Image: Bone marrow biopsy of a patient with multiple myeloma, showing diffuse infiltration by neoplastic plasma cells, which can be recognized by the eccentric nucleus and perinuclear halo (Photo courtesy of Dr. Michael G. Bayerl).
Multiple myeloma (MM) is the second most common blood cancer in the USA and 30% to 50% of multiple myeloma patients have extra copies of the gene that encodes the enzyme Adenosine Deaminase, RNA Specific (ADAR1).
ADAR1 is normally expressed during fetal development to help blood cells form. ADAR1 edits the sequence of RNA, a type of genetic material related to DNA. By swapping out just one RNA building block for another, ADAR1 alters the carefully orchestrated system cells use to control which genes are turned on or off at which times.
Scientists at the University of California San Diego School of Medicine (La Jolla, CA, USA) obtained bone marrow samples from MM patient and normal age-matched controls. Peripheral blood (PB) or bone marrow (BM) samples were processed by Ficoll density centrifugation and viable total mononuclear cells (MNC) were collected for further analyses and stored in liquid nitrogen. RNA editing site-specific quantitative real time polymerase chain reaction (RESSq-PCR) assay primer design was carried out for specific cancer and stem cell-associated loci. The team performed several other molecular procedures to confirm their results.
The scientists analyzed a database of nearly 800 multiple myeloma patient samples, and they discovered that 162 patients with low ADAR1 levels in their tumor cells survived significantly longer over a three-year period compared to 159 patients with high ADAR1 levels. While more than 90% of patients with low ADAR1 levels survived longer than two years after their initial diagnosis, fewer than 70% of patients with high ADAR1 levels were alive after the same period of time.
The team found that two events converge to activate ADAR1 in multiple myeloma, a genetic abnormality and inflammatory cues from the surrounding bone marrow tissue. Together, these signals activate ADAR1, which edits specific RNA in a way that stabilizes a gene that can make cancer stem cells more aggressive. They also found that silencing the ADAR1 gene in the xenograft model reduced multiple myeloma regeneration. Five to 10-fold fewer tumor cells were able to self-renew in mice lacking ADAR1, suggesting a new therapeutic target.
Catriona H. M. Jamieson, MD, PhD, professor of medicine and senior author of the study, said, “Several major advances in recent years have been good news for multiple myeloma patients, but those new drugs only target terminally differentiated cancer cells and thus can only reduce the bulk of the tumor. They don't get to the root cause of disease development, progression and relapse, cancer stem cells, the way inhibiting ADAR1 does. I like to call our approach 'precision regenerative medicine.” The study was published on December 4, 2017, in the journal Nature Communications.
University of California San Diego School of Medicine