The biologic drug interferon-alpha can benefit patients with blood cancers called myeloproliferative neoplasms by forcing mutant blood stem cells to become shorter-lived white blood cells, according to a study by Weill Cornell Medicine investigators. Because the broad activity of interferon-alpha can induce significant side effects, developing new focused strategies based on these mechanistic findings could meet an important need in cancer therapy.
Myeloproliferative neoplasms arise when DNA mutations in blood stem cells lead to the excess production of specific types of blood cell such as the megakaryocyte cells that make platelets. Interferon-alpha often helps patients by reducing these imbalances and depleting the pool of mutant blood cells. In the study, published Sept. 15 in Nature Genetics, the investigators used advanced single-cell profiling tools to discover how interferon-alpha exerts these effects.
Dr. Anna Nam
“These findings provide strategies for new ways to manage these and potentially other blood cancers,” said study senior author Dr. Anna Nam, an assistant professor of pathology and laboratory medicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and a pathologist at NewYork-Presbyterian/Weill Cornell Medical Center.
The co-first authors were Chhiring Lama, a research assistant, and Dr. Danielle Isakov, who completed the PhD portion of her MD/PhD program in the Nam Laboratory, during the study.
Blood stem cells live in bone marrow and give rise to all blood cells, including oxygen-carrying red blood cells, platelet-making megakaryocytes and the white blood cells of the immune system. Blood cells are classed into two broad categories or lineages, myeloid and lymphoid, and myeloproliferative neoplasms involve mutation-driven overproduction of myeloid cells.
Dr. Nam and her team used single-cell profiling methods based on technology she helped develop at Weill Cornell Medicine. The team recorded gene-activity patterns, surface proteins and other characteristics of thousands of individual blood cells sampled from consented patients with the myeloproliferative neoplasm known as essential thrombocythemia. The disorder features an overproduction of megakaryocytes and thus also platelets, which elevates heart attack and stroke risks. The team compared blood cells before and after interferon-alpha treatment, and compared how mutant and the admixed non-mutant blood cells respond differently to treatment.
Chhiring Lama and Dr. Danielle Isakov
Researchers haven’t really understood how interferon-alpha—a natural antiviral protein also used as a drug—works in such patients. But the findings illuminated this protein’s molecular effects as never before. They showed, for example, that interferon-alpha can trigger what appears to be an emergency infection response, pushing blood stem cells to mature rapidly into infection-fighting white blood cells called neutrophils. The latter don’t live for very long, so this inflammatory process depletes blood stem cells over time. Mutant blood stem cells are more susceptible to this process, compared with non-mutant blood stem cells, in patients who respond to interferon-alpha treatment.
The other major effect of interferon-alpha treatment, the researchers found, is to induce many blood stem cells to produce lymphoid cells, which helps bring the lymphoid cell population more into balance with myeloid cells. Interferon-alpha also suppressed inflammaging-related gene programs, as another beneficial effect of this therapy.
The results clarify interferon-alpha’s mechanisms of action, and suggest the possibility of finding more selective and potent ways to trigger these mechanisms to reduce mutant blood cells in myeloproliferative neoplasms and other blood cancers—and perhaps even in precancerous conditions, Dr. Nam said.
Another possibility her lab is investigating is whether natural interferon-alpha contributes to some autoimmune conditions through its aberrant triggering of this highly inflammatory infection-fighting response.
The research reported in this story was funded in part by a National Institutes of Health Director’s Early Independence Award and by the National Cancer Institute and the National Heart Lung and Blood Institute, both part of the National Institutes of Health. Additional funding was provided by a Hartwell Foundation Individual Biomedical Research Award, Burroughs Wellcome Fund Career Award for Medical Scientists, the Starr Cancer Consortium, and a Pew-Stewart Scholars for Cancer Research award.