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Variants could serve as biomarker to inform prognosis or guide treatment decisions

Andean Enriched NFKB1 Haplotype Reduces Inflammation and Improves Response to Ropeginterferon Alfa-2b in Polycythemia Vera (PV) and Essential Thrombocythemia (ET)

(SAN DIEGO – Dec. 10, 2024) – A study presented during the 66th ��ѻ��ý (ASH) Annual Meeting and Exposition reveals genetic factors that can affect the molecular pathways involved in inflammation, hypoxia sensing, blood clots, and the response to treatment among people with polycythemia vera (PV) and essential thrombocythemia (ET), part of a group of blood cancers known as myeloproliferative neoplasms.

Researchers reported that patients with a genetic profile common among the Aymara Indigenous community in the Andean mountains – namely the NFKB1 gene variant that encodes several different mRNA transcripts – correlated with a lower expression of genes involved in inflammation and a better response to Ropeginterferon-α, the primary drug used to treat PV and ET. The findings could help doctors tailor treatments based on a person’s inherited genes, which interact with acquired genetic mutations that cause PV and ET. This may eventually lead to opportunities to develop new therapies for PV and ET, according to researchers.

“We identified some genetic variants which are evolutionarily selected to be beneficial to the Aymara high-altitude population in the Andean mountains, and we have now shown, for the first time, that these variants are also present in other populations and correlate with some differences in disease phenotype,” said the study’s senior author, Josef T. Prchal, MD, a physician and professor of hematology and genetics at the Huntsman Cancer Institute at the University of Utah, Salt Lake City. “Our study suggests that with genotyping, the NFKB1 variant can be used as a biomarker for determining which patients may be more or less responsive to Ropeginterferon-α treatment.”

In PV, the bone marrow produces too many red blood cells, and in ET, the bone marrow overproduces platelets. Both PV and ET lead to chronic inflammation, raise the risk of dangerous blood clots, and can lead to leukemia. They can also boost hypoxia-inducible factors (HIFs), which can modify how certain genes help cancer cells survive in low-oxygen environments, making the cancer harder to eradicate.

For the study, the researchers analyzed genetic profiles, gene expression, and clinical outcomes among 30 people with PV and 15 people with ET. They assessed patients’ expression of genes involved in inflammation, HIF targets, and thrombosis (the formation of blood clots). The researchers also analyzed the linkages between a person’s NFKB1 genotype and their likelihood of achieving a complete hematologic response (a return to normal blood counts) after Ropeginterferon-α treatment.

The genetic markers used in the study reflect three genotypes of the NFKB1 variant (rs230511), delineated as C/C, C/T, and T/T. In previous studies, the research team estimated that the T variant (either C/T or T/T) is present in about 90% of people in the Aymara community and in about 30% of people of European, Asian, and Hispanic ancestry. In the Aymara population, the T variant was also correlated with increased inflammation in immune quiescence, or baseline immune, status, while under inflammatory stress, T variants exhibited a protective role by preventing excessive inflammatory gene expression. In this study, the researchers found that the T variant was associated with decreased inflammatory, prothrombotic, and HIF activity, and a better response to Ropeginterferon-α in PV and ET, which are characterized by chronic inflammation.

“Most high-altitude adaptation studies correlate genes with phenotypes such as high hemoglobin or low oxygen saturation, but the important finding that our study adds is that there is also an association with modulation of inflammation, which can affect outcomes for diseases like PV and ET,” said Dr. Prchal. “The people with a better response to Ropeginterferon-α showed more C/T genotype which was correlated with less inflammatory gene expression, so we suspect that people with this genotype will also tolerate the treatment better and have fewer side effects.”

The formation of dangerous blood clots is the major cause of illness and death related to PV and ET, and this risk is known to increase with age. According to the researchers, the new study findings suggest that genetic factors could also play a role in thrombotic risk, potentially in addition to other factors such as diet or environment.

While the study points to molecular markers associated with inflammation and thrombosis, the researchers noted that further studies are required to determine whether these markers also correlate with clinical outcomes such as the development of blood clots or leukemia, or whether a person’s genetic profile may affect their overall risk of developing myeloproliferative neoplasms. They added that it could also be helpful to study any differences in the C/T versus T/T genotype to further inform treatment decisions.

The study was funded by the National Institutes of Health’s National Heart, Lung, and Blood Institute and Dorothy Brown Innovation in Science.

Jihyun Song, PhD, of Huntsman Cancer Institute at the University of Utah, will discuss this study in the Late-Breaking Abstracts session on Tuesday, December 10, 2024, at 7:30 a.m. Pacific time in Hall B (San Diego Convention Center).

About the ��ѻ��ý

 The ��ѻ��ý (ASH) (hematology.org) is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. Since 1958, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology.

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Claire Whetzel, 202-629-5085
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