Overly zealous editing of messenger RNA in multiple myeloma cells appears to contribute to myeloma pathogenesis, and is prognostic of poor outcomes, investigators contend.
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Over-expression of RNA editing enzymes in the adenosine deaminases acting on RNA (ADAR) family, specifically ADAR1, lead to hyperediting of the multiple myeloma (MM) transcriptome that in turn appears related to a drug-resistant disease phenotype and worse prognosis, reported Phaik Ju Teoh, PhD, of the Cancer Science Institute of Singapore, and colleagues.
The investigators implicate aberrant editing of adenosine to inosine (A-to-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 multiple myeloma pathogenesis.
“To the best of our knowledge, this is the first report of ADAR1-mediated hypereditome being an independent prognostic factor. The compromised integrity of MM transcriptome drives oncogenic phenotypes, likely contributing to the disease pathogenesis. Our current work, therefore, recognizes the clear biological and clinical importance of A-to-I editing at both the whole-transcriptome and gene-specific level (NEIL1) in MM,” they wrote in Blood.
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 different cancer types, the investigators noted.
To see whether this process may also be involved in multiple myeloma, the investigators examined whole blood or bone marrow samples from healthy volunteers and patients with multiple myeloma.
They first looked at gene-expression profiling in the control and multiple myeloma samples and found that ADAR1 was overexpressed in the multiple myeloma cells, compared with nonmalignant plasma cells. Additionally, they saw that, at the protein level, ADAR1 was expressed at higher levels in patients with newly diagnosed or relapsed disease, compared with patients with smoldering myeloma or monoclonal gammopathy of undetermined significance.
They next determined that ADAR1 directly regulates hyperediting of the MM transcriptome, evidenced by the observation of a significant increase in A-to-G editing in the newly diagnosed and relapsed myeloma samples, compared with normal plasma cells. They confirmed this finding by observing the effects of ADAR1 levels on editing events across the transcriptome.
The authors followed this observation with experiments to see whether RNA editing by ADAR1 contributes to oncogenesis in myeloma cells. They silenced its expression and found that growth rate slowed and that ADAR1 wild-type protein introduced into cells promoted growth and proliferation.
“As the rescue with mutant ADAR1 is incomplete, we do not discount potential nonediting effects in ADAR1-induced oncogenesis in vivo. Nevertheless, taking into consideration the collective results from both the in vitro and in vivo studies, the RNA editing function of ADAR1 is important for its oncogenic effects in myeloma,” they wrote.
In the final steps, they identified NEIL1 as an important target for editing in multiple myeloma and observed that the editing compromised the ability of the proteins produced by the gene to accurately repair DNA damage.
“Further demonstrating its vital contribution to disease aggressiveness, patients with high ADAR1 expression showed less responsiveness toward standard and novel therapies. Therefore, our findings implied that a disturbed editome mediated by ADAR1 overexpression is both clinically and functionally crucial in our disease setting, and that ADAR1 confers oncogenic properties in myeloma in an editing-dependent manner,” they wrote.
The study was supported by the National Research Foundation Singapore, the Singapore Ministry of Education, and the National University of Singapore. The authors reported having no competing financial interests.
SOURCE: Teoh PJ et al. Blood. 2018;132(12):1304-17.