Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients

作者：Steven J. Howe, Marc R. Mansour, Kerstin Schwarzwaelder, Cynthia C. Bartholomae, Michael Hubank, Helena M. Kempski, Martijn H. Brugman, Karin Pike‐Overzet, S Chatters, Dick de Ridder, Kimberly C Gilmour, Stuart Paul Adams, Susannah I. Thornhill, Kathryn L. Parsley, Frank J. T. Staal, Rosemary E. Gale, David C. Linch, Jinhua Xu Bayford, Lucie Brown, Michelle Quaye, Christine Kinnon, Philip Ancliff, David K H Webb, Manfred Schmidt, Christof V. Kalle, Hubert Bobby Gaspar, Adrian James Thrasher · 发表于：Journal of Clinical Investigation · 年份：2008 · DOI：10.1172/jci35798 · 被引用次数：1298 · 研究领域：CRISPR and Genetic Engineering、Virus-based gene therapy research、CAR-T cell therapy research

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.