title: Distinct isoform of FABP7 revealed by screening for retroelement-activated genes in diffuse large B-cell lymphoma.
abstract: Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences harbor multiple regulatory motifs and hence are capable of influencing expression of host genes. In response to environmental changes, TEs are known to be released from epigenetic repression and to become transcriptionally active. Such activation could also lead to lineage-inappropriate activation of oncogenes, as one study described in Hodgkin lymphoma. However, little further evidence for this mechanism in other cancers has been reported. Here, we reanalyzed whole transcriptome data from a large cohort of patients with diffuse large B-cell lymphoma (DLBCL) compared with normal B-cell centroblasts to detect genes ectopically expressed through activation of TE promoters. We have identified 98 such TE-gene chimeric transcripts that were exclusively expressed in primary DLBCL cases and confirmed several in DLBCL-derived cell lines. We further characterized a TE-gene chimeric transcript involving a fatty acid-binding protein gene (LTR2-FABP7), normally expressed in brain, that was ectopically expressed in a subset of DLBCL patients through the use of an endogenous retroviral LTR promoter of the LTR2 family. The LTR2-FABP7 chimeric transcript encodes a novel chimeric isoform of the protein with characteristics distinct from native FABP7. In vitro studies reveal a dependency for DLBCL cell line proliferation and growth on LTR2-FABP7 chimeric protein expression. Taken together, these data demonstrate the significance of TEs as regulators of aberrant gene expression in cancer and suggest that LTR2-FABP7 may contribute to the pathogenesis of DLBCL in a subgroup of patients.
authors.affiliation: Terry Fox Laboratory, Department of Medical Genetics and.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lock
authors.affiliation: Terry Fox Laboratory, Department of Medical Genetics and.
authors.forename: Rita
authors.initials: R
authors.lastname: Rebollo
authors.affiliation: Terry Fox Laboratory, Department of Medical Genetics and.
authors.forename: Katharine
authors.initials: K
authors.lastname: Miceli-Royer
authors.affiliation: Terry Fox Laboratory, Department of Medical Genetics and.
authors.forename: Liane
authors.initials: L
authors.lastname: Gagnier
authors.affiliation: Terry Fox Laboratory, Department of Medical Genetics and.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Kuah
authors.affiliation: Terry Fox Laboratory, Department of Medical Genetics and.
authors.forename: Artem
authors.initials: A
authors.lastname: Babaian
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, 48940 Leioa, Spain; and.
authors.forename: Maialen
authors.initials: M
authors.lastname: Sistiaga-Poveda
authors.affiliation: Terry Fox Laboratory, Department of Medical Genetics and.
authors.forename: C Benjamin
authors.initials: CB
authors.lastname: Lai
authors.affiliation: Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, BC, Canada V5Z 4H4.
authors.forename: Oksana
authors.initials: O
authors.lastname: Nemirovsky
authors.affiliation: Department of Integrative Oncology, and.
authors.forename: Isabel
authors.initials: I
authors.lastname: Serrano
authors.affiliation: Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3;
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.affiliation: Department of Medical Genetics and Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada V6T1Z3;
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Karimi
authors.affiliation: Terry Fox Laboratory, Department of Medical Genetics and dmager@bccrc.ca.
authors.forename: Dixie L
authors.initials: DL
authors.lastname: Mager
mesh_terms: D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004251:DNA Transposable Elements / Q000235:genetics; D044127:Epigenesis, Genetic; D000071438:Fatty Acid-Binding Protein 7; D005227:Fatty Acids / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005820:Genetic Testing; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018626:Retroelements / Q000235:genetics; D020079:Terminal Repeat Sequences; D046888:Tissue Array Analysis; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D004251:DNA Transposable Elements; C107608:FABP7 protein, human; D000071438:Fatty Acid-Binding Protein 7; D005227:Fatty Acids; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018626:Retroelements; D025521:Tumor Suppressor Proteins
keywords: alternative promoters; endogenous retroviruses; gene regulation
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