Multiple Myeloma (MM) is a complex disease that frequently leads to fatal outcome and accurate risk classification to optimize the choice of therapy may have impact on clinical outcomes. MM stratification based upon cytogenetic abnormalities and protein-coding gene expression does not adequately correlate with the depth or durability of therapeutic response. Therefore, the new class of molecular effectors, non-coding RNAs (ncRNAs), may enhance the basic understanding of myelomagenesis, drug resistance and provide better stratification of myeloma subtypes. NcRNAs include long ncRNAs (lncRNAs) and microRNAs (miRNAs) that may act as positive or negative regulators of gene expression to control cell proliferation, apoptosis and drug resistance. We hypothesized that lncRNAs commonly deregulated in the 3 resistant cell lines would have significant overlap to the deregulated lncRNA in MM patients. To investigate the role of lncRNAs in resistance to proteasome inhibitors (PIs), we compared global lncRNA profiling in drug-naïve cells to cells with acquired resistance to the PIs bortezomib, carfilzomib and ixazomib. RPMI 8226 cells resistant to each of the three PIs were generated through successive exposure to bortezomib, carfilzomib or ixazomib. Total RNA was isolated and genome-wide ncRNA expression profiling was performed using Affymetrix 3.0 microarray chips LncRNA expression profiles from drug-resistant cells were compared to that of drug-naïve cells treated with vehicle alone. MM patients’ bone marrow aspirates were obtained after UCCOM IRB-approval. Bioinformatic analysis identified a panel of 18 lncRNAs that were significantly (>100-fold) deregulated in all three drug-resistant cell lines relative to drug-naïve cells. Strikingly, the majority of the deregulated lncRNAs exhibited a similar expression pattern in all 3 PI-resistant cell lines (Figure 2a). RPMI 8226 cells carry a t(14,16) and none of the deregulated lncRNAs detected localized to chromosomes 14 or 16, suggestive of a cytogenetic-independent mechanism of drug resistance. We also identified lncRNAs deregulated in MM patient samples relative to plasma cells from healthy age-matched individuals. We found a significant overlap (>90%) between deregulated lncRNAs in PI-resistant cells and MM cells. The lncRNA COL4A-2A was upregulated >5,000-fold in resistant cells and displayed extensive sequence complementarity to miRNA-29 that was downregulated in resistant cells. Taken together, we identified a curated panel of deregulated lncRNAs in common within myeloma cells generated with acquired resistant to three different clinically-relevant proteasome inhibitors and MM patients. Further investigation is warranted to shed light on the role of these lncRNAs in the development of MM, to identify their targets and to define their role in drug resistance.
Note: This abstract was not presented at the meeting.
Citation Format: Ehsan Malek, Rebekah Karns, Anil G. Jegga, Sajjeev Jagannathan, Nikhil Vad, Mohamed A.Y Abdel Malek, James J. Driscoll. Long non-coding RNAs deregulated in Multiple Myeloma impact therapeutic response to proteasome inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 153. doi:10.1158/1538-7445.AM2015-153