FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N
                        6
                        -Methyladenosine RNA Demethylase

Zejuan Li; Hengyou Weng; Rui Su; Xiaocheng Weng; Zhixiang Zuo; Chenying Li; Huilin Huang; Sigrid Nachtergaele; Lei Dong; Chao Hu; Xi Qin; Lichun Tang; Yungui Wang; Gia Ming Hong; Hao Huang; Xiao Wang; Ping Chen; Sandeep Gurbuxani; Stephen Arnovitz; Yuanyuan Li; Shenglai Li; Jennifer Strong; Mary Beth Neilly; Richard A. Larson; Xi Jiang; Pumin Zhang; Jie Jin; Chuan He; Jianjun Chen

doi:10.1016/j.ccell.2016.11.017

FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N ⁶ -Methyladenosine RNA Demethylase

Zejuan Li, Hengyou Weng, Rui Su, Xiaocheng Weng, Zhixiang Zuo, Chenying Li, Huilin Huang, Sigrid Nachtergaele, Lei Dong, Chao Hu, Xi Qin, Lichun Tang, Yungui Wang, Gia Ming Hong, Hao Huang, Xiao Wang, Ping Chen, Sandeep Gurbuxani, Stephen Arnovitz, Yuanyuan LiShenglai Li, Jennifer Strong, Mary Beth Neilly, Richard A. Larson, Xi Jiang, Pumin Zhang, Jie Jin, Chuan He, Jianjun Chen

Research output: Contribution to journal › Article › peer-review

1116 Scopus citations

Abstract

N ⁶ -Methyladenosine (m ⁶ A) represents the most prevalent internal modification in mammalian mRNAs. Despite its functional importance in various fundamental bioprocesses, the studies of m ⁶ A in cancer have been limited. Here we show that FTO, as an m ⁶ A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML). FTO is highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations. FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans-retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m ⁶ A levels in these mRNA transcripts. Collectively, our study demonstrates the functional importance of the m ⁶ A methylation and the corresponding proteins in cancer, and provides profound insights into leukemogenesis and drug response.

Original language	English (US)
Pages (from-to)	127-141
Number of pages	15
Journal	Cancer Cell
Volume	31
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2016.11.017
State	Published - Jan 9 2017
Externally published	Yes

Keywords

AML
ASB2
ATRA
cell differentiation
FTO
leukemogenesis
m6A
RARA
RNA modification
RNA stability

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

Access to Document

10.1016/j.ccell.2016.11.017

Cite this

Li, Z., Weng, H., Su, R., Weng, X., Zuo, Z., Li, C., Huang, H., Nachtergaele, S., Dong, L., Hu, C., Qin, X., Tang, L., Wang, Y., Hong, G. M., Huang, H., Wang, X., Chen, P., Gurbuxani, S., Arnovitz, S., ... Chen, J. (2017). FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N ⁶ -Methyladenosine RNA Demethylase. Cancer Cell, 31(1), 127-141. https://doi.org/10.1016/j.ccell.2016.11.017

Li, Z, Weng, H, Su, R, Weng, X, Zuo, Z, Li, C, Huang, H, Nachtergaele, S, Dong, L, Hu, C, Qin, X, Tang, L, Wang, Y, Hong, GM, Huang, H, Wang, X, Chen, P, Gurbuxani, S, Arnovitz, S, Li, Y, Li, S, Strong, J, Neilly, MB, Larson, RA, Jiang, X, Zhang, P, Jin, J, He, C & Chen, J 2017, 'FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N ⁶ -Methyladenosine RNA Demethylase', Cancer Cell, vol. 31, no. 1, pp. 127-141. https://doi.org/10.1016/j.ccell.2016.11.017

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title = "FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N 6 -Methyladenosine RNA Demethylase",

abstract = " N 6 -Methyladenosine (m 6 A) represents the most prevalent internal modification in mammalian mRNAs. Despite its functional importance in various fundamental bioprocesses, the studies of m 6 A in cancer have been limited. Here we show that FTO, as an m 6 A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML). FTO is highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations. FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans-retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m 6 A levels in these mRNA transcripts. Collectively, our study demonstrates the functional importance of the m 6 A methylation and the corresponding proteins in cancer, and provides profound insights into leukemogenesis and drug response. ",

keywords = "AML, ASB2, ATRA, cell differentiation, FTO, leukemogenesis, m6A, RARA, RNA modification, RNA stability",

author = "Zejuan Li and Hengyou Weng and Rui Su and Xiaocheng Weng and Zhixiang Zuo and Chenying Li and Huilin Huang and Sigrid Nachtergaele and Lei Dong and Chao Hu and Xi Qin and Lichun Tang and Yungui Wang and Hong, {Gia Ming} and Hao Huang and Xiao Wang and Ping Chen and Sandeep Gurbuxani and Stephen Arnovitz and Yuanyuan Li and Shenglai Li and Jennifer Strong and Neilly, {Mary Beth} and Larson, {Richard A.} and Xi Jiang and Pumin Zhang and Jie Jin and Chuan He and Jianjun Chen",

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doi = "10.1016/j.ccell.2016.11.017",

language = "English (US)",

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AU - Li, Zejuan

AU - Weng, Hengyou

AU - Su, Rui

AU - Weng, Xiaocheng

AU - Zuo, Zhixiang

AU - Li, Chenying

AU - Huang, Huilin

AU - Nachtergaele, Sigrid

AU - Dong, Lei

AU - Hu, Chao

AU - Qin, Xi

AU - Tang, Lichun

AU - Wang, Yungui

AU - Hong, Gia Ming

AU - Huang, Hao

AU - Wang, Xiao

AU - Chen, Ping

AU - Gurbuxani, Sandeep

AU - Arnovitz, Stephen

AU - Li, Yuanyuan

AU - Li, Shenglai

AU - Strong, Jennifer

AU - Neilly, Mary Beth

AU - Larson, Richard A.

AU - Jiang, Xi

AU - Zhang, Pumin

AU - Jin, Jie

AU - He, Chuan

AU - Chen, Jianjun

PY - 2017/1/9

Y1 - 2017/1/9

N2 - N 6 -Methyladenosine (m 6 A) represents the most prevalent internal modification in mammalian mRNAs. Despite its functional importance in various fundamental bioprocesses, the studies of m 6 A in cancer have been limited. Here we show that FTO, as an m 6 A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML). FTO is highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations. FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans-retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m 6 A levels in these mRNA transcripts. Collectively, our study demonstrates the functional importance of the m 6 A methylation and the corresponding proteins in cancer, and provides profound insights into leukemogenesis and drug response.

AB - N 6 -Methyladenosine (m 6 A) represents the most prevalent internal modification in mammalian mRNAs. Despite its functional importance in various fundamental bioprocesses, the studies of m 6 A in cancer have been limited. Here we show that FTO, as an m 6 A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML). FTO is highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations. FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans-retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m 6 A levels in these mRNA transcripts. Collectively, our study demonstrates the functional importance of the m 6 A methylation and the corresponding proteins in cancer, and provides profound insights into leukemogenesis and drug response.

KW - AML

KW - ASB2

KW - ATRA

KW - cell differentiation

KW - FTO

KW - leukemogenesis

KW - m6A

KW - RARA

KW - RNA modification

KW - RNA stability

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