Interferon Pushes Mutant Blood Stem Cells Toward Short-Lived Fates

The biologic drug interferon-alpha can benefit patients with blood cancers known as myeloproliferative neoplasms by driving mutant blood stem cells to differentiate into white blood cells that don’t live very long, according to a new study from Weill Cornell Medicine. Because interferon-alpha’s broad activity can also cause significant side effects, the researchers say these mechanistic insights could help guide the development of more targeted therapeutic strategies.

Myeloproliferative neoplasms occur when DNA mutations in blood stem cells drive the overproduction of specific blood cell types, such as the platelet-making megakaryocytes. Interferon-alpha is known to help patients by correcting these imbalances and shrinking the pool of mutant blood cells, but exactly how it accomplishes this has not been well understood. The study, published in Nature Genetics, used advanced single-cell profiling tools to investigate the drug’s underlying mechanisms.

Blood stem cells reside in the bone marrow and give rise to every type of blood cell, including red blood cells, megakaryocytes, and the white blood cells of the immune system, which fall into myeloid and lymphoid lineages. Myeloproliferative neoplasms specifically involve mutation-driven overproduction of myeloid cells. For this study, the research team profiled gene activity, surface proteins, and other features of thousands of individual blood cells collected from consenting patients with essential thrombocythemia, a myeloproliferative neoplasm marked by excess megakaryocytes and platelets that raises the risk of heart attack and stroke. They compared blood cells before and after interferon-alpha treatment and examined how mutant cells responded differently than non-mutant cells.

The findings revealed that interferon-alpha appears to trigger an emergency-like infection response, prompting blood stem cells to rapidly mature into neutrophils, short-lived infection-fighting cells. Because these cells don’t persist long, this process gradually depletes the blood stem cell pool, and mutant stem cells proved more vulnerable to it than non-mutant ones in patients who responded to treatment. The therapy also encouraged many blood stem cells to generate lymphoid cells, helping rebalance the lymphoid and myeloid populations, and it suppressed gene programs linked to inflammaging.

According to Anna Nam, the study’s senior author, “These findings provide strategies for new ways to manage these and potentially other blood cancers.” The results may point toward more selective and potent methods of triggering these same mechanisms, potentially benefiting patients with other blood cancers or even precancerous conditions. Nam’s lab is also exploring whether interferon-alpha’s inflammatory infection-fighting response might contribute to certain autoimmune conditions when triggered inappropriately.