Multiple Myeloma Uses "Wolf in Sheep's Clothing" Tactic to Avoid Immune Response in Bone

Multiple myeloma uses a trick akin to a wolf in sheep’s clothing to grow in and spread to new bone sites.
Multiple myeloma uses a trick akin to a wolf in sheep’s clothing to grow in and spread to new bone sites.

Multiple myeloma uses a trick akin to a wolf in sheep's clothing to grow in and spread to new bone sites.

By overexpressing Runx2, a gene that normally is a master regulator of bone formation, the cells of this largely incurable cancer produce proteins that mimic the normal bone-resident cells. This research was published in Blood (2015; doi:10.1182/blood-2014-12-613968).

This is the first study of the Runx2 expression in multiple myeloma, a cancer of the white blood cells that causes an estimated 11,000 deaths a year in the United States, said senior author Yang Yang, MD, PhD. Yang is an associate professor of pathology at the University of Alabama at Birmingham and also a scientist in UAB's Comprehensive Cancer Center and Center for Metabolic Bone Disease.

Runx2 has been linked to bone metastasis in several solid tumors, though researchers did not analyze the solid tumors for expression of bone-related genes.

“This new mechanism of Runx2 overexpression can give multiple myeloma cells a bone cell-like phenotype,” Yang said.

“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.”

A series of experiments in the multiple myeloma study, with both animal models and cells from human patients, highlights the role of the transcription factor Runx2 to express bone-related genes in myeloma cells.

These are genes that normally exist in bone residential cells, such as bone-forming osteoblasts and osteocytes, and the bone-resorbing osteoclast cells. These changes make the multiple myeloma cells more aggressive.

For animal models, Yang and colleagues used molecular genetic techniques to either increase or decrease the expression of Runx2 in a mouse myeloma cell line. The increased expression cells are called Runx2 knock-in cells, and the decreased expression cells are called Runx2 knock-down cells.

In mice, the Runx2 knock-in myeloma cells produced greater tumor growth and a wider spread of disease compared with the original myeloma cells; conversely, the Runx2 knock-down cells had less tumor growth and disease spread.

The researchers also tested a Runx2 knock-down variant of a human multiple myeloma cell line and found that it produced significantly less tumor growth in immunodeficient mice than the original human multiple myeloma cells.

The researchers used the Runx2 knock-in and knock-down cells to show that Runx2 overexpression activates the Akt/β-catenin/Survivin signaling system in the multiple myeloma cells. This is a different signaling system than the one activated by Runx2 in solid tumors.

RELATED: Panobinostat combination demonstrates benefit in relapsed/refractory multiple myeloma

Downstream of the signaling system, Runx2 overexpression led to overexpression of bone-related genes, including genes expressed by osteoblasts, osteoclasts, and osteocytes. The researchers explained that their results suggest that Runx2 contributes to tumor survival and growth in the bone microenvironment.

The overexpression of Runx2 also enhanced secretion of soluble factors that aid tumor progression and metastasis, including cytokines and growth factors.

Yang explained that Runx2 levels in myeloma cells may be a gene predictor of a patient's prognosis, good or bad. She also suggested that targeting Runx2 expression in multiple myeloma cells may represent a new therapeutic strategy for the treatment of aggressive multiple myeloma.

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