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

J Clin Invest. 2008 Sep;118(9):3143-50. doi: 10.1172/JCI35798.

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.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents / pharmacology
  • Chromosomes, Human, X*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • DNA-Binding Proteins / genetics
  • Follow-Up Studies
  • Genetic Therapy / adverse effects*
  • Genetic Therapy / methods*
  • Humans
  • Infant
  • LIM Domain Proteins
  • Male
  • Metalloproteins / genetics
  • Models, Biological
  • Mutagenesis
  • Mutation*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / complications
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / etiology*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / therapy
  • Proto-Oncogene Proteins
  • Receptor, Notch1 / genetics
  • Receptors, Interleukin-2 / genetics
  • Severe Combined Immunodeficiency / complications
  • Severe Combined Immunodeficiency / therapy*

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA-Binding Proteins
  • LIM Domain Proteins
  • LMO2 protein, human
  • Metalloproteins
  • NOTCH1 protein, human
  • Proto-Oncogene Proteins
  • Receptor, Notch1
  • Receptors, Interleukin-2