title: APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL.
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.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Abraham
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Berezovskaya
authors.affiliation: Department of Haematology, UCL Cancer Institute, University College London, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Farah
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Haematology, UCL Cancer Institute, University College London, London, UK.
authors.forename: T
authors.initials: T
authors.lastname: Leon
authors.affiliation: Department of Haematology, UCL Cancer Institute, University College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Fielding
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, Singapore, Singapore.
authors.forename: S H
authors.initials: SH
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.|Department of Medicine, Yong Loo Lin School of Medicine, Singapore, Singapore.
authors.forename: T
authors.initials: T
authors.lastname: Sanda
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
authors.forename: A S
authors.initials: AS
authors.lastname: Weintraub
authors.affiliation: Department of Hematology and Oncology, Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Hematology and Oncology, Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.|Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: S
authors.initials: S
authors.lastname: Shen
authors.affiliation: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Haematology, UCL Cancer Institute, University College London, London, UK.
authors.forename: M R
authors.initials: MR
authors.lastname: Mansour
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Young
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.|Division of Hematology/Oncology, Children's Hospital, Boston, MA, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Look
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000071478:APOBEC Deaminases / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002648:Child; D047369:Chromatin Immunoprecipitation; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D020570:Genes, myb; D006801:Humans; D019169:Jurkat Cells; D060588:LIM Domain Proteins / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D020598:Proto-Oncogene Proteins c-myb / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D020121:5' Untranslated Regions; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C065072:LMO1 protein, human; D009363:Neoplasm Proteins; D020598:Proto-Oncogene Proteins c-myb; D034741:RNA, Small Interfering; D014157:Transcription Factors; D000071478:APOBEC Deaminases