Abstract 3967: A novel translation program regulates tumor-initiating potential and chemoresistance in multiple myeloma

Abstract

Abstract Background: Despite the introduction of novel therapies, the majority of the multiple myeloma (MM) patients eventually relapse and develop chemoresistance, and the factors responsible for disease progression are not fully understood. Relapse suggest that MM cells that are resistant to chemotherapy and have the clonogenic growth potential to produce tumor cells exist, and we have found that tumor cells lacking the plasma cell antigen CD138 are enriched in these properties. Understanding the mechanisms regulating these MM cancer stem cells (CSCs) may lead to novel targeting strategies. Aberrant translation is a widespread characteristic of tumor cells and plays a major role in drug resistance. Thus, therapeutic agents that target translation hold promise as novel anti-cancer drugs. MM cells are characterized by heightened protein production in the form of immunoglobulin (Ig) and are highly dependent on proteolytic pathways such as the proteasome to maintain protein homeostasis. As a consequence, proteasome inhibitors (PIs) such as bortezomib (BTZ) have been established as a frontline therapy for the disease. Immature plasma cells with diminished Ig production are resistant to BTZ, and patients with low Ig producing tumors are more likely to relapse. Therefore, low protein synthesis may confer growth advantages to cancer cells such as chemoresistance and enhanced tumor regrowth potential. Methods & Results: To examine alterations in the translational landscape in therapy resistant MM, we treated MM cells with BTZ, and found that eukaryotic translation initiation factor-5 (eIF5) was highly upregulated. Importantly, over-expression of eIF5 led to increased chemotherapy resistance and enhanced clonogenicity. O-propargyl-puromycin incorporation showed a global translational reduction in cells over-expressing eIF5. Matched transcriptional RNA sequencing (RNA-seq) and ribosome profiling revealed that a subset of genes, including MSI2 and EZH1, escaped translation suppression by maintaining efficient translation in eIF5 over-expressing cells. In addition, clonogenic (CD138neg) MM cells exhibited increased eIF5 expression and decreased protein synthesis. Discussion: Understanding the mechanisms of chemoresistance in the cell populations responsible for residual disease and re-growth may lead to novel targeting strategies. Recent studies have indicated that stem cell behavior is coupled to protein synthesis regulation. However, the role of translational control in the maintenance of tumor-initiating cells has been explored only recently. Studies have implicated deregulation of initiation factors in various types of cancer. However, the role of eIF5 in cancer remains elusive. Our data reveals, for the first time, a novel eIF5-directed translational program that enhances chemoresistance and tumor-initiating potential in MM cells, making it a promising therapeutic target. Citation Format: Kiera Rycaj, Eun-Hee Park, Tori Tonn, Qiuju Wang, Can Cenik, Christian Gocke, William Matsui. A novel translation program regulates tumor-initiating potential and chemoresistance in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3967.