The t(4;14) chromosomal translocation found in 20% of multiple myeloma (MM) cases leads to a shorter survival rate in an already incurable disease. The candidate oncogene overexpressed from the t(4;14) translocation, WHSC1 (MMSET), is unable to transform cells in culture or drive tumorigenesis in mice on its own. Examination of a 2 MB region around the t(4;14) breakpoint revealed the overexpression of a 125 bp orphan H/ACA class non-coding RNA, ACA11, which was confirmed to be up-regulated in t(4;14) MM cell lines and patient samples. Further preliminary studies demonstrate ACA11 localizes to the nucleolus as part of an small nuclear ribonucleoprotein (snRNP) complex. In addition, ACA11 overexpression reduces the levels of reactive oxygen species (ROS) in response to oxidative stress and increases cell survival in the presence of chemotherapeutic agents. We hypothesize that the overexpression of ACA11 in t(4;14) MM reduces ROS-induced cell death leading to the development and/or progression of MM. The ultimate goal of this proposal is to elucidate the mechanism by which ACA11 exerts its inhibitory effects on ROS-induced cell cycle inhibition and cell death in t(4;14) MM cell lines. We hypothesize that the overexpression of the ACA11 snoRNA in t(4;14) MM results in the altered splicing of specific RNA transcripts involved in the cellular response to ROS. These selected transcripts will encode either RNA or proteins critical for B-cell survival in MM. Therefore, ACA11 and its associated snRNP's will be potential novel targets for MM treatment or diagnosis.
Three specific aims of the grant are proposed:
Aim 1 : To test the hypothesis that ACA11 must interact with snRNPs to exert its inhibition of oxidative stress induced cell death Aim 2: To test the hypothesis that ACA11 regulates ROS levels through modulating splicing of snoRNAs from ribosomal protein transcripts Aim 3: To test the hypothesis that overexpression of ACA11 leads to an inhibition of nucleolar stress-induced, p53-regulated ROS production
Multiple myeloma (MM) is an incurable malignancy of antibody-secreting plasma B-cells and those patients with a t(4;14) chromosomal translocation (20% of all cases) have a shorter survival. Our understanding of the underlying mechanisms of t(4;14)-driven MM progression is incomplete. This project proposes to study the mechanism of the t(4;14)-driven overexpression of the snoRNA, ACA11, using multiple myeloma cell lines with and without t(4;14) as a model. This proposal will examine the molecular mechanisms regulating ACA11- induced resistance to chemotherapies in MM cell lines. Ultimately, the information obtained from this proposal will be used to identify potential novel therapeutic targets for multiple myeloma treatment.
|Chu, Liang; Su, Mack Y; Maggi Jr, Leonard B et al. (2012) Multiple myeloma-associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress. J Clin Invest 122:2793-806|