title: Multiple myeloma-associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress.
abstract: 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.
authors: Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors: Liang
authors: L
authors: Chu
authors: Mack Y
authors: MY
authors: Su
authors: Leonard B
authors: LB
authors: Maggi
authors: Lan
authors: L
authors: Lu
authors: Chelsea
authors: C
authors: Mullins
authors: Seth
authors: S
authors: Crosby
authors: Gaofeng
authors: G
authors: Huang
authors: Wee Joo
authors: WJ
authors: Chng
authors: Ravi
authors: R
authors: Vij
authors: Michael H
authors: MH
authors: Tomasson
mesh_terms: D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D020869:Gene Expression Profiling; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D007438:Introns; D051379:Mice; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D009690:Nucleic Acid Conformation; D018384:Oxidative Stress; D012334:RNA, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020537:RNA, Small Nucleolar / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D018076:DNA, Complementary; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D020537:RNA, Small Nucleolar; D012097:Repressor Proteins; D012269:Ribosomal Proteins; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human