Multiple myeloma-associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress

• Published in: The Journal of clinical investigation 2012-08, Vol.122 (8), p.2793-2806
• Main Authors: Chu, Liang, Su, Mack Y, Maggi, Jr, Leonard B, Lu, Lan, Mullins, Chelsea, Crosby, Seth, Huang, Gaofeng, Chng, Wee Joo, Vij, Ravi, Tomasson, Michael H
• Format: Article
• Language: English
• Subjects: Animals; Base Sequence; Biomedical research; Cancer; Cell growth; Cell Proliferation; Cell Transformation, Neoplastic; Chemotherapy; Chromosomes, Human, Pair 14 - genetics; Chromosomes, Human, Pair 4 - genetics; Cytotoxicity; DNA, Complementary - genetics; DNA, Neoplasm - genetics; Gene Expression Profiling; Genes; Genetic aspects; Histone-Lysine N-Methyltransferase - metabolism; Humans; Immunoglobulins; Introns; Mice; Molecular Sequence Data; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Neuroblastoma; Nucleic Acid Conformation; Oxidative Stress; Patients; Proteins; Repressor Proteins - metabolism; Ribosomal Proteins - genetics; Ribosomal Proteins - metabolism; RNA; RNA, Neoplasm - chemistry; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; RNA, Small Nucleolar - chemistry; RNA, Small Nucleolar - genetics; RNA, Small Nucleolar - metabolism; Translocation, Genetic
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI63051

The histone methyltransferase WHSC1 (also known as MMSET) is overexpressed in multiple myeloma (MM) as a result of the t(4;14) chromosomal translocation and in a broad variety of other cancers by unclear mechanisms. Overexpression of WHSC1 did not transform wild-type or tumor-prone primary hematopoietic cells. We found that ACA11, an orphan box H/ACA class small nucleolar RNA (snoRNA) encoded within an intron of WHSC1, was highly expressed in t(4;14)-positive MM and other cancers. ACA11 localized to nucleoli and bound what we believe to be a novel small nuclear ribonucleoprotein (snRNP) complex composed of several proteins involved in postsplicing intron complexes. RNA targets of this uncharacterized snRNP included snoRNA intermediates hosted within ribosomal protein (RP) genes, and an RP gene signature was strongly associated with t(4;14) in patients with MM. Expression of ACA11 was sufficient to downregulate RP genes and other snoRNAs implicated in the control of oxidative stress. ACA11 suppressed oxidative stress, afforded resistance to chemotherapy, and increased the proliferation of MM cells, demonstrating that ACA11 is a critical target of the t(4;14) translocation in MM and suggesting an oncogenic role in other cancers as well.