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Letters to the Editor
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Figure 2. Gene Ontology (GO) analysis of genes differentially expressed in light-chain amyloidosis (ALA) and ALA plus multiple myeloma (ALA+MM) versus MM diagnoses and assigned into the category “biological process”. (A) The overlap of upregulated genes in ALA and ALA+MM. The top upregulated pathways are provided for the colored intersections. (B) The overlap of downregulated genes in ALA and ALA+MM. The top downregulated pathways are provided for the colored intersections. 1P=0.000002, 2P=0.000283, 3P=0.00078, 4P=0.000011, 5P=0.001867, 6P=0.04333 and 7P=0.02736.
GO terms (Figure 2B, Online Supplementary Table S11). The small number of deregulated genes between MM and ALA+MM only, did not allow for identification of pathways uniquely affected in these entities (Figure 2A- B, Online Supplementary Table S11).
Although our dataset was relatively small (18 samples), we detected a specific pattern of gene expression com- mon in ALA and ALA+MM versus MM. Interestingly, the expression profiles and pathways specific for ALA/ALA+MM pointed to downregulation of genes involved in mitochondrial RNA metabolism and transla- tion (Figure 2, Online Supplementary Table S11). Ribosomal deregulation in ALA was previously indicated by Kryukov et al.11 in 2016, however, our set of ribosomal proteins is involved in the function of mitochondrial rather than cytoplasmic ribosomes. We can speculate that downregulation of mitochondrial translation is a compensatory mechanism for increased stress. Downregulation of mitochondrial RNA to avoid oxida- tive stress was described by Crawford et al.12 in 1997 and oxidative stress as well as endoplasmtic reticulum stress were found to be elevated in ALA versus MM PC.13
One of the most important aims and biological ques- tions of our study was to characterize the mutation and subclonal profile of ALA+MM and determine whether it is more similar to ALA or MM. In order to answer this question, we first defined similarities at the level of the somatic variants. More mutated genes were shared between ALA+MM and MM. On the other hand, there were more similarities in the number of subclones between ALA and ALA+MM compared to MM. This observation is supported by a clonality study using cyto-
genetic methods.14 Results of Bochtler et al.14 demonstrat- ed that all PC dyscrasias containing amyloid deposits share less clones compared to non-ALA counterparts. Furthermore, we compared the gene expression levels to gain additional insights into ALA+MM. Surprisingly, transcription profiles of ALA and ALA+MM were indis- tinguishable, while MM was a clearly separate entity, but still closer to ALA+MM than to ALA.
Based on these results, we conclude that ALA+MM share a mutation profile which is more similar to MM, but these changes were not manifested on the gene expression level, or on the level of plasma cell infiltration. The typical myeloma symptoms present in ALA+MM may thus be caused by mechanisms other than the global expression profile of aPC.
Our detailed study of ALA diseases represents an important step towards improved understanding of their genetic and transcriptomic background, which is a perquisite for development of optimal treatment strate- gies in the future.
All sequencing reads mapped on the reference genome are deposited in European Genome-phenome Archive (EGA) with accession code EGAS00001004214. The gene expression data-matrix is available in the Online Supplementary Table S10.
Zuzana Chyra,1,2,3* Tereza Sevcikova,1,2,4* Petr Vojta,1,2,5
Janka Puterova,6,7 Lucie Brozova,8 Katerina Growkova,1,2,4 Jana Filipova,1,2,4 Martina Zatopkova,1,2,4 Sebastian Grosicki,9 Agnieszka Barchnicka,9 Wieslaw Wiktor-Jedrzejczak,10
Anna Waszczuk-Gajda,10 Alexandra Jungova,11
Aneta Mikulasova,12 Marian Hajduch,5 Martin Mokrejs,13°
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