The same signaling pathway can both cause and suppress disease in blood cells.
Howard Hughes Medical Institute scientists have discovered that a cellular signaling pathway that causes one type of leukemia when it’s overactive can also cause disease when it’s not active enough. The new study shows that when the pathway is functioning properly, it helps prevent a particularly devastating type of cancer.
The researchers, who published their findings May 12, 2011, in the journal Nature, say this is one of the first examples of a pathway that can both cause and suppress disease in the same tissue type.
If you had a drug with which you could activate Notch signaling, you could suppress this disease.
The Notch signaling pathway regulates a wide range of cellular activities, and has also been pinpointed as the cause of numerous cancers. But when Iannis Aifantis, a Howard Hughes Medical Institute early career scientist, looked at the role of Notch in the immune system, he and his collaborators stumbled upon something completely unexpected: When they eliminated Notch from the blood-forming stem cells of mice, the animals developed chronic myelomonocytic leukemia (CMML), a cancer of the white blood cells.
“This was a big surprise,” says Aifantis, who is an associate professor of pathology at New York University’s Langone Medical Center. “Usually if you delete an oncogene you get no tumor. Our results suggest that the whole pathway is a tumor-suppressor pathway, and that’s something that hasn’t been described before.”
CMML is a relatively rare cancer, one that’s most common in adults over the age of 65. But when it hits, it hits hard: Cure rates for the disease are low, with patients surviving, on average, less than two years after their diagnosis. Understanding what causes the disease may be the first step toward a fundamental change in how the disease is treated.
The Notch pathway is vital for embryonic development, and plays an important role in the renewal of adult tissues. Researchers have known for years that when the pathway is overactive in blood stem cells it causes a type of leukemia called T-cell acute lymphoblastic leukemia, which is a disease of the body’s immune cells. But the disease that developed in the absence of Notch—CMML—affects a completely different population of blood cells, the myeloid cells that ultimately give rise to blood cells.
If it truly was the absence of Notch that caused the mice to develop CMML, Aifantis reasoned, then restoring Notch activity should eliminate the disease. To test this, he and his colleagues used mice in which they had induced CMML by knocking out all bone-marrow stem cell Notch pathways. And sure enough, when they reactivated one of the Notch pathways, all traces of the leukemia disappeared.
To ensure that the results translated from mice to humans, the scientists then grew purified human bone marrow stem cells on stromal tissue that expressed Notch-specific molecules called ligands that are capable of binding to and activating the Notch pathway. In culture, the ligands effectively prevented the stem cells from differentiating into cancerous progenitors. Moreover, that preventive effect was lost when Notch activity was suppressed. Without Notch, the stem cells began to develop disease, becoming progenitor cells that could seed cancer throughout the bloodstream.
“This result suggests that reversible activation of the Notch pathway could specifically target leukemia-initiating stem cells in myeloid cancers,” Aifantis says. “If you had a drug with which you could activate Notch signaling, you could suppress this disease. Our findings could have some interesting therapeutic implications.”
When dealing with important embryonic signaling pathways such as Notch, however, there’s a fine line between treatment and harm. Because Notch signaling is vital to so many cellular processes, and because over-activation can cause disease, finding a way to nudge its activity in bone marrow stem cells without prompting another type of cancer could be a tricky proposition. If possible, the Notch-activating agent should be something that could provide only a temporary bump in activity. “The ideal way I see this working is that chemotherapy to get rid of myeloid leukemia could be combined with just a shot or two of an activator of the Notch pathway,” Aifantis says.
Since underactive Notch signaling has been implicated in other cancers, such as skin cancer, such a therapy could potentially be applicable to more than one disease.
Aifantis and his collaborators are already looking into potential treatments and have begun discussions with companies who might be able to produce such a therapy. “We want to make soluble ligands to activate the Notch pathway. If we can then combine that with standard chemotherapy protocols, we could reach perfect remission because we’d be able to get rid of both the bulk of the tumor and the cancer stem cells.”