rim of a bone spicule (pink)
New research indicates that multiple myeloma (MM) cells can “disguise” themselves as bone cells to elude the immune system, a trick that enables MM progression.
Investigators found evidence suggesting that MM cells mimic bone-marrow-resident cells by expressing bone-related genes, and this process is driven by overexpression of Runx2, a transcription factor that regulates bone formation.
“[R]unx2 overexpression can give multiple myeloma cells a bone-cell-like phenotype,” said Yang Yang, MD, PhD, of the University of Alabama at Birmingham.
“When the multiple myeloma cells come to the new bone sites, the bone immune cells think, ‘This is one of our neighbor cells,’ and therefore do not eliminate them. The bone immune cells do not recognize these cells as strangers.”
Dr Yang and her colleagues explained this phenomenon in Blood.
The investigators first conducted in vitro experiments and found that Runx2 expression in MM cells does not affect proliferation, but it does increase the cells’ invasiveness.
The team then used molecular genetic techniques to increase or decrease the expression of Runx2 in MM cells in vivo. They found that Runx2 overexpression promoted tumor growth and progression in mice. And mice with decreased Runx2 expression had less tumor growth and disease spread than control mice.
Further investigation revealed that Runx2 overexpression activates the Akt/β-catenin/survivin signaling pathway in MM cells. This is a different pathway than the one activated by Runx2 in solid tumors.
Downstream of the signaling pathway, Runx2 overexpression led to overexpression of bone-related genes, including genes expressed by osteoblasts, osteoclasts, and osteocytes.
Overexpression of Runx2 also enhanced secretion of soluble factors—including cytokines and growth factors—that aid tumor progression and metastasis.
In their final experiments, the investigators looked at Runx2 expression in human samples.
The team compared samples from 14 healthy bone marrow donors, 35 MM patients, and 11 patients with monoclonal gammopathy of undetermined significance (MGUS). Runx2 levels were significantly higher in MM cells than in plasma cells from normal and MGUS samples.
The investigators also assessed Runx2 expression in a larger group of 351 newly diagnosed MM patients. Runx2 levels were significantly higher in patients who had a high risk of early disease-related death. The risk of death was determined by an existing gene expression profile test.
“This suggests that Runx2 levels in myeloma cells may be a gene predictor of a patient’s prognosis, good or bad,” Dr Yang said.
She and her colleagues also believe that targeting Runx2 expression could be a feasible strategy for treating aggressive MM.
