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

The Journal of Clinical Investigation
Liang ChuMichael H Tomasson

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 a...Continue Reading

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Methods Mentioned

BETA
transgenic
affinity purification
cross-linking immunoprecipitation
antisense oligonucleotides
PCR
confocal microscopy
pull-downs
in vitro transcription
immunoprecipitation
ChIP-Seq

Software Mentioned

GraphPad
Bioconductor
Vienna RNA package
Proteome
Scaffold
IPA
Ingenuity
Qbaseplus
Biogazelle
Prism

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