title: Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients.
abstract: X-linked SCID (SCID-X1) is amenable to correction by gene therapy using conventional gammaretroviral vectors. Here, we describe the occurrence of clonal T cell acute lymphoblastic leukemia (T-ALL) promoted by insertional mutagenesis in a completed gene therapy trial of 10 SCID-X1 patients. Integration of the vector in an antisense orientation 35 kb upstream of the protooncogene LIM domain only 2 (LMO2) caused overexpression of LMO2 in the leukemic clone. However, leukemogenesis was likely precipitated by the acquisition of other genetic abnormalities unrelated to vector insertion, including a gain-of-function mutation in NOTCH1, deletion of the tumor suppressor gene locus cyclin-dependent kinase 2A (CDKN2A), and translocation of the TCR-beta region to the STIL-TAL1 locus. These findings highlight a general toxicity of endogenous gammaretroviral enhancer elements and also identify a combinatorial process during leukemic evolution that will be important for risk stratification and for future protocol design.
authors.affiliation: Centre for Immunodeficiency, Molecular Immunology Unit, UCL Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Howe
authors.forename: Marc R
authors.initials: MR
authors.lastname: Mansour
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schwarzwaelder
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bartholomae
authors.forename: Michael
authors.initials: M
authors.lastname: Hubank
authors.forename: Helena
authors.initials: H
authors.lastname: Kempski
authors.forename: Martijn H
authors.initials: MH
authors.lastname: Brugman
authors.forename: Karin
authors.initials: K
authors.lastname: Pike-Overzet
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chatters
authors.forename: Dick
authors.initials: D
authors.lastname: de Ridder
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Gilmour
authors.forename: Stuart
authors.initials: S
authors.lastname: Adams
authors.forename: Susannah I
authors.initials: SI
authors.lastname: Thornhill
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Parsley
authors.forename: Frank J T
authors.initials: FJ
authors.lastname: Staal
authors.forename: Rosemary E
authors.initials: RE
authors.lastname: Gale
authors.forename: David C
authors.initials: DC
authors.lastname: Linch
authors.forename: Jinhua
authors.initials: J
authors.lastname: Bayford
authors.forename: Lucie
authors.initials: L
authors.lastname: Brown
authors.forename: Michelle
authors.initials: M
authors.lastname: Quaye
authors.forename: Christine
authors.initials: C
authors.lastname: Kinnon
authors.forename: Philip
authors.initials: P
authors.lastname: Ancliff
authors.forename: David K
authors.initials: DK
authors.lastname: Webb
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmidt
authors.forename: Christof
authors.initials: C
authors.lastname: von Kalle
authors.forename: H Bobby
authors.initials: HB
authors.lastname: Gaspar
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Thrasher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology; D041321:Chromosomes, Human, X; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods*; D006801:Humans; D007223:Infant; D060588:LIM Domain Proteins; D008297:Male; D008667:Metalloproteins / Q000235:genetics; D008954:Models, Biological; D016296:Mutagenesis; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000209:etiology* / Q000628:therapy; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1 / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000628:therapy*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D008667:Metalloproteins; C497761:NOTCH1 protein, human; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D015375:Receptors, Interleukin-2