RROL lncRNA role in multiple myeloma

In this issue of Blood, Morelli et al¹ show that the novel long noncoding RNA (lncRNA) named RROL (RNA Regulator of Lipogenesis), derived from the MIR17HG gene, acts as a chromatin scaffold for protein interaction that results in the growth of multiple myeloma cells. Their study shows that RROL inhibition exhibits a potent antimyeloma activity both in vitro and in different in vivo models, suggesting a therapeutic potential.

LncRNAs are genes composed of more than 200 nucleotides that lead only to RNA transcripts, which do not translate into proteins, and have tissue- and cell-type–specific expression. The functional mechanism of the vast majority of identified lncRNAs is unknown or unexplored, but owing to the results obtained in diverse studies carried out in recent years, it has been possible to elucidate that lncRNAs, like coding genes, are involved in all crucial human cell functions. Although we still have much to discover, we also know that lncRNAs can be expressed from different genome regions (introns, intergenic) or chromatin states (promoters, enhancers), which can be very important in defining their likely function and can suffer various aberrations owing to both genetic and epigenetic alterations. Consequently, the deregulation of lncRNA expression can affect all biological cell functions, contributing to human carcinogenesis, metastasis, and even resistance to chemotherapy. In this sense, in the case of multiple myeloma (MM), the altered expression of lncRNAs has been associated with the development and progression of the disease, which affects patient survival.^2,3 This body of knowledge places us in a highly promising novel scenario in which carrying out thoughtful studies about the role of lncRNAs in relation to human tumors has great potential. LncRNAs may be the key to better stratification of patients with cancer, ie, as a biomarker for survival, and may provide essential targets for the development of innovative therapeutic strategies to improve the response to current chemotherapy treatments and improve patients’ quality of life.

To identify lncRNAs involved directly in MM survival and proliferation, Morelli et al performed systematic targeted viability screening in MM cell lines using a CRISPR interference library against 913 lncRNAs expressed in MM patient samples and cell lines. The authors determined that the inhibition of MIR17HG lncRNA expression led to the greatest decrease in MM cell growth, showing similar potential to inhibition of key MM genes such as MYC or IRF4, suggesting that MIR17HG lncRNA is the most critical lncRNA in terms of dependency in MM. MIR17HG is known as the precursor of microRNA (miRNA) cluster miR-17-92, and these miRNAs have been shown to be involved in different types of human tumors including MM, as previously shown by the authors.⁴ In addition to the miRNAs, in this study the authors observed that in MM cells, this MIR17HG gene produced a nuclear lncRNA transcript that they named RROL (see figure). They observed that high RROL expression was associated with shorter event-free and overall survival in 3 large cohorts of patients with newly diagnosed MM. These results demonstrated the potential of RROL as a biomarker for MM. Interestingly, the authors found that the inhibition of the RROL expression was the main factor responsible, regardless of the action of miR-17-92, for the essentialness of MIR17HG observed in MM and was, therefore, the principal mediator of MM dependence on this MIR17HG gene.

Morelli et al also demonstrated that RROL bound MYC and WDR82 proteins, facilitating their assembly and promoting their occupancy especially in the promoter region of ACC1 gene. They showed that WDR82, a regulatory component of the SET1 methyltransferase complex, was necessary to increase the 3HK4me3 levels in the promoter region of ACC1, which was the fundamental epigenetic modification for MYC to bind to the chromatin of this promoter region and generate transcriptional activity by increasing the expression of the last piece of this complex, which is the ACC1 gene. ACC1 (or ACACA, acetyl-CoA carboxylase alpha) is the first and rate-limiting enzyme in the fatty acid biosynthesis or de novo lipogenesis pathway, promoting tumorigenesis or, in this case, proliferation of MM cells (see figure). These results indicate that the aberrant expression of RROL has a direct impact on the metabolic adaptation of MM cells, which is absolutely necessary for their malignant growth and for continuous production of monoclonal immunoglobulins. Furthermore, this suggests that in order to have the most complete metabolic information, we need to take into account the expression of lncRNAs, as well as the coding genes, in the configuration of human metabolic pathways and the construction of genome-scale human metabolic models, which is being carried out with great effort and dedication by the human genome-scale metabolic network, known as HUMAN1.⁵ 

Finally, one of the most interesting points in the study by Morelli et al is that they developed 2 therapeutic ASOs against RROL lncRNA expression, showing their inhibition of the RROL-MYC-WDR82-ACC1 complex and their antimyeloma efficacy in 3 different in vivo MM models. Remarkably, this study reemphasizes the importance of RNA medicine or RNA-targeting therapeutics and suggests the urgent need to develop strategies that target the expression of disease-relevant RNA molecules or their structures and delivery technologies to enable these RNA-based therapies to reach their target cells.^6,7 This will surely lead to great advances in the treatment of patients with cancer, here MM, and of other human diseases.

Conflict-of-interest disclosure: The author declares no competing financial interests.