Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations

Maitri Y. Shah, Manuela Ferracin, Valentina Pileczki, Baoqing Chen, Roxana Redis, Linda Fabris, Xinna Zhang, Cristina Ivan, Masayoshi Shimizu, Cristian Rodriguez-Aguayo, Mihnea Dragomir, Katrien Van Roosbroeck, Maria Ines Almeida, Maria Ciccone, Daniela Nedelcu, Maria Angelica Cortez, Taghi Manshouri, Steliana Calin, Muharrem Muftuoglu, Pinaki P. BanerjeeMustafa H. Badiwi, Jan Parker-Thornburg, Asha Multani, James William Welsh, Marcos Roberto Estecio, Hui Ling, Ciprian Tomuleasa, Delia Dima, Hui Yang, Hector Alvarez, M. James You, Milan Radovich, Elizabeth Shpall, Muller Fabbri, Katy Rezvani, Leonard Girnita, Ioana Berindan-Neagoe, Anirban Maitra, Srdan Verstovsek, Riccardo Fodde, Carlos Bueso-Ramos, Mihai Gagea, Guillermo Garcia Manero, George A. Calin

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)432-447
Number of pages16
JournalGenome Research
Volume28
Issue number4
DOIs
StatePublished - Apr 1 2018

Fingerprint

Long Noncoding RNA
Single Nucleotide Polymorphism
RNA
Mutation
Neoplasms
Transgenic Mice
Alleles
RNA Editing
Causality
Bone Marrow
Gene Expression
DNA

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations. / Shah, Maitri Y.; Ferracin, Manuela; Pileczki, Valentina; Chen, Baoqing; Redis, Roxana; Fabris, Linda; Zhang, Xinna; Ivan, Cristina; Shimizu, Masayoshi; Rodriguez-Aguayo, Cristian; Dragomir, Mihnea; Van Roosbroeck, Katrien; Almeida, Maria Ines; Ciccone, Maria; Nedelcu, Daniela; Cortez, Maria Angelica; Manshouri, Taghi; Calin, Steliana; Muftuoglu, Muharrem; Banerjee, Pinaki P.; Badiwi, Mustafa H.; Parker-Thornburg, Jan; Multani, Asha; Welsh, James William; Estecio, Marcos Roberto; Ling, Hui; Tomuleasa, Ciprian; Dima, Delia; Yang, Hui; Alvarez, Hector; You, M. James; Radovich, Milan; Shpall, Elizabeth; Fabbri, Muller; Rezvani, Katy; Girnita, Leonard; Berindan-Neagoe, Ioana; Maitra, Anirban; Verstovsek, Srdan; Fodde, Riccardo; Bueso-Ramos, Carlos; Gagea, Mihai; Manero, Guillermo Garcia; Calin, George A.

In: Genome Research, Vol. 28, No. 4, 01.04.2018, p. 432-447.

Research output: Contribution to journalArticle

Shah, MY, Ferracin, M, Pileczki, V, Chen, B, Redis, R, Fabris, L, Zhang, X, Ivan, C, Shimizu, M, Rodriguez-Aguayo, C, Dragomir, M, Van Roosbroeck, K, Almeida, MI, Ciccone, M, Nedelcu, D, Cortez, MA, Manshouri, T, Calin, S, Muftuoglu, M, Banerjee, PP, Badiwi, MH, Parker-Thornburg, J, Multani, A, Welsh, JW, Estecio, MR, Ling, H, Tomuleasa, C, Dima, D, Yang, H, Alvarez, H, You, MJ, Radovich, M, Shpall, E, Fabbri, M, Rezvani, K, Girnita, L, Berindan-Neagoe, I, Maitra, A, Verstovsek, S, Fodde, R, Bueso-Ramos, C, Gagea, M, Manero, GG & Calin, GA 2018, 'Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations', Genome Research, vol. 28, no. 4, pp. 432-447. https://doi.org/10.1101/gr.225128.117
Shah, Maitri Y. ; Ferracin, Manuela ; Pileczki, Valentina ; Chen, Baoqing ; Redis, Roxana ; Fabris, Linda ; Zhang, Xinna ; Ivan, Cristina ; Shimizu, Masayoshi ; Rodriguez-Aguayo, Cristian ; Dragomir, Mihnea ; Van Roosbroeck, Katrien ; Almeida, Maria Ines ; Ciccone, Maria ; Nedelcu, Daniela ; Cortez, Maria Angelica ; Manshouri, Taghi ; Calin, Steliana ; Muftuoglu, Muharrem ; Banerjee, Pinaki P. ; Badiwi, Mustafa H. ; Parker-Thornburg, Jan ; Multani, Asha ; Welsh, James William ; Estecio, Marcos Roberto ; Ling, Hui ; Tomuleasa, Ciprian ; Dima, Delia ; Yang, Hui ; Alvarez, Hector ; You, M. James ; Radovich, Milan ; Shpall, Elizabeth ; Fabbri, Muller ; Rezvani, Katy ; Girnita, Leonard ; Berindan-Neagoe, Ioana ; Maitra, Anirban ; Verstovsek, Srdan ; Fodde, Riccardo ; Bueso-Ramos, Carlos ; Gagea, Mihai ; Manero, Guillermo Garcia ; Calin, George A. / Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations. In: Genome Research. 2018 ; Vol. 28, No. 4. pp. 432-447.
@article{22f550a7b2e84e728cbe8b0bcc5dc7fc,
title = "Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations",
abstract = "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.",
author = "Shah, {Maitri Y.} and Manuela Ferracin and Valentina Pileczki and Baoqing Chen and Roxana Redis and Linda Fabris and Xinna Zhang and Cristina Ivan and Masayoshi Shimizu and Cristian Rodriguez-Aguayo and Mihnea Dragomir and {Van Roosbroeck}, Katrien and Almeida, {Maria Ines} and Maria Ciccone and Daniela Nedelcu and Cortez, {Maria Angelica} and Taghi Manshouri and Steliana Calin and Muharrem Muftuoglu and Banerjee, {Pinaki P.} and Badiwi, {Mustafa H.} and Jan Parker-Thornburg and Asha Multani and Welsh, {James William} and Estecio, {Marcos Roberto} and Hui Ling and Ciprian Tomuleasa and Delia Dima and Hui Yang and Hector Alvarez and You, {M. James} and Milan Radovich and Elizabeth Shpall and Muller Fabbri and Katy Rezvani and Leonard Girnita and Ioana Berindan-Neagoe and Anirban Maitra and Srdan Verstovsek and Riccardo Fodde and Carlos Bueso-Ramos and Mihai Gagea and Manero, {Guillermo Garcia} and Calin, {George A.}",
year = "2018",
month = "4",
day = "1",
doi = "10.1101/gr.225128.117",
language = "English (US)",
volume = "28",
pages = "432--447",
journal = "PCR Methods and Applications",
issn = "1088-9051",
publisher = "Cold Spring Harbor Laboratory Press",
number = "4",

}

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.

PY - 2018/4/1

Y1 - 2018/4/1

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.

UR - http://www.scopus.com/inward/record.url?scp=85046134589&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85046134589&partnerID=8YFLogxK

U2 - 10.1101/gr.225128.117

DO - 10.1101/gr.225128.117

M3 - Article

C2 - 29567676

AN - SCOPUS:85046134589

VL - 28

SP - 432

EP - 447

JO - PCR Methods and Applications

JF - PCR Methods and Applications

SN - 1088-9051

IS - 4

ER -