid diseases affect the white blood cells of the bone marrow, and occur when those cells begin to divide uncontrollably. So Levine and Iannis Aifantis, an HHMI Early Career Scientist, created Tet2 knock-out mice by selectively deleting the Tet2 gene from just the animals’ blood cells—the same cells that become cancerous in leukemia. When they removed a blood sample from the mice and grew the cells in culture, they were immediately struck by the result. “Normally, when we plate blood cells in culture, they’ll divide a number of times and then stop. But the Tet2 mutant cells have an ability to keep perpetuating,” Levine says. The blood-forming stem cells in these mice had enhanced reproductive capabilities. “They’re better stem cells.”
Three to six months later, the mice themselves began to develop high white cell counts and enlarged spleens -- features common to human myeloid leukemias. “For the first time, we provide conclusive evidence that Tet2 loss leads to enhancement in blood stem cell function that ultimately progresses to leukemia. And the phenotype closely resembles what we see in human patients,” Levine says.
But the mouse model had both copies of Tet2 knocked out, something that isn’t always true in human disease. So Aifantis and Levine looked to see whether Tet2 heterozygous mice, which had one normal and one deleted Tet2 gene, had any abnormalities. The heterozygotes, which had only half the Tet2 activity of normal mice, also displayed an increase in white blood cell populations and increased stem cell function. “We’re not sure why, but this shows that very fine differences at the expression levels of this gene are very important for the induction of leukemia,” says Aifantis, who is also an associate professor of pathology at the New York University School of Medicine.
Aifantis and Levine published their findings online June 30, 2011, in the journal Cancer Cell. Now they hope to use the mouse model to pursue therapeutic possibilities. A related gene, Tet1, affects DNA methylation—a way of chemically up- or down-regulating a gene’s expression, and the researchers suspect Tet2 may have a similar function. “People believe that Tet2 controls levels of methylation of DNA, so deletion of Tet2 should lead to hypermethylation,” Aifantis says.
Aifantis, Levine and their collaborators are now planning to use the models to more closely investigate the mechanisms underlying methylation. When they deleted Tet2, a set of genes known to affect stem cell function were overly active, indicating that Tet2 had kept their expression low, and without its controlling effects those genes increased their activity and caused uncontrolled expansion of blood stem cell populations. To find out whether that’s how Tet2 protects against cancer, the researchers must find and knock out the genes it suppresses; if they are right, the mice should be cancer-free.
Additionally, since there are already cancer drugs in clinical testing that target methylation, such therapies might also be effective in battling acute leukemia, particularly in patients with Tet2 mutations. “As we identify more and more mutations that affect methylation of DNA, it suggests that drugs that affect methylation levels could be very useful,” Aifantis says. “That’s what we’re trying to test now.”