The MYC-Regulated RNA-Binding Proteins hnRNPC and LARP1 Are Drivers of Multiple Myeloma Cell Growth and Disease Progression and Negatively Predict Patient Survival

Simple Summary This study aimed to understand how the oncogenic transcription factor MYC affects cellular processes contributing to cancer. Therefore, we used cell lines derived from multiple myeloma (MM), a malignant plasma cell disorder that is highly dependent on MYC expression. Through quantitative mass spectrometry analysis, we examined how MYC depletion affects the proteome of MM cells. We observed that upon MYC depletion, the levels of the two RNA-binding proteins hnRNPC and LARP1 decreased, suggesting a direct regulation by MYC. Notably, a reanalysis of publicly available data demonstrated that high expression of hnRNPC and LARP1 was linked to poor survival and disease progression in MM patients, suggesting their potential as prognostic markers and therapeutic MYC target proteins. Our findings demonstrate the efficacy of our approach in identifying MYC-regulated target proteins that could potentially serve as predictors of both patient survival and disease progression in MM.Abstract Multiple myeloma (MM) is a malignant plasma cell disorder in which the MYC oncogene is frequently dysregulated. Due to its central role, MYC has been proposed as a drug target; however, the development of a clinically applicable molecule modulating MYC activity remains an unmet challenge. Consequently, an alternative is the development of therapeutic options targeting proteins located downstream of MYC. Therefore, we aimed to identify undescribed MYC-target proteins in MM cells using Stable Isotope Labeling with Amino Acids in Cell Culture (SILAC) and mass spectrometry. We revealed a cluster of proteins associated with the regulation of translation initiation. Herein, the RNA-binding proteins Heterogeneous Nuclear Ribonucleoprotein C (hnRNPC) and La Ribonucleoprotein 1 (LARP1) were predominantly downregulated upon MYC depletion. CRISPR-mediated knockout of either hnRNPC or LARP1 in conjunction with redundant LARP family proteins resulted in a proliferative disadvantage for MM cells. Moreover, high expression levels of these proteins correlate with high MYC expression and with poor survival and disease progression in MM patients. In conclusion, our study provides valuable insights into MYC's role in translation initiation by identifying hnRNPC and LARP1 as proliferation drivers of MM cells and as both predictive factors for survival and disease progression in MM patients.