title: Activation of theLMO2oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia.
abstract: Somatic mutations within noncoding genomic regions that aberrantly activate oncogenes have remained poorly characterized. Here we describe recurrent activating intronic mutations ofLMO2, a prominent oncogene in T-cell acute lymphoblastic leukemia (T-ALL). Heterozygous mutations were identified in PF-382 and DU.528 T-ALL cell lines in addition to 3.7% of pediatric (6 of 160) and 5.5% of adult (9 of 163) T-ALL patient samples. The majority of indels harbor putative de novo MYB, ETS1, or RUNX1 consensus binding sites. Analysis of 5'-capped RNA transcripts in mutant cell lines identified the usage of an intermediate promoter site, with consequential monoallelicLMO2overexpression. CRISPR/Cas9-mediated disruption of the mutant allele in PF-382 cells markedly downregulatedLMO2expression, establishing clear causality between the mutation and oncogene dysregulation. Furthermore, the spectrum of CRISPR/Cas9-derived mutations provides important insights into the interconnected contributions of functional transcription factor binding. Finally, these mutations occur in the same intron as retroviral integration sites in gene therapy-induced T-ALL, suggesting that such events occur at preferential sites in the noncoding genome.
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Sunniyat
authors.initials: S
authors.lastname: Rahman
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Michael
authors.initials: M
authors.lastname: Magnussen
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Theresa E
authors.initials: TE
authors.lastname: León
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Nadine
authors.initials: N
authors.lastname: Farah
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.
authors.forename: Zhaodong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Abraham
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Krisztina Z
authors.initials: KZ
authors.lastname: Alapi
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Mitchell
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Tom
authors.initials: T
authors.lastname: Naughton
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Adele K
authors.initials: AK
authors.lastname: Fielding
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Arnold
authors.initials: A
authors.lastname: Pizzey
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Sophia
authors.initials: S
authors.lastname: Bustraan
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Christopher
authors.initials: C
authors.lastname: Allen
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Teodora
authors.initials: T
authors.lastname: Popa
authors.affiliation: Department of Immunohematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Karin
authors.initials: K
authors.lastname: Pike-Overzet
authors.affiliation: Department of Immunohematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Garcia-Perez
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Gale
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: David C
authors.initials: DC
authors.lastname: Linch
authors.affiliation: Department of Immunohematology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frank J T
authors.initials: FJT
authors.lastname: Staal
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, MA; and.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Young
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.|Division of Hematology/Oncology, Children's Hospital, Boston, MA.
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
authors.affiliation: Department of Haematology, University College London Cancer Institute, London, United Kingdom.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Mansour
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D019169:Jurkat Cells; D060588:LIM Domain Proteins / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D020218:Response Elements
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D011518:Proto-Oncogene Proteins