Delving into tRNA-derived small RNAs in multiple myeloma: elevated 3'U-tRFSerTGA leads to poor disease prognosis.

Abstract

Background: Multiple myeloma (MM) is an incurable malignancy, marked by treatment resistance and frequent relapses, posing ongoing challenges to patients' long-term management. Herein, we have examined tRNA-derived small RNA fragments (3'U-tRFs), generated from precursor tRNAs, to identify MM-related 3'U-tRFs in ameliorating MM precision prognostics.

Methods: 3'U-tRF profiles were generated by small RNA-seq data. Target prediction and gene ontology analysis were assessed by tRFtarget and DAVID databases, respectively. CD138 + 3'U-tRF^SerTGA levels were quantified in our MM screening cohort (n = 136 patients) by RT-qPCR. Kaplan-Meier and Cox proportional regression analyses were performed, using disease progression and patients' mortality as clinical endpoints. Internal validation was conducted by bootstrap Cox regression while clinical benefit on patients' prognosis was assessed by decision curve analysis (DCA).

Results: Small RNA-seq data analysis highlighted the significantly increased 3'U-tRF^SerTGA levels in MM cell lines compared to normal cells (FC: 14.03). Our screening cohort confirmed the significantly higher risk for short-term progression and worse survival of the patients presenting elevated 3'U-tRF^SerTGA. 3'U-tRF^SerTGA-fitted multivariate models demonstrated superior risk-stratification of the patients for treatment response and prognosis.

Conclusions: Our study indicate the elevated 3'U-tRF^SerTGA as a strong independent predictor of poor first-line chemotherapy outcomes and MM progression, providing refined stratification of patient risk.