Could myeloma be preventable?

In patients with monoclonal gammopathy of undetermined significance (MGUS)—a benign, symptomless condition that sometimes precedes multiple myeloma (MM)—bone marrow mesenchymal stem cell (MBBSC) dysfunction may lead to pro-malignancy signaling and possibly be the very mechanism that allows for the development of MM, according to researchers from the University of Birmingham. Their results are published in the current issue of the journal Leukemia.

In the elderly, myeloma usually progresses from MGUS, which is common and affects up to 7% of those aged ≥ 85 years old. Annually, 1 in 100 patients with MGUS will develop myeloma, but predicting which will do so is not possible.

Lead researcher Daniel Tennant, BA, MSci, PhD, College of Medical and Dental Sciences, University of Birmingham, United Kingdom, and fellow researchers have found that early in MGUS, the behaviors of bone marrow connective tissue cells are altered, and seem to support cancer growth via increased expression of peptidyl arginine deiminase 2 (PADI2) by these dysfunctional MBBSC.

Indeed, they found that PADI2 was one of the most highly upregulated transcripts in BMMSCs in MGUS and MM patients, and is responsible for the enzymatic deamination of histone H3 arginine 26, which causes overproduction of IL-6, an important signaling molecule. IL-6 is then released into the bone marrow by these connective tissue cells, and binds with receptors found on the surface of cancerous plasma cells. They signal the cancer cells to multiply rapidly and resist signals of cell apoptosis. Previous research has shown that high IL-6 levels in bone marrow can significantly reduce the efficacy of chemotherapies containing bortezomib by causing resistance in malignant plasma cells.

Thus, these researchers concluded that agents targeting the PADI2 gene in patients with MGUS and MM may reduce the signaling that myeloma cells depend on, and thus increase the efficacy of 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. 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,” said Dr. Tennant.

Since PADI2 has also been associated with other diseases, including rheumatoid arthritis, Alzheimer’s disease, other types of cancer, and some autoimmune diseases, any new therapies directly against PADI2 may be effective for these conditions as well.

This research was funded by the charity Bloodwise, formerly Leukemia & Lymphoma Research, United Kingdom.