Multiple myeloma–associated chromosomal translocation activates orphan snoRNA ACA11 to suppress oxidative stress
Liang Chu, Mack Y. Su, Leonard B. Maggi Jr., Lan Lu, Chelsea Mullins, Seth Crosby, Gaofeng Huang, Wee Joo Chng, Ravi Vij, Michael H. Tomasson
Liang Chu, Mack Y. Su, Leonard B. Maggi Jr., Lan Lu, Chelsea Mullins, Seth Crosby, Gaofeng Huang, Wee Joo Chng, Ravi Vij, Michael H. Tomasson
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Research Article

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

Liang Chu, Mack Y. Su, Leonard B. Maggi Jr., Lan Lu, Chelsea Mullins, Seth Crosby, Gaofeng Huang, Wee Joo Chng, Ravi Vij, Michael H. Tomasson

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Figure 1

ACA11 is activated by t(4;14) in MM.

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ACA11 is activated by t(4;14) in MM. (A) Schematic diagram of the chromo...
(A) Schematic diagram of the chromosome 4p16.3 tiling oligonucleotide microarray, spanning 430 Kb across the t(4;14) breakpoint region (breakpoints are indicated by arrows). Annotated genes are indicated with exon structures. (B) Tiling microarray expression data of representative t(4;14)-positive and -negative patients with MM. (C) Heat map of t(4;14)-positive (Y; n = 4) and -negative (N; n = 12) patient samples. (B and C) Numbers indicate base pairs on chromosome 4 (human genome assembly GRCh37). (D) Real-time PCR of ACA11 in samples from patients with MM. The inset shows that ACA11 is significantly associated with t(4;14) status. Normal, normal plasma cells (n = 10); t(4;14)+, t(4;14)-positive patient samples (n = 6); t(4;14)–, t(4;14)-negative patient samples (n = 57). (E) Northern blot of ACA11 expression in human MM cell lines. t(4;14)-positive cell lines included KMS-11, OPM-2, LP-1, and H929 cells; t(4;14)-negative cell lines included U266, RPMI8226, and MM.1S cells; and non-MM cell lines included K562, HeLa, A375, and U1A cells. Loading controls were 28S and 18S rRNA. (F) ACA11 expression by real-time PCR is significantly associated with t(4;14) in MM cell lines. qRT-PCR data in D and F were normalized to the mean of 3 reference genes (GAPDH, UBC, YWHAZ). Data are presented as mean ± SD, with a box-whisker plot of minimum-to-maximum values (inset) (n = 3). The line within the box is the median value. The box represents the first and third quartiles. The whiskers show the largest and smallest events within at least 1.5 times the size of the box from the nearest edge.