Single-cell study reveals how interferon redirects mutant blood stem cells

Interferon-alpha can benefit people with myeloproliferative neoplasms by changing the developmental state of mutant blood stem cells, according to a peer-reviewed study by Weill Cornell Medicine investigators published September 15 in Nature Genetics. Single-cell profiling of blood cells from patients with essential thrombocythemia showed that treatment accelerated the maturation of stem cells into short-lived, infection-fighting neutrophils. Mutant stem cells appeared more susceptible to this response than non-mutant stem cells in patients who responded to interferon-alpha, providing a cellular explanation for the treatment’s ability to reduce the pool of mutant blood cells.

Myeloproliferative neoplasms arise when DNA mutations in blood stem cells lead to excessive production of particular myeloid blood cells. Essential thrombocythemia, the form examined in this study, features overproduction of megakaryocytes, the cells that produce platelets, and is associated with elevated risks of heart attack and stroke. Blood stem cells reside in bone marrow and give rise to red blood cells, platelet-producing megakaryocytes and immune cells through two broad lineages: myeloid and lymphoid.

The investigators recorded gene-activity patterns, surface proteins and other characteristics of thousands of individual blood cells sampled from consenting patients. They compared cells collected before and during interferon-alpha treatment and distinguished mutant cells from admixed non-mutant cells to examine how the two populations responded differently. Interferon-alpha pushed blood stem cells to mature rapidly into neutrophils, white blood cells that fight infection and do not live for very long.

As mature neutrophils are continually produced and older cells are removed, this accelerated maturation can progressively deplete the stem-cell pool over time. The study’s single-cell analysis indicated that mutant stem cells were more susceptible to this process than non-mutant stem cells in patients who responded to treatment. Rather than simply eliminating mutant cells at the moment of measurement, interferon-alpha appeared to redirect their developmental state, moving them out of the stem-cell compartment and toward a short-lived mature identity.

Interferon-alpha produced a second major effect by inducing many blood stem cells to develop into lymphoid cells, which helps bring the lymphoid population into greater balance with the overproduced myeloid cells. These observations show that interferon-alpha changes several aspects of blood-cell development in essential thrombocythemia: it promotes rapid neutrophil maturation, shifts some stem cells toward the lymphoid lineage and suppresses inflammation-associated gene programs. The study was based on patient samples and detailed cellular analysis rather than a trial of a more selective treatment, so it does not show that reproducing any of these effects alone would be safe or effective in people.

The authors said the mechanistic findings could guide efforts to develop more focused and potent strategies for reducing mutant blood cells in myeloproliferative neoplasms and potentially other blood cancers, with possible relevance to precancerous conditions. The Nam Laboratory is also investigating whether aberrant triggering of the inflammatory interferon response contributes to some autoimmune conditions. Because interferon-alpha has broad activity and can cause significant side effects, identifying the cellular pathways behind its effects may provide a foundation for treatments that could reproduce selected benefits with greater precision.

Subject of Research: Single-cell mechanisms of interferon-alpha action in essential thrombocythemia

Article Title: How interferon changes cancerous blood stem cells

Article References: How interferon changes cancerous blood stem cells. Original publication (Bibliographic details unavailable.)

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Keywords: interferon-alpha, myeloproliferative neoplasms, essential thrombocythemia, blood stem cells, single-cell profiling, neutrophil maturation, lymphoid lineage, DNA mutations, Nature Genetics, interferon, changes, cancerous