TY - JOUR
T1 - Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations
AU - Shah, Maitri Y.
AU - Ferracin, Manuela
AU - Pileczki, Valentina
AU - Chen, Baoqing
AU - Redis, Roxana
AU - Fabris, Linda
AU - Zhang, Xinna
AU - Ivan, Cristina
AU - Shimizu, Masayoshi
AU - Rodriguez-Aguayo, Cristian
AU - Dragomir, Mihnea
AU - Van Roosbroeck, Katrien
AU - Almeida, Maria Ines
AU - Ciccone, Maria
AU - Nedelcu, Daniela
AU - Cortez, Maria Angelica
AU - Manshouri, Taghi
AU - Calin, Steliana
AU - Muftuoglu, Muharrem
AU - Banerjee, Pinaki P.
AU - Badiwi, Mustafa H.
AU - Parker-Thornburg, Jan
AU - Multani, Asha
AU - Welsh, James William
AU - Estecio, Marcos Roberto
AU - Ling, Hui
AU - Tomuleasa, Ciprian
AU - Dima, Delia
AU - Yang, Hui
AU - Alvarez, Hector
AU - You, M. James
AU - Radovich, Milan
AU - Shpall, Elizabeth
AU - Fabbri, Muller
AU - Rezvani, Katy
AU - Girnita, Leonard
AU - Berindan-Neagoe, Ioana
AU - Maitra, Anirban
AU - Verstovsek, Srdan
AU - Fodde, Riccardo
AU - Bueso-Ramos, Carlos
AU - Gagea, Mihai
AU - Manero, Guillermo Garcia
AU - Calin, George A.
N1 - Publisher Copyright:
© 2018 Shah et al.
PY - 2018/4
Y1 - 2018/4
N2 - The cancer-risk-associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long noncoding RNA CCAT2 in the highly amplified 8q24.21 region have been implicated in cancer predisposition, although causality has not been established. Here, using allele-specific CCAT2 transgenic mice, we demonstrate that CCAT2 overexpression leads to spontaneous myeloid malignancies. We further identified that CCAT2 is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. CCAT2 induces global deregulation of gene expression by down-regulating EZH2 in vitro and in vivo in an allele-specific manner. We also identified a novel non-APOBEC, non-ADAR, RNA editing at the SNP locus in MDS/MPN patients and CCAT2-transgenic mice. The RNA transcribed from the SNP locus in malignant hematopoietic cells have different allelic composition from the corresponding genomic DNA, a phenomenon rarely observed in normal cells. Our findings provide fundamental insights into the functional role of rs6983267 SNP and CCAT2 in myeloid malignancies.
AB - The cancer-risk-associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long noncoding RNA CCAT2 in the highly amplified 8q24.21 region have been implicated in cancer predisposition, although causality has not been established. Here, using allele-specific CCAT2 transgenic mice, we demonstrate that CCAT2 overexpression leads to spontaneous myeloid malignancies. We further identified that CCAT2 is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. CCAT2 induces global deregulation of gene expression by down-regulating EZH2 in vitro and in vivo in an allele-specific manner. We also identified a novel non-APOBEC, non-ADAR, RNA editing at the SNP locus in MDS/MPN patients and CCAT2-transgenic mice. The RNA transcribed from the SNP locus in malignant hematopoietic cells have different allelic composition from the corresponding genomic DNA, a phenomenon rarely observed in normal cells. Our findings provide fundamental insights into the functional role of rs6983267 SNP and CCAT2 in myeloid malignancies.
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U2 - 10.1101/gr.225128.117
DO - 10.1101/gr.225128.117
M3 - Article
C2 - 29567676
AN - SCOPUS:85046134589
SN - 1088-9051
VL - 28
SP - 432
EP - 447
JO - Genome research
JF - Genome research
IS - 4
ER -