Cancer drug pushes mutant blood stem cells to become short-lived immune cells

by Weill Cornell Medical College

edited by Sadie Harley, reviewed by Robert Egan

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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 more 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 cells, such as megakaryocytes, which make platelets. Interferon-alpha often helps patients by reducing these imbalances and depleting the pool of mutant blood cells.

In the study, published in Nature Genetics, the investigators used advanced single-cell profiling tools to discover how interferon-alpha exerts these effects.

"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 Ph.D. portion of her MD/Ph.D. program in the Nam Laboratory during the study.

Tracing the disease at single-cell level

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 classified into two broad categories, or lineages: myeloid and lymphoid. Myeloproliferative neoplasms involve mutation-driven overproduction of myeloid cells.

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 consenting patients with the myeloproliferative neoplasm known as essential thrombocythemia.

The disorder features an overproduction of megakaryocytes and, therefore, platelets, which elevates heart attack and stroke risks. The team compared blood cells before and after interferon-alpha treatment and examined how mutant and admixed nonmutant blood cells responded differently to treatment.

An inflammatory push toward neutrophils

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 very long, so this inflammatory process depletes blood stem cells over time. Mutant blood stem cells are more susceptible to this process than nonmutant blood stem cells in patients who respond to interferon-alpha treatment.

A second shift in blood balance

The other major effect of interferon-alpha treatment, the researchers found, is to induce many blood stem cells to produce lymphoid cells, helping bring the lymphoid cell population more into balance with myeloid cells. Interferon-alpha also suppressed inflammaging-related gene programs, 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, 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.

Publication details

Lama, C., et al. Type 1 interferon perturbates clonal competition by reshaping human blood development. Nature Genetics (2026) www.nature.com/articles/s41588-026-02751-3

Journal information: Nature Genetics

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Oncology Provided by Weill Cornell Medical College Who's behind this story?

Sadie Harley

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