Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients
Steven J Howe, Marc R Mansour, Kerstin Schwarzwaelder, Cynthia Bartholomae, Michael Hubank, Helena Kempski, Martijn H Brugman, Karin Pike-Overzet, Stephen J Chatters, Dick de Ridder, Kimberly C Gilmour, Stuart Adams, Susannah I Thornhill, Kathryn L Parsley, Frank J T Staal, Rosemary E Gale, David C Linch, Jinhua Bayford, Lucie Brown, Michelle Quaye, Christine Kinnon, Philip Ancliff, David K Webb, Manfred Schmidt, Christof von Kalle, H Bobby Gaspar, Adrian J Thrasher, Steven J Howe, Marc R Mansour, Kerstin Schwarzwaelder, Cynthia Bartholomae, Michael Hubank, Helena Kempski, Martijn H Brugman, Karin Pike-Overzet, Stephen J Chatters, Dick de Ridder, Kimberly C Gilmour, Stuart Adams, Susannah I Thornhill, Kathryn L Parsley, Frank J T Staal, Rosemary E Gale, David C Linch, Jinhua Bayford, Lucie Brown, Michelle Quaye, Christine Kinnon, Philip Ancliff, David K Webb, Manfred Schmidt, Christof von Kalle, H Bobby Gaspar, Adrian J Thrasher
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.
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Source: PubMed