Scientists from the University of Birmingham and hospitals across the West Midlands in the UK say they have revealed how a common symptomless condition can develop into the blood cancer myeloma. They discovered that changes in the bone marrow needed for the cancer to grow have already taken hold in the preceding condition, raising the possibility that early medical intervention could prevent this incurable type of cancer from taking root.

The research paper (“Citrullination of Histone H3 Drives IL-6 Production by Bone Marrow Mesenchymal Stem Cells in MGUS and Multiple Myeloma”) is published in Leukemia.

Myeloma almost always progresses from an apparently benign condition known as MGUS, or monoclonal gammopathy of undetermined significance, which is especially common in the older population; as many as 7% of people over the age of 85 have MGUS. Only around one in 100 MGUS patients will develop myeloma each year and there is currently no way of accurately predicting which patients will do so, or when.

Myeloma never spreads to other organs, suggesting that myeloma cells rely on support from other cells in the bone marrow environment to survive. The Birmingham researchers showed that early on in MGUS development, cells that make up the bone marrow connective tissue change their behavior, and become more supportive of cancer growth. They found that a key gene, called PADI2 becomes particularly overactive in these connective tissue cells, which leads to the overproduction of a signaling molecule called interleukin-6 (IL-6).

Connective tissue cells release IL-6 into the bone marrow, where it binds with receptors on the surface of cancerous plasma cells, instructing them to multiply rapidly and resist cell death signals. It is already known that the presence of high levels of IL-6 in a patient's bone marrow significantly reduces the effectiveness of a key chemotherapy drug called bortezomib.

The researchers believe that drugs designed to target the PADI2 gene in MGUS and myeloma patients could significantly reduce the supportive signaling that myeloma cells depend on and may increase the effectiveness of current treatments. Significantly, the PADI2 gene has also been linked with the development of other types of cancer, rheumatoid arthritis, Alzheimer's disease, and autoimmune disease, so any drug developed could have wider applications beyond myeloma treatment.

“It is now clear that the bone marrow of patients with MGUS, traditionally thought of as a benign condition, is significantly different to that of healthy individuals,” said Daniel Tennant, Ph.D., who led the research at the University of Birmingham. “The bone marrow environment in these patients appears capable of supporting cancer growth, even though the majority of patients will not progress to myeloma. While this research is in the early stages, it offers the exciting possibility that early intervention could potentially delay or even prevent cancer development.”

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