TY - JOUR
T1 - The snoRNA target of t(4;14) in multiple myeloma regulates ribosome biogenesis
AU - Oliveira, Vanessa
AU - Mahajan, Nitin
AU - Bates, Melissa L.
AU - Tripathi, Chakrapani
AU - Kim, Kyusik Q.
AU - Zaher, Hani S.
AU - Maggi, Leonard B.
AU - Tomasson, Michael H.
N1 - Publisher Copyright:
© 2019 The Authors.
PY - 2019/7
Y1 - 2019/7
N2 - The orphan small nucleolar RNA (snoRNA) ACA11 is overexpressed as a result of the t(4;14) chromosomal translocation in multiple myeloma (MM), increases reactive oxygen species, and drives cell proliferation. Like other snoRNAs, ACA11 is predominantly localized to a sub-nuclear organelle, the nucleolus. We hypothesized that increased ACA11 expression would increase ribosome biogenesis and protein synthesis. We found that ACA11 overexpression in MM cells increased nucleolar area and number as well as argyrophilic nuclear organizing regions (AgNORs). Supporting these data, samples from t(4;14)-positive patients had higher AgNORs scores than t(4;14)-negative samples. ACA11 also upregulated ribosome production, pre-47S rRNA synthesis, and protein synthesis in a ROS-dependent manner. Lastly, ACA11 overexpression enhanced the response to proteasome inhibitor in MM cells, while no effect was found in response to high doses of melphalan. Together, these data demonstrate that ACA11 stimulates ribosome biogenesis and influences responses to chemotherapy. ACA11 may be a useful target to individualize the treatment for t(4;14)-positive myeloma patients.
AB - The orphan small nucleolar RNA (snoRNA) ACA11 is overexpressed as a result of the t(4;14) chromosomal translocation in multiple myeloma (MM), increases reactive oxygen species, and drives cell proliferation. Like other snoRNAs, ACA11 is predominantly localized to a sub-nuclear organelle, the nucleolus. We hypothesized that increased ACA11 expression would increase ribosome biogenesis and protein synthesis. We found that ACA11 overexpression in MM cells increased nucleolar area and number as well as argyrophilic nuclear organizing regions (AgNORs). Supporting these data, samples from t(4;14)-positive patients had higher AgNORs scores than t(4;14)-negative samples. ACA11 also upregulated ribosome production, pre-47S rRNA synthesis, and protein synthesis in a ROS-dependent manner. Lastly, ACA11 overexpression enhanced the response to proteasome inhibitor in MM cells, while no effect was found in response to high doses of melphalan. Together, these data demonstrate that ACA11 stimulates ribosome biogenesis and influences responses to chemotherapy. ACA11 may be a useful target to individualize the treatment for t(4;14)-positive myeloma patients.
KW - chromosomal translocation
KW - hematological malignancy
KW - protein synthesis
KW - reactive oxygen species
UR - http://www.scopus.com/inward/record.url?scp=85088983251&partnerID=8YFLogxK
U2 - 10.1096/fba.2018-00075
DO - 10.1096/fba.2018-00075
M3 - Article
AN - SCOPUS:85088983251
SN - 2573-9832
VL - 1
SP - 404
EP - 414
JO - FASEB BioAdvances
JF - FASEB BioAdvances
IS - 7
ER -