TY - JOUR
T1 - Impact of U2AF1 mutations on circular RNA expression in myelodysplastic neoplasms
AU - Wedge, Eileen
AU - Ahmadov, Ulvi
AU - Hansen, Thomas B
AU - Gao, Zongliang
AU - Tulstrup, Morten
AU - Côme, Christophe
AU - Nonavinkere Srivatsan, Sridhar
AU - Ahmed, Tanzir
AU - Jespersen, Jakob S
AU - Schlotmann, Balthasar C
AU - Schöllkopf, Claudia
AU - Raaschou-Jensen, Klas
AU - Ødum, Niels
AU - Kjems, Jørgen
AU - Bak, Rasmus O
AU - Walter, Matthew J
AU - Grønbæk, Kirsten
AU - Kristensen, Lasse S
PY - 2023/5
Y1 - 2023/5
N2 - Mutations in U2AF1 are relatively common in myelodysplastic neoplasms (MDS) and are associated with an inferior prognosis, but the molecular mechanisms underlying this are not fully elucidated. Circular RNAs (circRNAs) have been implicated in cancer, but it is unknown how mutations in splicing factors may impact on circRNA biogenesis. Here, we used RNA-sequencing to investigate the effects of U2AF1 mutations on circRNA expression in K562 cells with a doxycycline-inducible U2AF1
S34 mutation, in a mouse model with a doxycycline-inducible U2AF1
S34 mutation, and in FACS-sorted CD34+ bone marrow cells from MDS patients with either U2AF1
S34 or U2AF1
Q157 mutations. In all contexts, we found an increase in global circRNA levels in the U2AF1-mutated setting, which was independent of expression changes in the cognate linear host genes. In patients, the U2AF1
S34 and U2AF1
Q157 mutations were both associated with an overall increased expression of circRNAs. circRNAs generated by a non-Alu-mediated mechanism generally showed the largest increase in expression levels. Several well-described cancer-associated circRNAs, including circZNF609 and circCSNK1G3, were upregulated in MDS patients with U2AF1 mutations compared to U2AF1-wildtype MDS controls. In conclusion, high circRNA expression is observed in association with U2AF1 mutations in three biological systems, presenting an interesting possibility for biomarker and therapeutic investigation.
AB - Mutations in U2AF1 are relatively common in myelodysplastic neoplasms (MDS) and are associated with an inferior prognosis, but the molecular mechanisms underlying this are not fully elucidated. Circular RNAs (circRNAs) have been implicated in cancer, but it is unknown how mutations in splicing factors may impact on circRNA biogenesis. Here, we used RNA-sequencing to investigate the effects of U2AF1 mutations on circRNA expression in K562 cells with a doxycycline-inducible U2AF1
S34 mutation, in a mouse model with a doxycycline-inducible U2AF1
S34 mutation, and in FACS-sorted CD34+ bone marrow cells from MDS patients with either U2AF1
S34 or U2AF1
Q157 mutations. In all contexts, we found an increase in global circRNA levels in the U2AF1-mutated setting, which was independent of expression changes in the cognate linear host genes. In patients, the U2AF1
S34 and U2AF1
Q157 mutations were both associated with an overall increased expression of circRNAs. circRNAs generated by a non-Alu-mediated mechanism generally showed the largest increase in expression levels. Several well-described cancer-associated circRNAs, including circZNF609 and circCSNK1G3, were upregulated in MDS patients with U2AF1 mutations compared to U2AF1-wildtype MDS controls. In conclusion, high circRNA expression is observed in association with U2AF1 mutations in three biological systems, presenting an interesting possibility for biomarker and therapeutic investigation.
KW - Animals
KW - Doxycycline
KW - Mice
KW - Mutation
KW - Myelodysplastic Syndromes/genetics
KW - Neoplasms
KW - RNA Splicing
KW - RNA Splicing Factors/genetics
KW - RNA, Circular/genetics
KW - Splicing Factor U2AF/genetics
UR - http://www.scopus.com/inward/record.url?scp=85149954219&partnerID=8YFLogxK
U2 - 10.1038/s41375-023-01866-4
DO - 10.1038/s41375-023-01866-4
M3 - Journal article
C2 - 36922625
SN - 0887-6924
VL - 37
SP - 1113
EP - 1125
JO - Leukemia
JF - Leukemia
IS - 5
ER -