Integrated Transcriptomic Analysis Reveals a Distinctive Role of YAP1 in Extramedullary Invasion and Therapeutic Sensitivity of Multiple Myeloma.

ABSTRACT

Multiple myeloma (MM) is the second most common hematologic malignancy. There are no standard therapeutic guidelines for extramedullary invasion (EM). We performed a retrospective integrated transcriptomic analysis based on GEO, TCGA, and Oncomine datasets with a total of over 2,500 cases enrolled. GSVA analysis was performed on GSE24080. The external validation cohorts include GSE9782, GSE2658, MMRF-COMPASS, and Oncomine. The data of MGUS to relapsed MM were acquired from GSE6477, GSE5900, and Oncomine. The data of EM were acquired from GSE39683 and GSE66291. Single-cell level transcriptome data of MM and EM were acquired from GSE106218. GSVA analysis revealed that 559 cases could be divided into 2 groups based on the expression of oncogenic pathways with prognostic significances. Group 1 with a specific phenotype of YAP1-MYC+ exhibited an unpromising prognosis. The univariate analysis revealed YAP1 as a tumor suppressor in MM. The activity of DNA repair, glycolysis, and oxidative phosphorylation was significantly higher in YAP1-MYC+ MM, which is in concordance with EM myeloma cells based on single-cell analysis. Furthermore, we discovered that YAP1-MYC+ MM patients exhibited an improved response for IMiD treatment. Collectively, YAP1-MYC+MM patients might suffer a worse prognosis and stronger propensity for EM progression.