Micrograph showing MM
Overly zealous editing of messenger RNA in multiple myeloma (MM) cells contributes to MM pathogenesis and is associated with poor outcomes after certain treatments, investigators contend.
The team found evidence to suggest that overexpression of the RNA editing enzyme ADAR1 leads to hyperediting of the MM transcriptome that appears related to a drug-resistant disease phenotype and worse prognosis.
Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues reported these findings in Blood.
The investigators implicate aberrant editing of adenosine (A) to inosine (I) in malignant plasma cells and its effects on NEIL1, a gene that encodes proteins involved in base-excision repair of DNA, as important mechanisms in MM pathogenesis.
A to I editing is the most prevalent form of RNA editing in humans, and aberrant editing mediated by ADAR1 has recently been linked to the development of several cancer types, the investigators noted.
To see whether this process may also be involved in MM, the investigators examined whole blood or bone marrow samples from healthy volunteers and MM patients.
The team found that ADAR1 was overexpressed in MM cells compared to nonmalignant plasma cells.
Furthermore, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed MM compared to patients who had smoldering myeloma or monoclonal gammopathy of undetermined significance.
Response to treatment
The investigators also assessed ADAR1 expression in relation to MM patients’ responsiveness to treatment using data from the CoMMpass study.
The team found that patients with poor responses (stable or progressive disease) to bortezomib-based and immunomodulatory-based therapies had high ADAR1 mRNA.
There was no correlation between ADAR1 and responsiveness to carfilzomib-based treatments, but the investigators said this may be because of the relatively lower number of patients who received carfilzomib in this study.
The investigators also found that bortezomib was more effective in inhibiting the growth of MM cells with low ADAR1, and bortezomib-treated cells showed downregulation of ADAR1 expression in a dose- and time-dependent manner.
ADAR1-mediated editing
The investigators determined that ADAR1 directly regulates hyperediting of the MM transcriptome. This was evidenced by a significant increase in A to guanosine (G) editing in newly diagnosed and relapsed MM samples, compared with normal plasma cells.
The team confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The investigators followed this observation with experiments to see whether ADAR1-mediated editing contributes to oncogenesis in MM cells. The MM growth rate slowed when the team silenced ADAR1, and introducing wild-type ADAR1 into cells promoted growth and proliferation.
The investigators also identified NEIL1 as an important ADAR1 editing target in MM. The editing compromised NEIL1’s ability to accurately repair DNA damage.
This study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The investigators reported no competing financial interests.