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Title: APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL
Authors: Li, Z
Abraham, B.J
Berezovskaya, A
Farah, N
Liu, Y
Leon, T
Fielding, A
Tan, S.H 
Sanda, T 
Weintraub, A.S
Li, B
Shen, S
Zhang, J
Mansour, M.R
Young, R.A
Look, A.T
Keywords: apolipoprotein B mRNA editing enzyme catalytic polypeptide like
cytidine deaminase
5' untranslated region
apolipoprotein B mRNA editing enzyme catalytic polypeptide like
DNA binding protein
LIM protein
LMO1 protein, human
protein c Myb
small interfering RNA
transcription factor
tumor protein
acute lymphoblastic leukemia
binding site
chromatin immunoprecipitation
controlled study
gene frequency
gene mutation
gene translocation
human cell
human tissue
LMO1 gene
luciferase assay
lymphoid cell
priority journal
protein binding
protein motif
quantitative analysis
reverse transcription polymerase chain reaction
single nucleotide polymorphism
somatic mutation
transcription initiation site
5' untranslated region
acute lymphoblastic leukemia
antagonists and inhibitors
enhancer region
gene expression regulation
Jurkat cell line
nucleotide sequence
oncogene myb
point mutation
RNA interference
tumor cell line
5' Untranslated Regions
APOBEC Deaminases
Base Sequence
Binding Sites
Cell Line, Tumor
Chromatin Immunoprecipitation
DNA, Neoplasm
DNA-Binding Proteins
Enhancer Elements, Genetic
Gene Expression Regulation, Leukemic
Genes, myb
Jurkat Cells
LIM Domain Proteins
Neoplasm Proteins
Point Mutation
Polymorphism, Single Nucleotide
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Proto-Oncogene Proteins c-myb
RNA Interference
RNA, Small Interfering
Transcription Factors
Issue Date: 2017
Publisher: Nature Publishing Group
Citation: Li, Z, Abraham, B.J, Berezovskaya, A, Farah, N, Liu, Y, Leon, T, Fielding, A, Tan, S.H, Sanda, T, Weintraub, A.S, Li, B, Shen, S, Zhang, J, Mansour, M.R, Young, R.A, Look, A.T (2017). APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL. Leukemia 31 (10) : 2057-2064. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells, resulting in clonal selection. Although most cancer-causing mutations have been detected in the protein-coding regions of the cancer genome; driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention. Here we report a C-to-T single nucleotide transition that occurs as a somatic mutation in noncoding sequences 4 kb upstream of the transcriptional start site of the LMO1 oncogene in primary samples from patients with T-cell acute lymphoblastic leukaemia. This single nucleotide alteration conforms to an APOBEC-like cytidine deaminase mutational signature, and generates a new binding site for the MYB transcription factor, leading to the formation of an aberrant transcriptional enhancer complex that drives high levels of expression of the LMO1 oncogene. Since APOBEC-signature mutations are common in a broad spectrum of human cancers, we suggest that noncoding nucleotide transitions such as the one described here may activate potent oncogenic enhancers not only in T-lymphoid cells but in other cell lineages as well. © 2017 Macmillan Publishers Limited, part of Springer Nature.
Source Title: Leukemia
ISSN: 08876924
DOI: 10.1038/leu.2017.75
Rights: Attribution 4.0 International
Appears in Collections:Staff Publications

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