Abstract Multiple myeloma (MM) is an incurable malignancy of antibody secreting plasma B cells. The t(4;14) translocation is detected in 20% of MM and is associated with shortened patient survival. Although the t(4;14) is known to up regulate the MMSET proteins, its role in MM remains unclear. Previously, we identified a novel orphan box H/ACA class small nucleolar RNA (snoRNA), that is located within intron 19 of MMSET, and is expressed in MM cells harboring the t(4;14) translocation. H/ACA small RNAs are an evolutionarily conserved class of abundant noncoding RNAs (ncRNA) involved in a diverse range of processes including posttranslational modifications of functional RNAs, preribosomal RNA processing, and telomere maintenance, yet their contribution to human disease remains largely unexplored. In this study, t(4:14) positive and negative MM patient tumor cells were analyzed by RNA sequencing. This revealed a unique signature of up regulated genes involved in mitochondrial respiration and oxidative stress. Our hypothesis is ACA11 plays critical role in MM cell proliferation and cell transformation by increasing oxidative stress. We found that acute ACA11 overexpression leads to the increased oxidative stress in primary splenic B-cells, established myeloma cell lines, as well as embryonic fibroblasts. In particular, cells overexpressing ACA11 showed enhanced proliferation, significantly larger colony sizes in soft agar assays, and elevated ERK1/2 phosphorylation, a downstream consequence of oxidative stress. In addition, we found that the transcription factor nuclear factor erythroid-derived 2-related factor 2 (Nrf2), which regulates anti-oxidant signaling, dissociated from Keap1 and translocated to the nucleus, but failed to activate anti-oxidant downstream targets in ACA11 overexpressing cells. Furthermore, ACA11 up regulated TXNIP, which encodes an inhibitor of ROS scavenger thioredoxin. In conclusion, we propose that acute overexpression of ACA11 up regulates TXNIP and suppresses the ability of Nrf2 to induce target anti-oxidants genes, resulting in increased oxidative stress and cell proliferation. These changes may be critical events in the development and/or progression of multiple myeloma. Citation Format: Nitin Mahajan, Leonard B. Maggi, Michael H. Tomasson, Jason D. Weber. The multiple-myeloma associated snoRNA, ACA11 increases oxidative stress and cell proliferation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-298. doi:10.1158/1538-7445.AM2015-LB-298